(2022) 19:132
Wang et al. Journal of Neuroinflammation
https://doi.org/10.1186/s12974-022-02492-0

Open Access

REVIEW

Microglia in depression: an overview
of microglia in the pathogenesis and treatment
of depression
Haixia Wang1,2†, Yi He1,2†, Zuoli Sun1,2, Siyu Ren1,2, Mingxia Liu1,2, Gang Wang1,2* and Jian Yang1,2*

Abstract
Major depressive disorder is a highly debilitating psychiatric disorder involving the dysfunction of different cell types
in the brain. Microglia are the predominant resident immune cells in the brain and exhibit a critical role in depression.
Recent studies have suggested that depression can be regarded as a microglial disease. Microglia regulate inflammation, synaptic plasticity, and the formation of neural networks, all of which affect depression. In this review, we highlighted the role of microglia in the pathology of depression. First, we described microglial activation in animal models
and clinically depressed patients. Second, we emphasized the possible mechanisms by which microglia recognize
depression-associated stress and regulate conditions. Third, we described how antidepressants (clinical medicines andnatural products) affect microglial activation. Thus, this review aimed to objectively analyze the role of microglia indepression and focus on potential antidepressants. These data suggested that regulation of microglial actions might
be a novel therapeutic strategy to counteract the adverse effects of devastating mental disorders.
Keywords: Major depressive disorder, Microglial activation, Antidepressants, NLRP3 inflammasome, Neurogenesis,
Kynurenine pathway
Background
Major depressive disorder (MDD) is a public healthproblem that affects approximately 322 million people worldwide [1]. During the coronavirus disease 2019
(COVID-19) pandemic, a meta‐analysis reported that
45% of COVID‐19 patients experienced depression [2].
Over 700,000 people die from suicide every year due todepressive disorder, which results in a heavy burden on
individuals and society [3]. Clinical symptoms of MDD
include persistent low mood, appetite loss, decreased†

Haixia Wang and Yi He contributed equally in writing of this article.

*Correspondence: gangwangdoc@ccmu.edu.cn; yangjian@ccmu.edu.cn
1
The National Clinical Research Center for Mental Disorders and Beijing Key
Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical
University, 5 Ankang Lane, Dewai Avenue, Xicheng District, Beijing 100088,
China
Full list of author information is available at the end of the article

interest in favorite activities, despair, sleepy disorders,
and, in severe cases, suicidal behavior [4]. Unfortunately,
due to its complexity and heterogeneity that are determined by genetic and environmental factors, the biological mechanisms underlying depression remain unclear.
Currently, theories concerning depression primarily
focus on the monoamine neurotransmitter depletion
hypothesis, neuroplasticity hypothesis, and hypothalamus–pituitary–adrenal (HPA) axis hypothesis [5].
However, limitations are associated with these specificpathological mechanisms, such as an inability to explain
the delayed effect of antidepressants and a lack of focus
on cells other than neurons in the central nervous system(CNS) [6, 7].
Microglia are the first line in the innate immune
system in the CNS and actively regulate microenvironmental changes in healthy and disordered brains.
Microglial activation regulates inflammation, synaptic© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of thislicence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​
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Wang et al. Journal of Neuroinflammation(2022) 19:132

refinement, synaptic pruning, and neuronal connectivity[8]. Depression is considered a microglia-associated disorder (microgliopathy) [9]. Ample evidence suggests thatmicroglia-mediated neuroinflammation interacts withall three theories correlated with MDD listed above [10,11]. Neuroinflammation and the HPA axis are thought tofunction in a coordinated manner, and their dysregulation might mediate the onset of depression [10, 12–14].
Some clinical antidepressants affect the activation of
microglia and neuroinflammation [15–17]. Nonsteroidal
anti-inflammatory drugs appear to alleviate depressive
symptoms by inhibiting microglial activation [18]. Minocycline is a semisynthetic tetracycline antibiotic that
decidedly improves depressive-like behaviors by inhibiting microglial activation in the prefrontal cortex (PFC)and hippocampus (HIP) [19]. Microglial activation canbe divided into the classic activation of M1 or alternate
activation of M2 under optimal conditions [20]. Recently,
pharmacological principles that modulate microglial
polarization may provide beneficial treatments to alleviate the recurrence of psychiatric disorders [21–23].
Therefore, we conducted a systematic review using the
Pubmed electronic database. Search themes included
depression and microglia, neurogenesis, stress, and antidepressants. Articles from 1992 to 2021 were reviewedthat focused on the connection between microglia anddepression. In this review, we described the activation states of microglia in animal models and clinicallydepressed patients. We elucidated the mechanisms
underlying depression and the therapeutic potential oftargeting microglia. Finally, we highlighted the protective
effects of antidepressants that act through modulating
microglia in stress-induced animal models of depression.
Microglia: origin and function
Origin and development of microglia

Microglia were first described as a distinct cell type by
Spanish neuroscientist Pio del Rio-Hortega in 1919 andaccount for approximately 5–10% of the total cell population in the brain [24]. The number of microglia in theadult mouse brain is estimated at 3.5 million, with variations in density across different regions. For example,
more microglia are found in the HIP, substantia nigra(SN), olfactory telencephalon, and basal ganglia. Fewer
microglia are observed in the fiber tracts, cerebellum,
and the majority of brainstem [25]. Ontogenetically,
recent fate-mapping studies have revealed that microglia originate from erythromyeloid progenitor cells inthe developing embryonic yolk sac, and migrate into
the embryonic CNS to differentiate into mature microglia. CNS microglia form a self-renewing cell population

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through proliferation and apoptosis throughout life of theindividual [26, 27].
Characteristics and functions of microglia

As CNS immune effector cells, microglia are similar
to peripheral macrophages with respect to their morphology and functions [28]. Under normal conditions,
neurons serve a regulatory role in the CNS. Microglia
provide protection and nutritional support to neurons,
influence neuronal homeostasis, regulate synaptogenesis,
and activate astrocytes (Fig. 1) [29, 30]. Resting microglia
are characterized by a small soma with multiple symmetrically distributed protrusions that protrude at a rateof 0.4–3.8 μm/min to maintain either an extended orcontracted state to sense changes in surrounding environment. Microglia are maintained in a relatively restingstate in part by signals from neurons and astrocytes [31].
In response to challenges, such as tissue injury, pathogens, or other pathological processes, microglia quickly
respond to the homeostatic imbalance and undergo
considerable morphological transformation to provide
defense mechanisms [32]. Specifically, the processes
retract, the soma enlarges, and the ramification of the
distal branches decreases. Activated microglia undergo
additional morphological change and present a characteristic “amoeba-like” shape. The number of transformed
microglia increases, and they migrate to the injuredsite at a rate of 1–2 μm/min for tissue repair [33, 34].
The activated microglia gradually shift from providing
nutritional support and repairing neurons to neuronal
dysfunction. These changes in function may be more persistent after continuous exposure to certain stimuli. This
response further recruits peripheral innate immune cells(e.g., macrophages) and adaptive immune cells (e.g., B
cells) to cross the blood–brain barrier and eventually leadto cognitive and emotional disorders [35–37].
The polarization of microglia

Microglia exist in a resting state under normal physiological conditions and carry out “immune surveillance”
functions [38, 39]. When CNS damage or infection
occurs, microglia can be broadly divided into the classic
activation (M1) or alternative activation (M2) phenotype. M1 microglia result in pro-inflammatory cytokine
release and increased expression of several differentiation marker 86 and 16/32 (CD86, CD16/32) and inducible nitric oxide synthase (iNOS). M2 microglia are
inclined to express anti-inflammatory cytokines, arginase-1 (Arg1), transforming growth factor-β1 (TGF-β1),
CD206, and chitinase-3-like-3 [22]. M1 microglia remove
apoptotic cells, pathogens, and inhibit normal neuron
growth, which adversely affects synaptic transmission.

Wang et al. Journal of Neuroinflammation(2022) 19:132

Page 3 of 26

Fig. 1 Multiple physiological roles of microglia in the CNS. Microglia are the center that maintain proper neuronal functioning of the CNS, including
regulation of neuronal death, neurite formation, synaptic pruning, and synaptogenesis. In addition, microglia specify neural progenitor cell (NPC)
and oligodendrocyte progenitor cell (OPC) growth and differentiation, facilitate myelination, and induce astrocyte activation. Lastly, microglia
exhibit a phagocytic role concerning misfolded proteins and cellular debris [27]

M2 microglia promote phagocytosis of cell fragments
and misfolded proteins, tissue repair, and support neuron survival. Intriguingly, M2 microglia are driven by thecoordinated regulation of multiple anti-inflammatory
mediators and against M1-induced inflammation that
ultimately achieve immune suppression and neuronalprotection (Fig. 2) [40].
However, the status of microglia may include a range ofdifferent but overlapping functional phenotypes that are
in response to changes in their local environment. Novel
single-cell technologies, such as single-cell RNA sequencing and cytometry by time-of-flight mass spectrometry, have emerged as superior methods to characterizeimmune cell types and states, the transition from normal
to disease, and respond to therapy. For instance, microglia were isolated from LPS-injected mice that showeddownregulation of homeostatic markers (e.g., Tmem119,
Mef2c, P2ry13, P2ry12, and Siglech) and upregulation of
inflammatory genes (e.g., Ccl2, Gpr84, and Nfkbia) bysingle-cell RNA sequencing and multicolor flow cytometry [41]. In the brains of a transgenic mouse model of
Alzheimer’s disease (AD), a novel type of microglia (disease-associated microglia, DAM) was identified using

single-cell analysis. Researchers further discovered that
Trem2 is necessary for transformation from DAM stage-1
to DAM stage-2 [42]. With the development of unbiased
and high-throughput analytical methods, it is possible tocomprehensively characterize the spatial and temporal
heterogeneity of microglia during CNS development anddisease [43, 44]. Based on current research of microglial
phenotypes, the classification using M1 and M2 subtypes
is oversimplified and not universally accepted. We willuse “pro-inflammatory” or “anti-inflammatory” microglia
in subsequent descriptions to highlight the contributionof microglia in depression.
Microglia in depression
Clinical evidence

