(2021) 18:258
Woodburn et al. J Neuroinflammation
https://doi.org/10.1186/s12974-021-02309-6

Open Access

REVIEW

The semantics of microglia activation:neuroinflammation, homeostasis, and stress
Samuel C. Woodburn, Justin L. Bollinger and Eric S. Wohleb*

Abstract
Microglia are emerging as critical regulators of neuronal function and behavior in nearly every area of neuroscience.
Initial reports focused on classical immune functions of microglia in pathological contexts, however, immunological concepts from these studies have been applied to describe neuro-immune interactions in the absence of disease, injury, or infection. Indeed, terms such as ‘microglia activation’ or ‘neuroinflammation’ are used ubiquitously todescribe changes in neuro-immune function in disparate contexts; particularly in stress research, where these terms
prompt undue comparisons to pathological conditions. This creates a barrier for investigators new to neuro-immunology and ultimately hinders our understanding of stress effects on microglia. As more studies seek to understand therole of microglia in neurobiology and behavior, it is increasingly important to develop standard methods to study anddefine microglial phenotype and function. In this review, we summarize primary research on the role of microglia inpathological and physiological contexts. Further, we propose a framework to better describe changes in microglia1
phenotype and function in chronic stress. This approach will enable more precise characterization of microglia in different contexts, which should facilitate development of microglia-directed therapeutics in psychiatric and neurological disease.
Keywords: Microglia, Inflammation, Homeostasis, Stress, Parainflammation, Depression
BackgroundIn the early 1900s, Pío del Río-Hortega described a new
type of phagocytic brain cell, of mesodermal origin, thathe termed “microglia” [1–3]. Decades later, microglia
were recognized as macrophages, evidenced by morphological similarities to peripheral macrophages and theirrecognition by antisera against common monocyte markers [4–7]. Still, microglia are unique among macrophages.
Unlike their fetal liver or bone marrow-derived relatives,
microglia arise from embryonic yolk sack progenitorsand maintain transcriptional and functional identities
distinguishing them from other macrophages which may
infiltrate the brain under pathological conditions [8–15]. As such, microglia are considered brain-resident*Correspondence: eric.wohleb@uc.edu
Department of Pharmacology & Systems Physiology, Universityof Cincinnati College of Medicine, Cincinnati, OH, USA

macrophages and are uniquely suited to regulate neuralhomeostasis and behavior. In particular, recent studies
indicate that microglia can modulate neuronal activity,
facilitate learning, and shape social behavior [16–24].
The underappreciated role of microglia in physiologicalconditions contrasts earlier work, which mainly focusedon microglial function in pathological contexts such as
injury and disease, where neuronal death or degeneration
is observed [25, 26]. These initial studies characterizedneuro-immune responses in such contexts and clearly
defined the term “neuroinflammation,” which was guided
by four primary features of peripheral inflammation:
macrophage (microglial) activation, increased cytokinesand chemokines, recruitment of peripheral immune cells,
and local tissue damage [25, 27]. These studies also demonstrated that microglia and peripheral immune cells
have dual roles: driving neuroinflammation and subsequent pathology, as well as resolving neuroinflammation© The Author(s) 2021. 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
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Woodburn et al. J Neuroinflammation(2021) 18:258

and repairing the nervous system [28, 29]. Adding to thecomplexity of neuro-immune systems, these roles do not
likely represent discrete functional states in vivo. Indeed,
there is ample evidence that inflammation simultaneously
drives tissue damage and repair [25, 30–33]. Nonetheless, these functions collectively represent various facetsof microglia activation, which is classically identified bysubstantial increases in cytokine production, the adoption of an amoeboid morphology, and changes in relevant
protein markers (Fig. 1.) [34–37]. It should be noted that
there is ongoing refinement of approaches to characterize macrophage/microglia activation [for a comprehensive overview, see: [25, 30, 32, 33]. There are limitations
to these definitions because biological systems do not fit
cleanly into well-defined categories. As a result, terms
such as “microglia activation” and “neuroinflammation”
have broadened over the years to include most immunerelated processes in the nervous system. While this has
occurred in multiple areas of study, this review will focus
on the functional states of microglia and their contributions to the neurobiology of stress.
Accumulating evidence indicates that microglia playa role in the synaptic and behavioral changes associatedwith chronic stress [38, 39]. However, there remain fundamental issues in the conceptual framework used toPage 2 of 16