A growing body of research has shown that damage tothe typical structure and function of microglia in thedeveloping and adult brain is associated with the etiology
of depressive disorders. Changes in microglia in different
brain regions, including the PFC, HIP, anterior cingulate
cortex (ACC), and amygdala, are involved in the development of depression. Previous studies have shown thatconsiderable microglial activation occurs in the PFC andWang et al. Journal of Neuroinflammation(2022) 19:132

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Fig. 2 Microglial M1/M2 polarization and their regulatory functions in the CNS. Resting microglia are stimulated with pathogen-associatedmolecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) via toll-like receptors (TLRs). In the presence of lipopolysaccharide(LPS) and interferon-γ (IFN-γ), microglia polarize to the M1 phenotype and produce pro-inflammatory mediators including interleukin-1β (IL-1β),IL-6, tumor necrosis factor-α (TNF-α), CCL2, reactive oxygen species (ROS), and NO. In contrast, IL-4, IL-13, or IL-10 cause alternative activation into M2
microglia that inhibit M1 functions by releasing anti-inflammatory cytokines and neurotrophic factors [40]

ACC during severe episodes of MDD. Microglial activation in ACC also is positively correlated with the severity of the depressive episode [45]. Positron emission
tomography (PET) scans have shown that microglia are
increased in ACC during episodes of MDD [46]. At thesame time, the TSPO levels (a marker of microglial activation) were increased in MDD patients [47]. A crosssectional study using 18F-FEPPA PET showed a strong
relationship between the total distribution volume of
TSPO and the duration of untreated MDD, total illness
duration, and antidepressant exposure [48]. Correspondingly, in an autopsy study of patients with MDD, theconcentrations of quinolinic acid (QUIN) produced by
microglia were increased in the subgenual ACC and anterior midcingulate cortex of suicide victims [49]. In thedorsal ACC white matter from depressed suicide patients,
microglial density was increased significantly, as identified by elevated gene expressions of ionized calciumbinding adapter molecule 1 (Iba-1), CD45, and monocyte
chemoattractant protein-1 [50]. Another study reported
similar results that were obtained in the prefrontal whitematter [51]. Nevertheless, the role of microglia-mediatedinflammation in the occurrence of depression is still
controversial. Additional evidence demonstrated thatmicroglia decrease in depression. In subjects with familial MDD, glia cells were clearly reduced while the number of neurons remained unchanged [52]. Brain imaging

revealed cortical atrophy in the subgenual part of Brodmann’s area 24 [52]. A similar reduction in glial density
was also observed in the orbital cortex, ACC, and dorsolateral PFC, based on a laminar analysis [53–55]. In addition, the numbers of glial cells were reduced, especiallyon the left side of the amygdala in MDD patients, whenassessed using stereological methods [56]. However, no
reduction in the numbers of glia was found in area 3b of
the somatosensory cortex in patients with depression,suggesting that glial reduction in mood disorders is limited to specific brain structures [57].
In addition to depression disorder, microglial activation
has been reported in other mental disorders such as anxiety [58], schizophrenia [59], and autism spectrum disorders [60, 61]. Anxiety disorders often emerge early in life
and are associated with other diseases. Clinical reportson microglia and anxiety disorders remains extremely
limited, except in animal models of depression [58]. A
PET imaging study demonstrated increased microglial
activity in patients with schizophrenia and persons at
ultra-high risk of psychosis [62]. In autism, increases in
microglia were observed in cortical areas (fronto-insularand visual cortex) of the brain [63]. Conversely, several
studies reported no significant microgliosis or changes
in the expression of glial cell markers in schizophrenia
and autism [60]. Therefore, there are different opinions
concerning microglial activation in the development ofWang et al. Journal of Neuroinflammation(2022) 19:132

these mental diseases, which may be related to assessments during different stages of disease onset or individual heterogeneity. The treatment of depression should bepersonalized based on the status of major depression andmicroglial function in individual patients. It also is worth
noting that suicide has a high prevalence in the longterm course of mental diseases. Postmortem analysis hasrevealed that an elevated microglial density in schizophrenia and depressive patients is associated with suicide[59], indicating altered microglial activity might be critical in psychiatric disorders.
Preclinical evidence

Considerable research has focused on the relationshipbetween MDD and microglia in various animal models.
Sustained microglial activation that exhibited high levelsof pro-inflammatory cytokines has been observed in different brain regions [64–68], while inhibition of microglia
alleviated depressive-type behaviors [69]. In this review,
we illustrated the effects of microglial activation in animal models of depression, including acute/chronic stressand rodent pharmacological models. The search themesthat were used included “LPS, chronic mild stress (CMS),

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chronic social defeat stress (CSDS), chronic restraint
stress (CRS), olfactory bulbectomy (OBX), or learned
helplessness (LH) combined with microglia and depression, respectively. The results indicated that microglia
involved in nearly all models mentioned above. Amongthem, microglia were most evident in the models associated with LPS, CMS, and CRS, as well as CSDS-induced
neuroinflammation, as shown in Fig. 3.
In a mouse model of acute depression, intraperitoneal injection of LPS activated the nod-like receptor
pyrin containing 3 (NLRP3) expression and IL-1β cleavage in the HIP. Immunofluorescence staining showedthat NLRP3 was primarily expressed in Iba-1 positive
microglia when compared with control mice [70]. In
BV2 microglial cells, LPS exposure induced an imbalance between the pro-inflammatory and anti-inflammatory microglial phenotype [71], activated TLR4/nuclear
factor-kappa B (NF-κB) pathway, and downregulated
TREM2 expression [72]. In the HIP and cortex of CMSexposed mice, immunofluorescence staining revealed
that the activated microglia (Iba-1 positive cells), as
well as increased pro-inflammatory microglial markers(IL-1β, TNF-ɑ, IL-6, INF-γ, and iNOS) and decreased

Fig. 3 Annual changes in the number of published papers focused on animal models of depression and microglia

Wang et al. Journal of Neuroinflammation(2022) 19:132

anti-inflammatory markers (Ym1, IL-4, IL-10, and Arg-1),
suggesting a transformation of the microglial phenotype[73]. The CSDS paradigm also produces mood alterations
and microglial activation, as well as ROS elevation. In
addition, depletion of microglia using PLX5622 protects
against behavioral abnormalities in the light–dark (LD)and social interaction (SI) tests [74]. These studies provide evidence that depressive-like behaviors and inflammation are present in chronic stress and pharmacologicalrodent models, which might be associated with persistentinterference in microglia-related signaling. Other animalmodels that demonstrate an association between depression and microglia are shown in the Additional file 1:
Table S1.
Since 1992, numerous studies have verified the concept that CNS microglia-mediated inflammation may
contribute to depression and is closely related to regional
selectivity and disease severity. Even though a strong
correlation between microglia and depression has been
observed in patients and animal models, determining
whether microglial abnormalities actually play a significant role in depression remains challenging.
The role of microglia in the pathogenesis of depression
Microglia–neuron communication in depression

Microglia–neuron communication functions bi-directionally. Microglia impart considerable influence on
numerous aspects of neuronal function. Similarly, neurons regulate microglial functions mainly through soluble
factors such as chemokines, cytokines, and neurotransmitters. Among these factors, CX3CL1 and CD200 are
primarily expressed by neurons, and their receptors,
CX3CR1 and CD200R, are expressed on microglia [75].
Dysfunctional interactions between neurons and microglia are critical factors in severe neurological disorders,
including depression, schizophrenia, and AD.
The communication between CX3CL1 and CX3CR1
contributes to the ability of microglia to maintainfunctional stability. Depending on the degree of brain
damage, CX3CL1 leads to increased microglia proinflammation or maintenance of microglia in a quiescence state [76, 77]. In a LPS-induced depression model,
the decreased expression of CX3CL1 and microglial activation were observed in the HIP [78]. The serum levelsof CX3CL1 in patients with moderate–severe depression were higher than in the control group [79]. A similar
observation was made for the plasma levels of CX3CL1
from MDD patients with co-morbid cocaine addiction[80]. Cx3cr1-deficient mice displayed transient microglial
reductions during the early postnatal period and subsequent defects in synaptic pruning. Defective synaptic
pruning has been associated with less effective synaptictransmission and decreased neural circuit formation,

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and social interaction, as well as increased repetitive
behavior, which also have been observed in several neuropsychiatric disorders. These findings suggest thatmicroglia-mediated disruption of synaptic pruning could
be associated with neurodevelopmental and neuropsychiatric disorders [81]. More importantly, previous studies have suggested that hyper-ramified microglia (process
branching and/or soma enlargement) is connected todepressive-like behavior in rodents. The CX3CR1-deficient mice showed definite resistance to repetitive swim
stress-induced depressive-like behavior and microglia
hyper-ramification changes compared to wild-type mice[82]. Also, CX3CR1-deficient mice also demonstrated
the impairment in long-term potentiation (LTP). Treatment with an IL-1β receptor antagonist significantly
reversed the cognitive function and synaptic plasticity
impairments observed in CX3CR1-deficient mice [83].
The prenatal stress produced behavioral disturbances inanxiety and depressive behavior in adult offspring of rats.
The underlying mechanism may be related to the upregulation of CXCL12 and its receptor, as well as decreased
CX3CL1-CX3CR1 expression in the HIP and frontal cortices, whereas exogenous CX3CL1 application alleviatedthe observed changes [84, 85]. Furthermore, CX3CR1
deficiency has been shown to impair neuron–microglia
responsiveness to chronic stress [86]. Treatment withantidepressants such as fluoxetine, venlafaxine, or tianeptine normalized these behavioral and biochemical alterations [84].
Recently, CD200-CD200R has been shown to berelated to the pathogenesis of depression through animalmodels studies that focused on using different stressinducing protocols. For instance, exposure to inescapable
tail shock resulted in reduced CD200R level in the HIP,
basolateral (BLA), and central nucleus of the amygdale[87]. Similar observations have been reported in maleand female rats [88]. However, a paradoxical observation
indicated that unavoidable foot shocks in rats reduced
the transcription level of CD200R in the hypothalamus,
but not the HIP [89]. These discrepancies between published reports concerning the HIP might be attributed tothe use of different protocols by the two research groups.
In an IFN-α-induced model of depression, vulnerable
mice displayed increased levels of MHC-II, CD86, andCD200R. These mice displayed depressive-like behaviors
characterized by increased immobility time in the forced
swimming test (FST) and tail suspension test (TST), as
well as decreased explorative behavior in the novel object
exploration test [90].
Microglia and neurogenesis in depression

During brain development, microglia regulate synaptic transmission, prune neuronal synapses, and facilitate

Wang et al. Journal of Neuroinflammation(2022) 19:132

the formation of neural circuits. Once homeostasis isdisturbed, microglia are converted into an active state
and release pro-inflammatory cytokines, chemokines,
and reactive oxidants. The pro-inflammatory microglia
are involved with the upregulation of pro-inflammatory
mediators, which is usually considered a harmful event.
Whereas anti-inflammatory microglia display protective
effects in neuronal survival and adult neurogenesis [91].
Activation of microglia is a critical mechanism in neurogenesis inhibition in the presence of inflammationand stress [9]. Hippocampal neurogenesis is a complex
neurobiological process involving the generation andfunctional integration of newborn cells into brain neural circuits [92]. Several studies have demonstrated thatstress strongly suppresses adult hippocampal neurogenesis. Both acute and chronic stress have been reported
to reduce adult neurogenesis by decreasing neuroprogenitor proliferation and newborn cell survival [93–95],
and also impair newborn neuron maturation [96, 97].
LPS infusion via a cannula for 4 weeks reduced the survival of new neurons in the subgranular zone/granulecell layer (SGZ/GCL) of the HIP, while 6 days of intracortical LPS infusion in rats did not affect the proliferation of new cells [98]. In addition, LPS-induced
neuroinflammation suppressed proliferation and differentiation of neural stem cells in the dentate gyrus (DG)of the HIP, which was indicated by the decreased number of BrdU-, DCX- and NeuN-positive cells [99]. In an
8-week CMS-induced depression paradigm, C57BL/6
mice exhibited an increase in the number of Iba-1 positive cells and levels of IL-1β, IL-6, and TNF-α [100].
Another report on the CMS showed that an imbalance of peripheral inflammation markers and decreased
CX3CL1/CX3CR1 immunoreactivity were associatedwith reduced numbers of BrdU/Ki-67/DCX+ (nascent,proliferating and DCX-associated) cells in the DG of the
HIP [101]. Furthermore, in a graded study of the CMS for
5, 6, or 7 weeks, the investigators found that the pro- or
anti-inflammatory microglial changes in the cortex and
HIP, as well as BrdU/DCX+ cells, decreased in the DG[102]. Similar results related to the relationship between
depressive-like behaviors and changes in microglia andneurogenesis have been reported in psychosocial stressmodels, including maternal separation [103], maternal sleep deprivation [104], chronic water-immersion
restraint stress (CWIRS) [105], and CSDS [106, 107].
On the other hand, IL-4 and IL-10 induce alternative
activation of anti-inflammatory factors that play a critical neuroprotective function in tissue remodeling andnerve regeneration. Treatment with IL-4 markedly inhibited IL-1β-caused depressive behavior by regulating glial
activation and neurotransmitter levels in the HIP [108].
IL-4 stimulation increased the expression of insulin-likePage 7 of 26

growth factor-1 in microglia, which has been reported topromote neurogenesis [109, 110]. Recent research demonstrated that IL-4-driven A­ rg1+ microglia modulate
stress resilience through brain-derived neurotrophic factor (BDNF)-dependent neurogenesis in CMS mice [111].
IL-10-stimulated microglia enhanced the proliferationof NPCs but did not affect neuronal differentiation. IL10-secreting microglia supported neuronal differentiation and the survival of newly formed cells in vitro [112].
­CX3CR1CreERIL-10 knockout mice exhibited depressionand anxiety-like behaviors, along with decreased NR2B
(N-methyl-D-aspartate receptor (NMDAR) subunit) andsynaptophysin (SYP) levels in the mPFC, and increased
NR2B and postsynaptic densitin-95 (PSD95) levels in
the amygdala [113]. Furthermore, hippocampal neurogenesis was reduced in CX3CR1-deficient mice, andantagonizing CX3CR1 resulted in increased hippocampal IL-1β level and decreased neurogenesis in young rats
[114]. Minocycline, a microglial inhibitor, reversed thepathogenic phagocytic potential of neurotoxic microglia,
and reduced the negative phenotypes associated with
reduced neurogenesis in depression models induced bychronic stress and LPS [115]. Therefore, these data suggest that microglia are correlated with reduced neurogenesis induced by exposure to stress and, in turn, may
be responsible for the development of depressive-likebehaviors.
Microglia‑mediated activation of NLRP3 in depression

The NLRP3 inflammasome is a multi-molecule complex
containing cytosolic NLRP3, adaptor protein ASC, andpro-caspase-1 precursor. NLRP3 plays a vital role in production of pro-inflammatory cytokines during the stressprocess [116]. The NLRP3 inflammasome is currently
considered to be an essential molecular platform forregulating pro-inflammatory cytokines release. NF-κB
nuclear translocation is an indispensable event in theinitiation of NLRP3 activation, which further confirmedthat NF-κB nuclear translocation might play a role inassembling the NLRP3 inflammasome. When NLRP3 isactivated by repetitive stress, it modulates caspase-1 activation, which, in turn, promotes IL-1β and IL-18 maturation in microglia, where excessive secretion of cytokines
contributes to the development and progression of MDD[117–119].
NLRP3 inflammasome activation has even been
observed in depressive patients and numerous animalmodels of depression. Previous studies have revealed that
the NLRP3 inflammasome was activated in blood cells
from MDD patients, and the levels of IL-1β and IL-18
were increased in serum. The increase in pro-inflammatory factors was positively correlated with Beck Depression Inventory scores [120], suggesting that NLRP3

Wang et al. Journal of Neuroinflammation(2022) 19:132

might have a critical role in mediating the developmentof depression [121]. In another experimental study, a sustained CMS procedure (12 weeks) enhanced the levels of
IL-1, NLRP3, ASC, TLR2, NF-κB, p-IKKα, and IKKβ in
rat PFC, while these alterations were reversed with fluoxetine [122]. Immunofluorescent analysis has confirmedthat the NLRP3 inflammasome was primarily activatedonly in microglia in the PFC (Iba-1/NeuN+ cells) [122].
Using NLRP3 inflammasome inhibitors AC-YVADCMK and VX-765 significantly improved depressive-likebehavior, as shown by improvements in sucrose intake inthe sucrose preference test (SPT) and immobility time in
the FST of CMS mice [94, 123]. Moreover, activation of
P2X7R and NLRP3 inflammasome-associated proteinsin hippocampal microglia could mediate depressivelike behaviors, which provide new therapeutic targets
for depression [124]. In a LPS-induced acute depression mouse model, NLRP3, ASC, and caspase-1 mRNA
expressions were remarkably increased compared to thecontrol group [125]. In addition, IL-1β secretion wasclosely controlled by the NLRP3 inflammasome, whichplays an important role in the pathogenesis of depression[108]. Minocycline has an acute antidepressant role in
CRS, CUMS, and LH models by inhibiting microglia and
NLRP3 activation [126–129]. Fluoxetine conferred anantidepressant effect in part by inhibiting NLRP3 inflammasome activation [130]. Clomipramine reversed LPSinduced increases in IL-1β, IL-6, TNF-α, and NLRP3
gene expressions in vivo, as well as in vitro in BV2 cells[131]. Electro-acupuncture treatment for 4 weeks markedly reversed CMS-induced increases in NLRP3 inflammasome-associated components (NLRP3, ASC, andcaspase-1) and the expressions of mature IL-1β, as well
as IL-18, TNF-α, IL-6, P2X7 receptor, and Iba-1 [132].
Iptakalim negatively regulates NLRP3 expression and, inturn, affects microglia-mediated neuroinflammation by
inhibiting the activation of NLRP3/caspase-1 axis in the
HIP of CMS mice [94]. These findings suggest that microglial NLRP3 activation is a central mediator involved indepressive-like behaviors in animal models and MDD
patients.
Microglia‑mediated kynurenine pathway in depression

Chronic stress stimulation or inflammation may contribute to tryptophan (TRP) metabolism associated with thekynurenine pathway (KP). The generation of neuroactive
kynurenine metabolites leads to subsequent depressivelike symptoms [133]. KP metabolizes tryptophan into
several bioactive metabolites in the brain, including
QUIN (an NMDAR agonist) and kynurenic acid (KYNA,
an α7-AChR and NMDAR antagonist). KYNA is primarily formed in astrocytes [134], which exhibit a neuroprotective function via their ability to eliminate glutamate