integrate immunological concepts with stress research.
Indeed, the language used to study peripheral macrophages in the context of infection is not adequate todescribe microglial function in chronic stress; especiallyconsidering the vast biological differences between thesetwo contexts. Despite this, researchers often use theterm “neuroinflammation” to describe immune-relatedchanges caused by chronic stress, which prompts comparisons to tissue injury or disease states and ultimately
hinders our understanding of stress effects on microglia.
This is significant because preclinical stress models areoften used to gain insight into the neurobiology of psychiatric disorders. Thus, simplifying the role of microglia and neuro-immune systems in these models maylead to spurious therapeutic targets that ultimately hinder further clinical research. As advanced approaches(e.g., single cell RNA-Seq) improve our understanding of
microglial phenotypes and functions, it is important todefine specific features of microglia across model systems
and disease states. This will increase the likelihood thatcongruent molecular and cellular pathways will be identified, which may facilitate the development of therapeutic approaches targeting microglia. In this review, we will
discuss microglial functions in pathological and homeostatic conditions; as well as highlight the need to refineFig. 1 Phenotypic distinctions between homeostatic and “activated” microglia. Under typical conditions (A), microglia display a ramified
morphology and a unique pattern of gene expression, making them identifiable through a number of different techniques. However, a variety of
immunogenic stimuli can elicit dramatic morphological and functional changes in microglia. Immunologically activated microglia (B) possess anamoeboid morphology; marked by increased soma size and less ramified processes. Markers for microglia activation vary widely depending on
the type and severity of insult, but surface proteins associated with classical immune functions (e.g., antigen presentation, phagocytosis) tend to
be increased, while those associated with homeostasis may be reduced. Functions of activated microglia are also highly variable, with the same
cells potentially driving tissue damage and repair processes simultaneously. Morphological features may not correspond to assumed functionalroles. Nonetheless, classical immune functions of activated microglia include phagocytosing cellular debris, large increases in cytokine signaling,
recruitment of peripheral immune cells to the parenchyma, and destroying infected or dying cells

Woodburn et al. J Neuroinflammation(2021) 18:258

terms used to describe microglia in different contexts.
Moreover, we propose an alternative framework in which
neuron–microglia interactions coordinate neurobiological adaptations to stress, congruent with an immune state
called ‘parainflammation’ (not neuroinflammation).
Microglia in inflammatory contexts

Inflammation is triggered by immunogenic stimuli (i.e.,pathogens or tissue injury), resulting in various biochemical cascades aimed at resolving these threats to homeostasis. Consequently, tissue damage and repair processes
are enhanced during inflammation, often in tandem, until
it resolves through complex regulatory mechanisms. In
the brain, neuroinflammation manifests as elevated levelsof pro-inflammatory cytokines, macrophage (microglia)
activation, peripheral leukocyte infiltration, and damage
to nervous tissue [25]. Although it is becoming increasingly clear that neuro-immune interactions play a role inmost facets of brain function, it is typically under circumstances of disease, injury, and infection that all four ofthese hallmarks are present [27, 40]. In high enough concentrations (i.e., during neuroinflammation), immunogenic molecules can “activate” microglia, causing them toadopt an amoeboid morphology, and drastically increase
their production of cytokines and reactive oxygen species (ROS). However these functional changes vary basedon the type of stimuli and severity of insult [41]. Thus, inorder to understand microglial function in a disease context, it is important to appreciate the intricacies of neuroinflammation. To this end, we will discuss a few examplesof microglial function in neuroinflammatory contexts.
Multiple sclerosis and experimental autoimmune
encephalomyelitis