Page 8 of 26

spillover. QUIN is produced mainly by microglia [135]and has a strong excitotoxic role through enhancing
NMDAR activation [136]. Microglia regulate KP balanceby preferentially producing oxidative metabolites, including QUIN. Other metabolites of KP, including 3-hydroxykynurenine (3-HK) and anthralinic acid, do not directly
affect neuronal activity but are involved in complicatedpro-oxidation and anti-oxidation processes [137].
Recent studies have found that microglial QUIN
expression was increased in the subgenual and supracallosal regions of the ACC in post-mortem brains ofsuicide patients with severe depression. In contrast,
additional research revealed decreased QUIN in left
CA1 or right CA2/3 areas of the HIP in uni- and bipolar depression patients [138]. Moreover, a meta-analysis
revealed decreased KYNA and kynurenine (KYN) levels
in patients with depression and increased QUIN level in
antidepressant-free patients [139]. Similar results havebeen reported concerning the increase of QUIN in peripartum depression and adolescent MDD [140, 141]. In
addition to clinical data, enhanced levels of 3-HK and
QUIN have been observed in several models of depression [142, 143]. LPS and other infectious agents, including viruses, upregulate the release of inflammatory
cytokines by binding to TLRs, which in turn directly andindirectly induce KP metabolism via pro-inflammatory
cytokines [144]. Ketamine treatment could reduce the
LPS-induced depressive-like alterations observed in thenovelty suppressed feeding test (NSFT) and splash test(ST) [145]. In a genetic animal model, the level of KYNA
was reduced in the PFC of Flinders sensitive line rats
compared with Flinders resistant line control rats [146].
In addition, CMS contributed to QUIN production andits release from microglia in the HIP. QUIN resulted in
the elevation of Glu level via NMDARs and mGluR1, as
well as the increased expression of NR2B and mGluR1,
which lead to depressive-like symptoms [147]. CRS
exposure induced depressive-like behavior in C57BL/6 J
mice, which was attributed partially to disruption of theneuroprotective/neurotoxic balance of the kynurenine
metabolic pathway in the gut and brain [148]. Enzyme
indoleamine 2,3-dioxygenase 1 (IDO1) is considered to
be a rate-limiting enzyme for tryptophan metabolism in
KP [149]. Treatment with the IDO inhibitor, 1-methyltryptophan, partially prevented CRS-induced depression- and anxiety-like changes [148]. The chronic forced
swim test and tail suspension test in mice enhanced KYN/
TRP and reduced the 5-HT/TRP ratio, which indicatedactivation of IDO1 [150]. In the poststroke depression(PSD) mouse model, 3-hydroxyanthranilate 3,4-dioxygenase (HAAO), QUIN, IDO1, Iba-1, and ROS wereremarkably increased in the nucleus accumbens (NAc),
HIP, and hypothalamus. At the same time, treatment

Wang et al. Journal of Neuroinflammation(2022) 19:132

with aripiprazole ameliorated the abnormal behaviors in
PSD mice that were accompanied by decreased levels of
IDO1, HAAO, QUIN, and ROS [151]. IDOInh is a specific inhibitor of IDO1 and has been shown to reverse
fear learning and memory in CSDS-induced depressed
mice by decreasing KYN and 3-HK levels in the bloodand brain [152]. Consequently, it has been proposed thatkynurenine metabolites directly interact with microglial
activity, which provides a reliable target for investigating
the mechanisms underlying antidepressant drugs.
Effects of antidepressants on microglia

Currently, numerous reports using different experimental models have indicated that antidepressants, including
clinical and plant-based drugs, exert their antidepressanteffects, in part, by regulating microglial phenotypes. Regulation of microglia has been proposed as a potentiallyeffective therapeutic strategy in chronic inflammatory
diseases [29, 30]. In this section, we summarized the current knowledge of antidepressants (clinical medicine andnatural products) that act against microglial dysfunction
in stress-induced depression models (Tables 1 and 2).
Clinical antidepressive drugs

Clinical antidepressants, including selective serotonin
reuptake inhibitors (SSRIs) and tricyclic antidepressants(TCAs), have exhibited effects on microglial activationand neuroinflammation [153]. Other compounds, including minocycline, melation, FCPR16, pioglitazone, iptakalim, and caffeine, also influence microglial polarizationand depressive-like behavior [91], as shown in Table 1.
The SSRIs (fluoxetine, citalopram, and escitalopram)exhibit antidepressant roles in LPS, CMS, CSDS, andCWIRS models, as seen by alleviating nest-building deficits, reducing immobility time in the FST and TST, andincreasing sucrose intake in the SPT (Table 1). Thesebehavioral changes were accompanied by decreases
in the microglial marker Iba-1 expression in different
brain regions. In addition, pro-inflammatory factors levels (IL-1β, TNF-α, and NO) were downregulated, andanti-inflammatory factors levels (IL-4, IL-10, Arg-1, andTGF-β1) were upregulated [16, 101, 105, 154, 155]. Tricyclics, including clomipramine and imipramine, reversed
depressive behaviors induced by LPS, LH, and CSDS by
reducing the number of activated hippocampal microglia (Table 1). These traditional antidepressants promote
the activation of anti-inflammatory microglia to releaseanti-inflammatory cytokines and neurotrophic factors,
suggesting that reducing inflammation may be part of
the function of clinical antidepressants [107, 131, 156].
Cytokines levels are strongly correlated with the efficacy of antidepressant treatment in patients. For example, higher levels of IL-6 and TNF-α are more commonly

Page 9 of 26

found in treatment-resistant patients than responders[157]. Nevertheless, some results revealed conflicting
views that antidepressants might sometimes increase
the inflammatory load in the brain. For instance, citalopram treatment elevated the levels of TNF-α andIFN-γ in the PFC, and these effects were inhibited by
the anti-inflammatory agent ibuprofen [158]. Phenelzine, a monoamine oxidase inhibitor, has been shownto enhance the microglia-mediated immune responses
by increasing the expressions of iNOS, TNF-α, andIL-6 in LPS-treated BV-2 cells. It has been verified thatphenelzine also increased the levels of NO, TNF-α, andIL-6 via the NF-κB signaling pathway in LPS-activatedprimary microglia cells [159]. These differences may
depend on regional brain specificity and heterogeneity
among depression models and patients, but the conflicting causes and mechanisms need further study. Ketamine
has exhibited potential antidepressant effects in vivo
and in vitro by inhibiting microglia-mediated neuroinflammation [160]. Partial depletion of microglia with
PLX3397 blocked the rapid and sustained antidepressanteffects of (R)-ketamine (an isomer of ketamine), suggesting that antidepressant effects of ketamine may be partly
attributed to microglial activation [161].
Minocycline is a potential agent for the treatment ofdepression [19]. In several studies, chronic minocycline
treatment clearly alleviated depressive-like symptoms
by inhibiting microglia and HPA axis hyperactivity. The
powerful neuroprotective effects of minocycline weremainly mediated by modulating pro-inflammation andanti-inflammation balance in the PFC and HIP, as well as
upregulating the BDNF-mediated synaptic plasticity instress models [14, 162–164]. Meanwhile, CMS-inducedchanges in behavior, hippocampal LTP, CD11b expression, NLRP3 inflammasome, BDNF, and p-GluR1 levels
were restored with chronic minocycline treatment [128,165–168]. Peroxisome proliferator-activated receptor γ(PPARγ) is a nuclear receptor that regulates inflammation and microglial polarization and is a potential treatment target in MDD. Pioglitazone, a PPARγ agonist,significantly ameliorated depressive-like behaviors in
CMS mice by regulating the expression of pro-inflammatory markers (IL-1β, IL-6, TNF-α, iNOS, and CCL2)
together with anti-inflammatory markers (Ym1, Arg1,
IL-4, IL-10, and TGF-β) in the HIP [169]. Other drugs
that play a potential antidepressant role in modulating
microglial phenotype are shown in Table 1.
Plant‑derived natural compounds and formulations
with antidepressant properties

Recently, the regulatory properties of some plant-derived
natural compounds and formulations have shown efficacy
in treating depression. In this review, the antidepressive

Wang et al. Journal of Neuroinflammation(2022) 19:132

Page 10 of 26

Table 1 Traditional antidepressants regulate the microglia-mediated neuroinflammation in animal models of depression
Treatment

Animal models

Behavioral test

Analyzed regions

Microglia

Pro-inflammation

Anti-inflammation

Fluoxetine [154]

CSDS

OFT, EPM, SIT

Serum

—

—

Hip

Iba-1(–)

ELISA: TNF-α ↓,HMGB1 ↑

CorticalCD11 b/P2X7R+↓

Fluoxetine [170]

CMS

Nest-building test,
Dexamethasone
suppression test

Amygdala
HIP

—

—

—

—

CD11 b/P2X7R+↓——

Proteins: CD68,
Iba-1 ↓

Proteins: IL-1β, TNF-α, —iNOS ↓ELISA: IL-1β, IL-6,
TNF-α
Proteins: TLR4,
NLRP3 ↓———

Proteins: IL-6, IL-1β ↓IL-10 (–)

ELISA: IL-1β, IL-6,
TNF-α ↓—CWIRS

SPT, FST, TST

HIP

Fluoxetine [155]

LPS

SPT, FSTHIP

Iba-1/COX-2+↓
in DG

Citalopram [101]CMS

SPT, FST

HIP

Escitalopram [16]CMS

OFT, SPT, TST, FST,
NSFT

HIP

Iba-1+↑;­ X3CL1+↑,C­CX3CR1+↑ in DG

Cerebral cortex—

SIT, SPT, TST, FST

Serum

—

HIP

Iba-1+↓ in DG

PFC

Iba-1/HMGB1+↓

Serum

—

Brain

Protein: Iba-1 ↓

Serum

—

Dorsal HIP

mRNA: CD14,
CD86 ↑

Sertraline [171]

CSDS

CMS

SPT, TST, FST

Sertraline [172]

CMS

TST, FST

Vortioxetine [17]LPS

OFT, SPT, NORT

Ventral hippocampus (vHIP)
Imipramine [173]mRNA: Arg-1, CD206↑

CD11 b/P2X7R+↓

Fluoxetine [105]Imipramine [107]mRNA:TNF-α, IL-1β,
RAGE, TLR4 ↑Proteins: T-HMGB1,
T-p65, IκB ↑, TLR4 ↓—Protein: TNF-α ↓IL-10 (–)

mRNA: IL-1β, IL-6,
TNF-α ↓
Proteins: p-p65/p65,
cleved-Caspase-3,
ac-NF-κB ↓—Proteins: TNF-α,
IL-1β ↓—

Proteins: TNF-α,iNOS, IL-1β, p-p65NF-κB, p65-NF-κB,
p-IκB-α ↓—mRNA: TNF-α, IL-6,
IDO1 ↑

mRNA: IL-4, TGF-β1 ↑ELISA: IL-6, CORT ↓—ELISA: TNF-α, IL-1β,
NO ↓—ELISA: TNF-α, IL-1β ↓—mRNA: IL-1β, IL-6,
IDO1 ↑

mRNA: IL-4, IL-1Rα ↑——Iba-1+↓——

mRNA: IL-1β, TNF-α,
IL-6 ↓———

Proteins: pro-IL-1β,
IL-1β, NLRP3, caspase-1—

mRNA: CD14,
CD86, CD11b ↑Repeated social
defeat

OFT, social avoidance test

PlasmaImipramine [156]

LH

—

Hilus

Clomipramine
[131]

LPS

TST, FSTHIP

Iba-1+↓

Agomelatine [174]

LPS

—

vHIP

Melation [70]LPS

TST, FSTHIP

mRNA: CD11b,
CX3CL1, CX3CR1↓, CD68 ↑SRT2104 [175]

CMS

OFT, SPT, TST, FST

HIP

mRNA: IL-6, IL-1β,
Iba-1+,­ D11b+ ­CD45low+ iNOS ↓C(–)
CD11b+ ­MHCII+↓

mRNA: IL-10,
TGF-β, Arg-1 ↑­CD11b+CD206+↑

Pioglitazone [169]

CMS

OFT, SPT, TST, FST

HIP

Iba-1+↓

mRNA: Ym1, Arg1,
IL-4, IL-10, TGF-β ↑

Brain

—

Proteins: CD45,
CD11b ↓

Iba-1/NLRP3+↓

mRNA: IL-1β, IL-6,
TNF-α, iNOS, CCL2 ↓Wang et al. Journal of Neuroinflammation(2022) 19:132

Page 11 of 26

Table 1 (continued)
Treatment

Animal models

Behavioral test

Analyzed regions

Microglia

Pro-inflammation

Anti-inflammation

Clemastine [176]

CMS

SPT, TST, FST

Serum

—
Protein: Iba-1 ↓ELISA: IL-1β, TNF-α ↓—HIPmRNA: IL-1β, IL-6 ↑mRNA: MRC2, IL-10 ↑CORT ↓—

Proteins: p-IkBα,
p-p65-NF-κB, TNF-α,
IL-6 ↓—

mRNA: TNF-α, IL-6
Proteins: p65, IL-1β,
NLRP3, caspase-1 ↓mRNA: IL-10 ↑Minocycline [163]

OBX + spinal nerve
ligation

OFT

PFC

—

Minocycline [14]CMS

SPT, FST, EMP

Serum

—

HIP

mRNA: CD11b,
IFN-γ/IL-4, IFN-γ/
IL-10 ↓
Iba-1+↓

Memantine [177]

OBX

Emotional behavior, TST, FST

HIP

Iptakalim [94]CMS

SPT, TST, FST

Serum

—

HIP

MAC-1+↓ in DG

Simvastatin [178]

LPS or CMS

SPT, FST, NSFT

HIP

Iba-1+↓

ONO-2952 [179]

CSDS

OFT, EMP, TST, FST

NAc

—

BLA

DHE/Iba1+↓

PFC—

Proteins: IL-1β, TNF-α, Protein: Arg-1 ↑iNOS ↓

mRNA: IFN-γ, TNF-α,
IL-1β, IL-17 ↓Protein: CD11b ↓ELISA: IL-1β ↓mRNA: TGF-β1, IL-4,
IL-10, IL-13 ↑—Proteins: p65-NF-κB,
IL-1β, TNF-α, IL-6 ↓—Proteins: IL-1β, IL-6,
IL-12 ↓—

Proteins: TNF-α,
IL-6 ↓—

Proteins: IL-1β,
IL-12 ↓—

mRNA: TNF-α, TLR4,IL-1β ↓—

Proteins: IL-1β, IL-6,
iNOS ↓

Proteins: IL-1β, IL-6,
Arg-1 ↑

Iba-1+, ­CX3CL1+,­CX3CR1+↑ in DG——
mRNA: IL-4, IL-10,
CD206, Arg-1 ↑Protein: Arg-1 ↑mRNA: Iba-1 ↑mRNA: IL-1β, IL-6,
TNF-α, CD68 ↓Proteins: p-p65, IκB,
iNOS ↓ELISA: IL-1β, IL-6,
TNF-α ↓
mRNA: NLRP3, ACS,
caspase-1, iNOS,
CD16 ↓
Proteins: iNOS,
CD16, NLRP3, ACS,
caspase-1 ↓

vHip

—

Iptakalim [180]CRS

OFT, FST

Hypothalamus

TNF-α/CD11b+↓

Caffeine [105]CWIRSSPT, FST, TST

HIP

Apelin-13 [181]CWIRS

OFT, SPT, TST, FST

HIP

Protein: Iba-1 ↓CD68+↓

Melatonin [101]CMS

SPT, FSTHIP

ω-3 polyunsaturated fatty acids[182]

Ovariectomized

SPT, FST, NSFT, TST

HIP

Fingolimod [183]CMS

OFT, SPT, FST, WMW HIP

Iba-1+↑, Iba-1/
iNOS+↑, Iba-1/
Arg-1+↓ in CA1
Iba-1+↓ in DG

Protein: IL-12 ↓—Proteins: CD68, iNOS, —TNF-α, IL-1β ↓ELISA: IL-10 ↑mRNA: Arg-1,
CD206 ↑
Proteins: Arg-1,
CD206 ↑

↑upregulated; ↓downregulated; (–) no significant difference;—no explicit data

effect of natural products such as ginsenosides (Rg1, Rg3,
and Rb1), resveratrol, salvianolic acid B, and magnolol on
microglia-mediated neuroinflammation are summarizedin Table 2. The chemical structures of several naturalcompounds that may act as potential inhibitors of proinflammatory microglial activation in MDD are illustrated in Fig. 5.

Flavonoids

Flavones are subgroups of flavonoids composed of a
backbone of 2-phenylchromen-4-ketone, and their biological activities have been reported in vitro and in vivo[184]. Flavonoids achieve their antidepressive effects
through modulating microglial activation and NLRP3
inflammasomes. Baicalin, a flavonoid found in the rootof Scutellaria, could ameliorate depressive behaviors inWang et al. Journal of Neuroinflammation(2022) 19:132

Page 12 of 26

Table 2 Plant-derived natural compounds and formulations that regulate microglia-mediated neuroinflammation in animal models ofdepression
Treatment

Animal models

Behavioral test

Analyzed regions

Microglia

Pro-inflammation Anti-inflammation

Crocin [226]

LPS

OFT, FST, TST, FST

HIP—

Baicalin [186]CMS

OFT, FST, TST, FSTHIP—ELISA: IL-1β, IL-18,
Protein: CD206 ↑TNF-α ↓
Proteins: CD16/32,
iNOS, p-65-NF-κB ↓Catalpol [205]

CMS

OFT, EPM, FST

HIP

Iba-1+↓

Ganoderic acid A[227]

MCAO + CMS

OFT, SPT

HIP—

Ginsenoside Rb1
[73]

CMS

OFT, SPT, TST, FST

HIP

Iba-1+↓

CortexIba-1+↓

HIP

Iba-1+(–)

CortexIba-1+↓

OLT, NORT, NSFT

HIP

Iba-1+↓

Salvianolic acid B[213]

Curcumin [215]CMS

GWI + CRS

SPT, TST, FST

Ginsenoside Rb1
[197]

CRS

OFT, TST, FST

HIP

Protein: Iba-1 ↓Arctigenin [171]

CMS

SPT, TST, FST

Serum

—

PFC

Iba-1/HMGB1+↓
Protein: Iba-1 ↓Iba-1+↓

Astragalin [231]

CMS

SPT, TST, FST

HIP

Saikosaponin-d
[190]

LPS

OFT, FST, TST, FST

HIP

Iba-1+↓ in CA1

Asperosaponin VI
[228]

LPS

OFT, FSTHIP

Iba-1+↓

PFC

Iba-1+, iNOS/
Iba-1+↓HIP—

5-O-Methylvisammioside [233]

LPS

OFT, FST, FST, EPM

Proteins: IL-1β, IL-6,
TNF-α, TLR4 ↓—ELISA: TNF-α, IL-1β,
IL-6 ↓
mRNA: TNF-α, IL-1β,
IL-6, iNOS, CD68 ↓Proteins: iNOS,
CD68 ↓ELISA: IL-10 ↑mRNA: IL-10, CD206,
Arg-1 ↑
Proteins: CD206,
Arg-1 ↑

mRNA: TNF-α,
IL-1β ↓

mRNA: TGF-β, Arg-1↑

mRNA: IL-1β, TNF-α, mRNA: CD206 ↑iNOS, IL-6, CD206 ↓Proteins: NLRP3,
cleaved caspase-1,IL-1β ↓ROS ↓mRNA: TNF-α,
IL-1β ↓

mRNA: TGF-β, Arg-1↑

ELISA: TNF-α ↓mRNA: IL-1β,
TNF-α ↓ELISA: IL-10 ↑mRNA: IL-10, TGF-β ↑ELISA: TNF-α ↓mRNA: IL-1β,
TNF-α ↓ELISA: IL-10 ↑mRNA: IL-10, TGF-β ↑——Proteins: TNF-α,
IL-1β ↓—ELISA: TNF-α, IL-1β,
NO ↓—Proteins: Nuclear
p65-NF-κB, NLRP3,
cleaved caspase-1,
cleaved IL-1β,
cleaved gasderminD↓—

Proteins: TNF-α,
IL-1β, IDO ↓—Proteins: CD68,
IL-1β, IL-6, TNF-α,
HMGB1, TLR4, p65NF-κB, p-IκB-α ↓—mRNA: IL-1β, IL-6,—
TNF-α, iNOS ↓Proteins: IL-1β, TNFα, TLR4, p-NF-κB/
NF-κB ↓
mRNA: IL-1β, IL-6,
TNF-α, iNOS ↓Proteins: IL-1β, TNFα, TLR4, p-NF-κB/
NF-κB ↓

Proteins: NF-κB,
IκB-α ↓—

Wang et al. Journal of Neuroinflammation(2022) 19:132

Page 13 of 26

Table 2 (continued)
Treatment

Animal models

Behavioral test

Analyzed regions

Microglia

Pro-inflammation Anti-inflammation

Scutellarin [230]

LPS

OFT, SPT, FST

HIP

Iba-1+↓—

Ginsenoside Rg1
[200]

CMS

SPT, FSTvmPFC

Iba-1+↓

Proteins: NLRP3,
caspase-1, IL-1β ↓ROS ↓Ginsenoside Rg3
[201]