Microglia activation is observed in various central
nervous system (CNS) diseases and is important for
coordinating the immune system’s resources during disease-associated neuroinflammation. For example, activated microglia are the main phagocytes observed inearly stage multiple sclerosis (MS) lesions. This changes
over time, with recruited bone marrow-derived macrophages taking over as the lesion advances [42, 43]. Further insights come from mouse hepatitis virus (MHV)
infection, which causes demyelinating disease in models
of experimental autoimmune encephalomyelitis (EAE).
Early after MHV infection, microglia increase expressionof cytokines which suppress viral infection and signal toadaptive immune cells [44, 45]. Ultimately, this contributes to T-cell and peripheral macrophage infiltration,
increased brain cytokine levels, and tissue damage; here
in the form of plaques or lesions where activated macrophages are believed to contribute to demyelination [45,46]. Recent studies demonstrate that the initial microglial

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response is a critical determinant of EAE severity.
Depleting microglia with the colony stimulating factor 1 receptor (CSF1R) antagonist PLX5622 prior to
MHV infection delayed virus clearance and was linked
to reduced infiltration and activation of C
­ D4+ T cells, aswell as decreased production of interferon gamma (IFNγ); a critical suppressor of viral replication [44, 47–49].
This dampened immune response was associated with an
80% increase in mortality [44, 47]. This is consistent withother studies reporting greater demyelination at peak disease and less remyelination during recovery in mice lacking microglia [47, 49, 50]. Thus, while microglia appear toplay a role in cytokine production and demyelination inthis model, it is evident that they also promote adaptive
immune responses and aid in processes to repair tissue in
EAE [45]. It remains to be seen whether microglial functions characterized in EAE precisely correspond to thoseoccurring in patients with MS [43]. Nonetheless, thiswork highlights the complexities of neuroinflammationand microglial phenotypes in disease.
Ischemic stroke

Microglia are often first responders to brain or nerve
injury. In fact, studies show that just minutes after
ischemic stroke, microglia adopt an amoeboid morphology, display enhanced isolectin B4 binding, and haveincreased levels of compliment receptor 3 (CR3, a.k.a.
CD11b) as well as major histocompatibility complex(MHC) I and II [51]. These activated microglia produce
high levels of TNFα, leading to endothelial necroptosis
and BBB destruction [52]. This secondary tissue damage may also contribute to the infiltration of peripheral monocytes in the brain parenchyma, where they
proliferate and gradually take over as the predominantphagocytes at the site of injury [53]. Both microglia andperipheral monocytes are involved with clearing debris
after stroke, which attenuates inflammation; however
they may also phagocytose injured yet viable neurons,leading to greater tissue damage [54–56]. While thesefindings indicate that microglia drive pathology in stroke,
there is evidence to suggest microglia also play a neuroprotective role. Mice lacking TREM2, a receptor highly
expressed by microglia and believed to play a role inphagocytosis, show exacerbated ischemic damage after
stroke [57]. Moreover, injured cells release high quantities of purines (ATP/ADP), which microglia detect andextend their processes toward via the purinergic receptor P2Y12 [58, 59]. Recent work showed that after stroke,neurons in the ischemic penumbra recruit microglial
processes through a P2Y12 dependent mechanism,
leading to the formation of an immunological synapse
between the two cells [17]. Notably, this was attenuatedin P2Y12 knockout mice and coincided with increased

Woodburn et al. J Neuroinflammation(2021) 18:258

neuronal calcium load, disrupted cortical network function, and greater area of ischemia-induced disconnection[17]. Altogether these findings show that microglia have
dual roles in driving the pathological hallmarks of neuroinflammation and preserving and repairing damaged tissue in stroke [60].
Alzheimer’s disease