LPS

—

CortexIba-1+↓

Hypothalamus
Brain

Magnolol [219]

CMS

OFT, SPT, FST, TST

HIP

mRNA: IL-1β, IFN-γ,
TNF-α ↓ELISA: IL-1β, IFN-γ,
TNF-α ↓———

Iba-1+↓——

mRNA: IL-1β, IL-6,
TNF-α

—

Iba-1+↓ in DG;
Iba-1/CD16/32+↓,
Iba-1/CD206+↑——ELISA: IL-4, IL-10 ↑mRNA: Arg1, Ym1,
Fizz1, Klf4 ↑iNOS+, COX-2+,
Iba-1+↓Brain—

ELISA: TNF-α, IL-1β,
IL-6, IL-12 ↓—ELISA: TNF-α, IL-6 ↓Proteins: CD86 ↓,CD206 ↑

Geniposide [208]LPS

SPT, TST, FST, OFT

HIP

Serum

—

Arctiin [210]CMS

TST, FST, OFT, SPT

PFC

Iba-1+/HMGB1+↓
Protein: Iba-1 ↓

Serum

—

Median raphe
nucleus—

HIP

Iba-1+↓

Cortex—

Ginkgolide B [234]

Depression in post
myocardial infarction

OFT, SPT

Leonurine [235]

CMS

TST, FST, SPT

HIP—

Hesperidin [232]

CMS

FST, SPT, OFT

PFC

Iba-1+↓

20(S)-Protopanaxadiol [229]

CMS

SPT, TST, FST

HIP

Iba-1+↓

CortexIba-1+↓

Ferulic acid [236]

CMS

SPT, FST

PFC

Resveratrol [224]LPS

OFT, TST, FST

HIP(+)-Sesamin [69]CMS

OFT, FST, TST, EMP

HIP
Prelimbic cortex

Quercetin [187]

OBX

OFT, FST—

Iba-1+↓ in DG-SGZ
Protein: Iba-1 ↓Protein: Iba-1 ↓HIP—

Cortex—ELISA: TNF-α, IL-6 ↓——Proteins: TNF-α,—
IL-1β, iNOS, HMGB1↓ELISA: TNF-α, IL-1β,iNOS ↓ELISA: IL-1β ↓mRNA: IL-1β ↓—ELISA: IL-1β ↓mRNA: IL-1β ↓—mRNA: NLRP3,
caspase-1, ASC ↓Proteins: NLRP3,
caspase-1, ASC ↓ELISA: IL-1β, IL-6,
TNF-α ↓—ELISA: IL-1β ↓mRNA: IL-1β ↓—Proteins: IL-1β, IL-6, —TNF-α, p-IKKβ/IKKβ,p-p65/p65 ↓Proteins: iNOS,
COX-2, acetylated
p65 (ac-p65) ↓

—

—

—

mRNA: IL-6, IL-1β,
TNF-α, NF-κB,
CD11b ↓
Proteins: NLRP3,
caspase-1 ↓

—

—

—

mRNA: COX-2,—
iNOS, IL-1β, TNF-α ↓mRNA: COX-2,—
iNOS, IL-1β, TNF-α ↓ELISA: TNF-α, IL-6 ↓ELISA: TNF-α, IL-6 ↓——Wang et al. Journal of Neuroinflammation(2022) 19:132

Page 14 of 26

Table 2 (continued)
Treatment

Animal models

Behavioral test

Analyzed regions

Microglia

Pro-inflammation Anti-inflammation

Theaflavins [246]

LPS

TST

HIP

MIP-1α/CD11b+,
ELISA: TNF-α,
TNF-α/CD11b+↓ in IL-1β ↓microglia—

Epigallocatechin3-gallate [99]

LPS

—

HIP

Iba-1+↓ in DG—

Gypenosides [192]

CMS

SPT, TST

HIP

Iba-1+↓ in DG

mRNA: IL-1β, IL-6,
TNF-α ↓
Proteins: TLR4, Rel
A, pRel A ↓ELISA: IL-1β, IL-6,
TNF-α ↓

Kososan [237]CSDS

Social avoidance
test

HIP

Iba-1+↓

Aquilariae Lignum
ethanol extracts
[238]

CRS

—

HIP

Rosemary Extracts
[239]

CRS

OFT, TST, FST

mRNA: IL-6 ↓Proteins: IL-6,
TNF-α ↓———

Iba-1+↓

Proteins: TNF-α,
IL-1β, iNOS ↓

—

Serum

—

—

HIP

Protein: Iba-1 ↓ELISA: IL-1β, TNF-α↓mRNA: NLRP3,
IL-1β, IL-6, IL-18,
TNF-α ↓
Proteins: NLRP3,
ASC, cleaved
caspase-1—

mRNA: IL-1β, IL-6,
TNF-α ↓—ELISA: TNF-α, IL-6,
IL-1β ↓—

Radix Polygalae
extract [240]CRS

OFT, SPT, NSFT

PFC

Iba-1+↓

Bangpungtongsung-san [241]Reserpine

OFT, TST, FST

HIP—XingnaoJieyu
decoction [242]

MCAO + CMS

OFT, FST

CortexIba-1+↓

HIP

Iba-1+↓

Ganoderma
lucidum polysaccharides [243]

CSDS

OFT, SPT, TST, FST

HIP

Iba-1+↓

Water extract ofArmillaria mellea(Vahl) P. Kumm
[244]

CMS

OFT, FST

CerebralProtein: Iba-1 ↓Xiaoyaosan [245]

CMS

SPT, OFT, FST, NSFTHIP

Myelophil [96]CMS

OFT, TST, FST

HIP

Iba-1+↓↑upregulated; ↓downregulated; (–) no significant difference;—no explicit data

CMS model [185, 186]. Oral administration of baicalin(20, 40 mg/kg/day) for 3 weeks significantly improved
sucrose intake, locomotor activities, and behavioral
despair in CMS rats. The mechanism of baicalin against
CMS-induced depression was partially achieved byincreasing levels of DCX, neuron-specific enolase (NSE),
and BDNF, reducing oxidative stress, and modulating the GSK3/NF-κB/NLRP3 signal cascade in the HIP[185]. In addition, baicalin supplementation (30, 60 mg/

Iba-1+↓ in CA1,
DG, CA3

Proteins: IL-1β, TNF- —α, p-p65-NF-κB ↓ELISA: TNF-α, IL-6,
IL-1β ↓—

Proteins: IL-1β,
TNF-α ↓

Proteins: IL-10,
BDNF ↑

Proteins: IL-1β,
TNF-α ↓—

mRNA: COX-2 ↓ELISA: IL-1β, TNF-α↓
Proteins: NLRP3,
ASC, pro-IL-1β,
IL-1β ↓——

kg/day, p.o.) for 3 weeks also inhibited TLR4 activationand pro-inflammatory cytokine secretion in CMS mice.
Furthermore, it was confirmed that the inhibition might
be realized through PI3K/AKT/FoxO1 pathway in LPSstimulated BV2 cells [186]. Quercetin is a flavanol present in apples, onions, and berries [37]. Treatment with
quercetin (40, 80 mg/kg/d, p.o.) for 2 weeks significantly
reversed OBX-induced increase in immobility time in the
FST, possibly by inhibiting TNF-α, IL-6, and caspase-3

Wang et al. Journal of Neuroinflammation(2022) 19:132

in the HIP and cortex. Co-treatment with minocycline(25 mg/kg, p.o.) significantly potentiated its protective
effects when compared to treatment with quercetin alone[187]. Treatment with quercetin (40 mg/kg/day, p.o.) for
2 weeks alleviated depressive-like behavior in the SPT
and FST of LPS-challenged rats via regulation of BDNFrelated imbalance of Copine 6 and TREM1/2 in the HIP
and PFC [188].
Terpenoids

Terpenoids, especially triterpenoids, monoterpenes andsesquiterpenes, are the most abundant natural compounds found in several vegetables and fruits. Recently,
some terpenoids have been reported to have preventive
efficacy against neurological diseases by modulating theactivation of microglia, especially on depression. Saponins, which are triterpene glycosides, are abundant insome plants, and their general biological activities havebeen summarized [189]. Saikosaponin-D is a triterpenoid saponin derived from Radix bupleuri and exhibits
anti-inflammatory, anti-oxidative, and other pharmacological activities [190]. Previous studies have suggested
that treatment with saikosaponin-D (0.75, 1.50 mg/kg/
day, p.o.) for 3 weeks remarkably ameliorated the CMSinduced depressive-like behaviors in rats, mainly by
improving HPA axis functions and hippocampal neurogenesis [191]. Moreover, additional research confirmedthat saikosaponin-D administration ameliorated LPSinduced depressive-like behaviors, as shown by increased
sucrose consumption in the SPT and decreased immobility time in the TST and FST. These performances appear
to be mediated by inhibition of microglial activation andregulation of the high mobility group box 1 (HMGB1)/
TLR4/NF-κB signaling pathway [190]. Gypenosides, themajor ingredients of Gynostemma pentaphyllum, exert
a neuroprotective function in the CNS. Treatment with
gypenosides (50, 100 mg/kg/day, p.o.) for 4 weeks significantly relieved depressive-like behaviors of CMS micein the TST and FST, which was mediated, in part, by
inhibiting microglial activation and NF-κB signaling andincreasing BDNF levels in the HIP [192, 193].
Ginsenosides are one of ginseng’s most biologically
active ingredients and have a triterpenoid glycosidestructure [194]. Direct and indirect evidence support
that some ginsenosides (such as ginsenoside Rg3, Rb1,
and Rg1) induce the anti-inflammatory actions of macrophages and microglia [195]. Ginsenoside Rb1 is atypical 20(S)-protopanaxadiol-type saponin and exerts
significant antidepressive effects in chronic stress models [73, 196, 197]. It is known that Rb1 regulates microglial activation, protects neurons from inflammatory
and oxidative damage, and promotes neurogenesis [198,Page 15 of 26199]. Recently, treatment with Rb1 (20 mg/kg/d, p.o.)in CMS-treated mice for consecutive 4 weeks alleviated depressive-like behaviors in the SPT, TST, and FST
mainly through PPARγ-mediated transitions in microglial phenotype (TNF-α, IL-1β, TGF-β, and Arg-1) inthe HIP and cortex [73]. Rb1 attenuated a decrease in
BDNF and the ratio of p-AKT/AKT expression, andincreased IL-1β, TNF-α, and Iba-1 levels in the HIP in
a CRS model. In line with in vivo reports, Rb1 lowered
the protein expressions of IL-1β and TNF-α in BV-2
cells [197]. In addition to Rb1, ginsenoside Rg1 and Rg3
exhibited potential anti-inflammatory effects, which
protected against microglial activation in stress-injured
rodents [200, 201]. A previous study reported thatchronic pretreatment with ginsenoside Rg1 (40 mg/kg/d,i.p.) for 5 weeks significantly suppressed inflammatory
responses by alleviating microglial and astrocyte activation through decreased overexpression of IL-1β, IFN-γ,
and TNF-α. These effects were accompanied by attenuation of dendritic spine and synaptic defects, and upregulation of synaptic-related proteins in the ventral medial
prefrontal cortex (vmPFC). Ginsenoside Rg1 inhibitedneuronal apoptosis by increasing Bcl-2 and decreasing cleaved caspase-3 and caspase-9 expressions after
CMS exposure. Furthermore, ginsenoside Rg1 increased
the nuclear factor erythroid 2-related factor (Nrf2) andinhibited p38 mitogen-activated protein kinase (p-p38
MAPK) and p65-NF-κB activation in the vmPFC [200].
Moreover, ginsenoside Rg3 at oral doses of 20 and 30 mg/
kg attenuated upregulation of TNF-α, IL-1β, and IL-6
mRNA expression in brains of C57BL/6 mice after systemic LPS injection. Morphological activation of microglia, and Iba-1, cyclooxygenase-2 (COX-2), iNOS protein
expression was reduced with Rg3 treatment [201]. Our
previous studies also found that ginsenosides Rd and Re(10, 20, or 40 mg/kg, p.o.) have potentially neuroprotective and anti-inflammatory properties, as manifested bysignificantly reducing the expression of hippocampal
pro-inflammatory factors and NLRP3 inflammasome
related protein, as well as enhancing endogenous antioxidant factor Nrf2, and mediating PI3K-AKT and BDNF
signaling pathways in mice exposed to CRS [129, 202].
Taken together, the anti-inflammatory effects of ginsenosides have been confirmed, and the negative regulationof pro-inflammatory cytokines and enzymes has beenfound to underlie the anti-inflammatory properties ofginsenosides in pro-inflammatory microglia in depression. However, additional studies are needed to investigate whether other ginsenosides or their metabolites canrelieve depressive symptoms through modulating microglial phenotype and the molecular mechanisms involvedin neuroinflammation.

Wang et al. Journal of Neuroinflammation(2022) 19:132

Iridoid glycosides

Catalpol, an iridoid glucoside, is primarily isolated from
Radix rehmannia and is commonly used as a traditional
Chinese medicine [203]. Previous studies have beenreported that catalpol exhibits a wide range of pharmacological effects, including exhibiting anti-diabetic,
anti-tumor, anti-inflammatory, and antioxidant activities. Growing evidence indicates that catalpol has arobust antidepressant effect that acts through its antiinflammatory and anti-oxidative properties in vitro andin vivo [203, 204]. Catalpol (5, 10, or 20 mg/kg/day, i.g.)
administration for 5 weeks ameliorated CMS-induced
depressive-like behavior in the SPT, and its underlying
mechanisms might be at least partially ascribed to reducing HPA axis dysfunction, upregulating BDNF and its
specific binding receptor tyrosine kinase B (TrkB), downregulating COX-2 expression, thus reducing prostaglandin E2 level in the brain [204]. It was also confirmed thatcatalpol at 20 mg/kg decreased the expression of NLRP3
inflammasome-associated proteins and inhibited proinflammatory microglial polarization in the HIP (IL-1β,
TNF-α, and iNOS) [205]. Geniposide, a type of iridoid
glycoside extracted from the ripe fruit of Gardenia jasminoides Ellis, exhibits numerous bioactivities, including anti-diabetic, anti-oxidative, and anti-inflammatory
actions [206]. It has been demonstrated that administration of geniposide (10, 40 mg/kg/day, p.o.) for 1 or
3 weeks ameliorated LPS- and CMS-induced depressivelike behavior in the SPT, TST, and FST by regulating theBruton’s tyrosine kinase (BTK)/TLR4/NF-κB, BDNF/
TrkB, and BTK/JAK2/STAT1 signaling pathways [207,208]. Also, the beneficial effect of geniposide on anxiety- and depressive-like behaviors in mice may possibly
act through induction of microglial polarization towards
anti-inflammatory phenotype and inhibition of IL-6 andTNF-α release [208].
Phenylpropanoids

Arctigenin and its glycoside, arctiin, are the major active
ingredients of the dried ripe fruit of Arctiumlappa L.
Arctiin can be metabolized into arctigenin by humanintestinal microflora after oral consumption [209]. Arctiin has antidepressive effects that appear to act throughinhibition of the NF-κB mediated HMGB1/TLR4 andTNF-α/TNF receptor 1 (TNFR1) pathways, which consequently attenuated microglial activation and neuroinflammation [210]. Similarly, arctigenin showed
antidepressive effects by inhibiting microglial activationand neuroinflammation via HMGB1/TLR4/NF-κB andTNF-α/TNFR1/NF-κB signaling pathways [171]. Salvianolic acid B (SalB) is one of the phenolic acid compounds
derived from Salvia miltiorrhiza, which has various
pharmacological effects, including anti-inflammatory,

Page 16 of 26

antioxidant, and anti-apoptotic [211, 212]. CMS micetreated with SalB (20 mg/kg/day, i.p.) for 3 weeks significantly reversed decreased sucrose preference index in
the SPT and increased immobility time in the FST and
TST. In addition, the decreased expression of IL-1β and
TNF-α and increased expression of IL-10 and TGF-β
were accompanied by increased apoptosis (cleaved-caspase ­3+) and microglial activation (Iba-1+) in the HIP
and cortex that were reversed after SalB treatment [213].
Curcumin is a representative natural phenolic compoundof turmeric and a potential candidate for regulation ofbrain function due to its antioxidant and anti-inflammatory properties. In a CRS model, systemic administrationof curcumin (10, 20, or 30 mg/kg, i.p.) daily for 3 weeks
significantly attenuated oxidative stress and lipid peroxidation, prevented apoptosis, and increased antioxidant
defense activity [214]. Curcumin (10 mg/kg, i.p.) also wasbeneficial for maintaining improved memory and moodfunctions after 30 days of daily therapy in a Gulf War Illness (GWI) with stress-treatment model. At the molecular level, enhanced numbers of D
­ CX+ cells, decreased+
numbers of Iba-1/ED-1 cells, and elevated antioxidant
genes with normalized mitochondrial respiration might
be the basis of the regulatory mechanism that is mediatedby curcumin treatment [215]. Magnolol, a hydroxylated
biphenyl compound extracted from Magnolia tree, hasendothelial cell protective, antioxidant, and anti-inflammatory functions [216]. It is noteworthy that magnolol
exhibits antidepressant effects, as evident by increased
sucrose consumption and decreased the immobility timein the SPT, TST, and FST. In an OBX model, magnolol(50, 100 mg/kg/day, p.o.) treatment for 2 weeks produced
antidepressant-like effects by enhancing neurogenesis(as indicated by BrdU positive cells) in the HIP [217]. In
a CMS model, treatment with magnolol (20, 40 mg/kg/
day, p.o.) for 4 weeks increased BDNF expression andnormalized serotonergic system [218]. In agreement withprevious studies, the protective effect of magnolol (50,
100 mg/kg/day, p.o.) given for 3 weeks to CMS-treatedfemale mice also appeared to be associated with inhibition of pro-inflammatory microglia (TNF-α, IL-1β, andIL-6) and activation of anti-inflammatory microglia (IL-4,
IL-10, Arg1, Ym1, Fizz1, and Klf4) via Nrf2/hemeoxygenase (HO-1)/NLRP3 signaling pathway [219].
OthersResveratrol is one of the most well-known dietary stilbenoids. Resveratrol confers health benefits due to its
antioxidant, anti-inflammatory, anti-aging, and immuneregulatory activities [220]. Resveratrol is found in theskin of red grapes, peanuts, and other medicinal plants.
Recent studies have found that resveratrol ameliorated
depressive-like behaviors in several animal models

Wang et al. Journal of Neuroinflammation(2022) 19:132[221–223]. In a LPS model, mice were treated for 2 weeks
with resveratrol (20 mg/kg/day, i.p.), which abrogated
the increased immobility in the FST and TST. Immunohistochemical staining revealed that resveratrol reversed
increased microglial activation (Iba-1+) and inhibition ofneurogenesis (BrdU/DCX+) in the DG [224]. Moreover,
3 doses of resveratrol (20 mg/kg/day, i.p.) promoted theactivation of sirtuin type 1 and blocked the decline ofhippocampal neurogenesis triggered by ethanol exposure
during early postnatal life [225]. The carotenoids crocin
was able to regulate microglial activation associated withneurological disorders. Crocin decreased the expression of LPS-induced NO, TNF-α, and ROS productionin BV-2 cells and improved locomotor activity, sucrose
intake, and reduced immobility time in LPS-treated Kunming mice [226]. The health benefits associated withcrocin might be due to its potent ability to regulate the
NLRP3 inflammasome and NF-κB, as well as anti-inflammatory phenotypic conversion [226]. Moreover, emerging data have shown that plant-derived compounds canexert neuroprotective effects that prevent neurologicaldisorders in depression. For instance, ganoderic acid A[227], asperosaponin VI [228], 20(S)-protopanaxadiol[229], scutellarin [230], astragalin [231], hesperidin [232],
5-O-methylvisammioside [233], ginkgolide B [234],
leonurine [235], ferulic acid [236], and (+)-sesamin [69]were found to inactivate microglia in stress-induced
depression models. Recent information concerning theantidepressant activity of phytochemicals through regulation of microglial polarization is illustrated in Table 2.
In addition, several herbal extracts and traditional formulations reported to improve depression-like behavior by
regulating microglia are shown in Table 2 [237–245].