Numerous studies demonstrate that microglia and neuroinflammation play a role in the pathogenesis of Alzheimer’s disease (AD). Genome-wide association studies
have suggested that individuals with variants of immune
genes such as CD33 and TREM2 are at greater risk ofdeveloping AD, and single-cell RNA sequencing studies suggest that immunologically activated microglia arepresent in both animal models of AD and tissue fromAD patients [61–65]. Additionally, studies in human tissue found increased trafficking of peripheral leukocytes
in brain tissue from AD patients, suggesting blood–brain
barrier (BBB) decline and immune-driven pathology
in AD [66–68]. In line with this, 5 × and 3 × FAD mice,
which overexpress human mutations associated withfamilial AD, show increased neutrophil extravasation into
the parenchyma at sites of amyloid beta (Aβ) plaques,
where they release extracellular traps and IL-17. Importantly, depleting neutrophils reduced Aβ42 levels andwas associated with better cognitive outcomes, suggesting that neutrophils play a role in AD pathogenesis [66].
Collectively, these studies point to neuroinflammation
as a contributing factor in AD, however the precise roleof microglia in AD is more complicated [69]. As mentioned above, mutations affecting TREM2 function arerisk factors for AD, and importantly, TREM2 is involvedin Aβ clearance by microglia [70, 71]. Further, stimulating microglia proliferation via TREM2 agonism in miceengineered to express one of these human polymorphisms, led to decreased plaque load and neuronal dystrophy, suggesting that stimulating immune function
from microglia may be beneficial in AD [72]. This is inline with recent work which identified a subtype of disease-associated microglia (DAM), which are associatedwith Aβ plaques and promote their clearance througha mechanism involving TREM2 [73]. Thus, rather than
suppressing immune function altogether, it may be usefulto promote selective microglia responses to help restore
homeostasis [74]. In contrast, other work suggests thatmicroglia release Aβ and tau “seeds”, which exacerbate
AD progression [75, 76]. Given these complexities, additional research will be required to fully appreciate therole of microglia in AD.

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Meningitis

In cases of CNS infection, neuroinflammation caused by
microglia activation is critical for detecting and eliminating pathogens, but is not without consequence [77]. For
instance, bacterial infection of the subarachnoid spacecauses astrocytes, endothelia, and microglia to secrete
large amounts of pro-inflammatory cytokines, including
tumor necrosis factor alpha (TNF-α), interleukin 1 beta
(IL-1β), and interleukin 6 (IL-6), which drive inflammation in the meninges [78]. These cytokines also activate
endothelial integrins and stimulate chemokine secretion, promoting peripheral leukocyte recruitment [79,80]. Further, Streptococcal pneumonia, the microorganism most commonly associated with bacterial meningitis, can penetrate the blood–brain barrier (BBB), andmicroglia react directly to the bacterium’s cell wall in
the parenchyma [79, 81]. In vitro models and rodent
studies show that components of the pneumococcal cellwall cause microglia to produce nitric oxide, as well as avariety of different cytokines and chemokines, increasing leukocyte extravasation to the parenchyma [79, 82].
This leads to a predicament where on one hand, invading
pathogens will trigger apoptosis via bacterial exotoxins,
ultimately resulting in death [83, 84]. On the other hand,
neuroinflammation caused by cytokines and ROS fromthe immune system can stop infection, but at the cost of
associated tissue damage [78].
Peripheral infection

Exposure to pathogens in peripheral tissue elicits neuroimmune signaling and microglia responses that are
drastically different from CNS infection. In preclinical models, viral (i.e., poly-IC) or bacterial components(i.e., lipopolysaccharide; LPS) are used to mimic peripheral infection and study associated neuro-immune
interactions. This work shows that immune cells (often
tissue-resident macrophages) in peripheral tissues initiate pro-inflammatory signaling cascades that affect otherimmune mediators. In particular, circulating cytokines
promote IL-1β secretion from macrophages in circumventricular organs, as well as perivascular macrophages
and endothelia of the neurovasculature. These proinflammatory signals are transmitted to and propagatedby microglia in the parenchyma. [85–87]. These microglia responses mediate important physiological (e.g.,
fever) and behavioral (e.g., lethargy) components of sickness that promote survival [88]. This form of microglial
activation is transient and occurs without causing overt
neuropathology [41, 88–92]. Recent reports indicatethat peripheral administration of LPS can cause transient BBB disruption and microbleeds in the brain [90,92]. These neuro-immune interactions may contributeto the observed changes in inflammatory mediators inWoodburn et al. J Neuroinflammation(2021) 18:258

the brain, but further studies are needed to define thesemechanisms. It is important to emphasize that peripheral infection alters microglia function indirectly, as viral(i.e., poly-IC) or bacterial components (i.e., lipopolysaccharide; LPS) do not typically reach the brain parenchyma, and that effects of LPS will vary depending on
the route of administration, dose, and duration of exposure [93]. Thus, studies using immune challenges, suchas LPS, need to consider how neuro-immune pathways(e.g., vagus nerve; endothelial cells) transmit immune signals to microglia and the brain, and whether peripheral
inflammation in these models truly drives neuroinflammation as well.
Microglia in non‑inflammatory contexts

Foundational to the idea of discrete macrophage activation states is the notion that these cells show limited
activity or exist in a “resting” state prior to activation.
Keeping with this, many studies note morphologicalshifts between the complex ramifications protrudingfrom “resting” microglia in homeostasis and that of reactive or “amoeboid” microglia seen in diseased tissue [34,35]. However, by focusing on microglia in the context of
disease, these studies overlooked the dynamic nature of
microglia in homeostasis. Seminal work utilized in vivo
two-photon imaging in transgenic mice expressing EGFP
driven by the Cx3cr1 promoter to investigate microglial function under baseline conditions [94, 95]. Thesestudies demonstrated that microglia display nearly constant movement, with their processes undergoing cycles
of extension and retraction as they survey the extracellular space [94]. Further, the authors noted that neuronal
activity appeared to influence process motility, and thatmany microglial processes contained pieces of phagocytized material which were gradually transported to the cellbody. Thus, instead of quiescent cells in a “resting” state,
this work demonstrated that microglia are constantly
surveilling and utilize processes associated with immune
activation (i.e., phagocytosis) in physiological conditions.
Further studies elaborated on this work and demonstrated that microglia are actively involved in neurodevelopment. In early development, neurons establish
many more synaptic contacts than persist in a mature
brain. As these young neurons send and receive signals
to each other, synapses lacking sufficient input are gradually pruned while more active synapses are maintained[96, 97]. Interestingly, work by Stevens et al. showed thatinactive projections from retinal ganglion cells (RGC) inthe dorsal lateral geniculate nucleus (dLGN) were pruned
in a complement-dependent manner [98]. In the periphery, the complement system comprised freely circulating
proteins that, when bound to pathogens, trigger a signaling cascade which enhances the ability of macrophages toPage 5 of 16

detect and phagocytose those pathogens [99–102]. Laterwork by Schafer et al. demonstrated that microglia mediate engulfment of inactive RGC projections within thedeveloping LGN in a complement- and activity-dependent manner, which allowed for typical circuit development [103].
A number of mechanisms have been shown to guidemicroglia-mediated synaptic pruning, with inhibition ofthese pathways linked to atypical behavioral phenotypes[22, 104–106]. For example, mice lacking either TREM2or CX3CR1, both receptors highly expressed by microglia, show impaired synaptic pruning during development [107]. Consequently, mice lacking either of thesereceptors exhibit altered brain connectivity and deficits
in social behavior in adulthood. Additional studies evenshow compromised LTP alongside deficits in contextual fear conditioning and spatial learning memory in
CX3CR1-deficient mice. [24, 108, 109]. Expanding onthese developmental studies, recent work suggests thatthe complement system regulates microglial phagocytosis of synapses in the adult hippocampus and contributes to forgetting [110]. Meanwhile other experiments
indicate that microglial phagocytosis of the extracellularmatrix around hippocampal neurons promotes memory
consolidation via a mechanism dependent on neuronderived IL-33. Collectively these findings indicate thatmicroglial phagocytosis is not only triggered by pathogens or injury, but it is critical for proper neurodevelopment and neuroplasticity as well.
A similar theme emerges in work examining purine(e.g., ATP/ADP)-mediated chemotaxis by microglia.
Accumulating evidence indicates that this process, traditionally associated with tissue damage (see previous
section), guides homeostatic neuron-microglia interactions [111]. Different labs have consistently shown that
stimulation of NMDA receptors on highly active neurons causes them to release ATP/ADP into the extracellular space, which is detected by microglial P2Y12
receptors [19, 105, 112–114]. Upon binding extracellularpurines, ­Gi coupled P2Y12 receptors promote extensionof microglial processes toward activated neurons [17, 18,115, 116]. Studies examining neuron-microglia interactions in the visual cortex showed that visual experiencecaused microglia to interact with dendritic spines of V1
neurons, and that depriving animals of light during visual
critical periods increased their phagocytosis of neuronalmaterial [117]. This was driven in part by P2Y12 signaling, as disrupting P2Y12 during monocular deprivation
limited microglial remodeling of V1 synapses, which inturn abrogated typical ocular dominance [105]. Interestingly, recent studies show that this process is opposedby noradrenergic signaling, as β2-adrenergic receptors
on microglia were shown to limit experience-dependentWoodburn et al. J Neuroinflammation(2021) 18:258