Conclusions
This review has summarized the current knowledge
regarding microglial activation in depression as seen inclinical and preclinical studies. Microglia are the primaryresident immune cells that are currently considered asa critical link between neurological and immunologicalactivity in the CNS [247]. These cells modulate neuronal
function not only during an inflammatory response, butalso during developmental synaptic pruning and plasticity in healthy brains [27]. The heterogeneous statesof activated microglia exist on a continuum ranging
from neuroprotection to neurotoxic/pathogenic activity (Figs. 1 and 2) [248]. In this review, we summarized
microglial activation in depressed patients and animalmodels (Additional file 1: Table S1), as well as the possible mechanisms associated with the pathogenesis of
MDD (Fig. 4). Moreover, we described the therapeuticrole of traditional antidepressants and phytochemicals instress-induced depression models (Tables 1 and 2).

Page 17 of 26

Recently, natural compounds have been considered to
be potential agents for the prevention or treatment ofneuropsychiatric diseases due, in part, to their antioxidant and anti-inflammatory activities [249]. Numerous
studies have shown that natural compounds and formulations are beneficial in the treatment of depression
through their ability to regulate microglial functions, as
listed in Table 2. The chemical structures of these bioactive compounds are highlighted in Fig. 5. Most compounds have been shown to modulate inflammatory
response, oxidative stress, and ameliorate symptoms
of depression through inhibiting microglial activation.
However, additional research is needed to determine
whether these compounds promote the transformationof microglia with a pro-inflammatory phenotype to ananti-inflammatory phenotype, or whether they dependon regulation of downstream signaling pathways that are
activated by microglia. In a pathological state, changes in
microglial phenotypes depend on the disease stage andseverity. Therefore, developing protocols that control
the stage-specific conversion of pro-inflammatory/antiinflammatory actions in appropriate time frames mightprovide better therapeutic outcomes. Thus, changing
the activity of microglia to a stable state through pharmacological or non-pharmacological methods will be
the focus of future research, which also may provide newideas for targeted treatment of depression. Moreover, it
has been shown that some polyphenolic compounds are
not completely absorbed via the gastrointestinal tract but
still possess anti-inflammatory actions due to metabolites
that are produced by intestinal microflora [250]. However, information concerning the role of these activatedmetabolites through microglia regulation is still minimal.
Therefore, the discovery of potential inhibitors against
microglial activation from metabolites may also be
another promising strategy for the prevention of depression in the future.
In addition, data primarily obtained from studies thatused specific microglial manipulation methods help
improve our understanding of the mechanisms underlying neurogenesis, inflammation, and neurotransmitter metabolism dysfunction in depression. Genetic andpharmacological methods that directly or indirectly
modify the activation status of microglia have been used
and achieved some success, such as the Cx3cr1−/− orCd200-deficient mouse models and the minocycline or
PLX4497 treatment models [75, 251]. Moreover, it should
be noted that the dichotomy of microglial activation
states (M1/M2) is an oversimplified conceptual framework. This dichotomy is not generally accepted as it may
not accurately reflect the heterogeneous microglial profiles that can be observed in complicated homeostatic or
disease conditions [252–254]. The spatial and temporal

Wang et al. Journal of Neuroinflammation(2022) 19:132

Page 18 of 26

Fig. 4 Schematic diagram of microglial activation involved in the pathogenesis of depression. Dysfunction of neuron–microglia interactions,particularly the CX3CL1-CX3CR1 and CD200-CD200R interactions, lead to behavioral and biochemical alterations. In addition, the most relevantmarkers of the NLRP3 inflammasome and neurogenesis used in the reviewed studies are indicated. We also included the generation of neuroactive
kynurenine metabolites in depression disorders

distribution of microglial subsets can be better assessedusing newly developed unbiased and high-throughput
methods. Novel single-cell techniques enable scientists
to overcome such limitations and reveal the surprisingcontext-dependent heterogeneity of microglia [247, 255].
Specific subsets and key targets of microglia have been
revealed in the development of AD and regulators suchas TREM2 that control disease severity has been identified [42]. Currently, advanced technologies and tools
are being used to comprehensively decipher the role ofmicroglial heterogeneity in the pathology of depression,
particularly in the modulation, inhibition, and stimulation of contextually relevant microglia functions. These
technologies also are being used to target microglia to
explore the treatment of neuropsychiatric diseases, which
remains to be explored further.

Taken together, the data analyzed in this review suggest that microglial changes mainly affect the regulation of inflammatory response, neurogenesis, andtryptophan metabolism with respect to the development of depression. However, other factors should not
be ignored. The discovery of natural compounds thatexert antidepressant effects by inhibiting microglial
activation may contribute to the effectiveness of preventing and treating depression. Additional information regarding the neuroprotective properties of thesecompounds that act through the regulation of microglial phenotypes remains to be explored in the future.
High-performance omics technologies are expected toprovide more effective molecular targets and identify
additional specific signaling pathways in drug screening
and disease diagnosis.

Wang et al. Journal of Neuroinflammation(2022) 19:132

Page 19 of 26

Fig. 5 Chemical structures of several plant-derived natural compounds that act as potential inhibitors of M1-type microglia activation in animalmodels of depression

Wang et al. Journal of Neuroinflammation(2022) 19:132

Abbreviations
MDD: Major depressive disorder; COVID-19: Coronavirus disease 2019; HPA:
Hypothalamus–pituitary–adrenal; CNS: Central nervous system; PFC: Prefrontal
cortex; HIP: Hippocampus; vHIP: Ventral hippocampus; BLA: Basolateral; SN:
Substantia nigra; NPC: Neural progenitor cell; OPC: Oligodendrocyte progenitor cell; CD86, CD16/32: Differentiation marker 86 and 16/32; iNOS: Inducible
nitric oxide synthase; Arg1: Arginase-1; TGF-β1: Transforming growth factor-β1;
BDNF: Brain-derived neurotrophic factor; DAM: Disease-associated microglia;
PAMPs: Pathogen-associated molecular patterns; DAMPs: Danger-associatedmolecular patterns; TLRs: Toll-like receptors; LPS: Lipopolysaccharide; IFN-γ:Interferon-γ; IL-1β: Interleukin-1β; TNF-α: Tumor necrosis factor-α; ROS: Reactive oxygen species; ACC​: Anterior cingulate cortex; QUIN: Quinolinic acid;
PET: Positron emission tomography; Iba-1: Ionized calcium-binding adapter
molecule 1; CMS: Chronic mild stress; CSDS: Chronic social defeat stress; CRS:
Chronic restraint stress; OBX: Olfactory bulbectomy; LH: Learned helplessness;
NLRP3: Nod-like receptor pyrin containing 3; NF-κB: Nuclear factor-kappa B;
SPT: Sucrose preference test; FST: Forced swimming test; TST: Tail suspension
test; LD: Light–dark; SIT: Social interaction test; NORT: Novel object recognition
test; AD: Alzheimer’s disease; SGZ/GCL: Subgranular zone/granule cell layer;
CWIRS: Chronic water-immersion restraint stress; NMDAR: N-Methyl-d-aspartate receptor; SYP: Synaptophysin; PSD95: Postsynaptic densitin-95; SSRIs:
Selective serotonin reuptake inhibitors; TCAs: Tricyclic antidepressants; TRP:
Tryptophan; KP: Kynurenine pathway; KYNA: Kynurenic acid; 3-HK: 3-Hydroxykynurenine; KYN: Kynurenine; NSFT: NOvelty suppressed feeding test; ST:
Splash test; IDO1: Enzyme indoleamine 2, 3-dioxygenase 1; PSD: Poststroke
depression; BDNF: Brain-derived neurotrophic factor; HAAO: 3-Hydroxyanthranilate 3, 4-dioxygenase; NAc: Nucleus accumbens; LTP: Long-term potentiation; PPARγ: Peroxisome proliferator-activated receptor γ; NSE: Neuron-specificenolase; vmPFC: Ventral medial prefrontal cortex; COX-2: Cyclooxygenase-2;
TrkB: Tyrosine kinase B; BTK: Bruton’s tyrosine kinase; HMGB1: High mobility
group box 1; TNFR1: TNF receptor 1; SalB: Salvianolic acid B; GWI: Gulf war
illness.

Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s12974-​022-​02492-0.
Additional file 1: Table S1. The animal models of depression involving
microglial changes.
Acknowledgements
The authors would like to thank the Hotchkiss Brain Institute, the National
Clinical Research Center for Mental Disorders & Beijing Key Laboratory of
Mental Disorders, Beijing Anding Hospital, Capital Medical University, andNatural Sciences and others for their financial contributions. The authors haveno competing financial interests with respect to the work described here. All
figures were generated with BioRender and ChemDraw.
Author contributions
All authors participated in writing the manuscript. All authors read andapproved the final manuscript.
Funding
This work was supported by the Beijing Young Top-Notch Talent Support
project (2018000021223ZK36), Beijing Talents Project (2020A38), Beijing Hospitals Authority Youth Programme (QML20181901), National Natural Science
Foundation of China (82171526 and 31970918), Beijing Biobank of ClinicalResources-Mental Disorders (BBCR-MD), and Beijing Municipal Administrationof Hospitals Incubating Program (PX2018065).
Availability of data and materials
Not applicable.

Declarations
Ethics approval and consent to participate
Not applicable.

Page 20 of 26

Consent for publication
Not applicable.
Competing interests
The authors declare that they have no conflicts of interest.
Author details
1
The National Clinical Research Center for Mental Disorders and Beijing Key
Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, 5 Ankang Lane, Dewai Avenue, Xicheng District, Beijing 100088, China.
2
Advanced Innovation Center for Human Brain Protection, Capital Medical
University, 10 Xi tou tiao, You An Men Wai, Fengtai District, Beijing 100069,
China.
Received: 15 March 2022 Accepted: 18 May 2022

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