plasticity in awake mice by inhibiting microglial surveillance [118].
Beyond guiding neuroplasticity, convergence of microglia processes toward active neurons is implicated inregulating neuronal activity through physical contact.
For example, microglia have been shown to rescue thesomatic potential of hyperactive neurons by physicallycontacting their axons, while pharmacologically inhibiting microglial detection of neuronal activity (and thus
limiting their contacts with neurons) is associated withincreased neuronal death [18]. Similarly, neuronal hyperexcitability induced by kainic acid provokes more severe
and more frequently lethal seizures in mice lacking
P2Y12 [19], further implicating microglia in regulatingneuronal excitability. Perhaps the most direct evidenceof this however comes from a recent study showing thatupon detection, microglia catabolize extracellular ATP
into adenosine, which in turn suppresses hyperactive
neurons by binding to the adenosine receptor A1R [119].
This inhibitory mechanism was crucial for attenuating seizure severity in mice treated with pro-convulsive
doses of a D1 agonist, demonstrating a protective role
for microglia. Taken together these studies suggest ATPmediated chemotaxis by microglia is not only important
for responding to injury, but also for maintaining brain
homeostasis by limiting pathological neural activity.
Another function of activated macrophages is secretion of growth factors and cytokines. This too has been
observed in microglia absent neuroinflammation. For
example, Parkhurst et al. showed that microglial brainderived neurotrophic factor (BDNF) secretion was
important for synaptic integrity. In these studies, microglia-specific depletion of BDNF reduced cortical expression of certain glutamate receptors, which subsequently
altered NMDA and AMPA mEPSCs [20]. These deficits
in synaptic function ultimately translated to reduced
learning-associated spine growth and subsequent behavioral impairments in rotarod training, indicating thattrophic support from microglia is an important neurobiological component of learning. Cytokines are also
known to modulate synaptic plasticity under physiological conditions. Initial studies performed both in vivo andin acute hippocampal slices showed that Il1β transcript
was increased after LTP induction, and that applicationof IL-1 receptor antagonist (IL-1ra) interfered with LTP
maintenance [120]. Similarly, mice engineered to overexpress IL-1ra in the brain show learning deficits, reduced
GluA1/2 expression, and impaired BDNF signaling[121]. It should be noted that cytokine signaling is complex, and the same molecule might have entirely different effects depending on concentration, or the presenceof other cytokines [122]. Consistent with this, IL-1β hasa concentration-dependent relationship with LTP. Under

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physiological conditions, IL-1β concentrations are relatively low and can enhance LTP and improve recall of aconditioned stimulus. In contrast, when IL-1β concentrations are high (i.e., inflammation or aging), IL-1β impairs
LTP by acting at the synapse [123–125]. Other immune
factors such as TNFα, IL-10, CXCL16, and CX3CL1 havealso been implicated in LTP, with microglia acting either
as potential sources of, or the cells affected by these molecules [126–131]. While much work is needed to fully
appreciate microglial contributions to synaptic plasticity, these studies demonstrate the importance of neuroimmune interactions in homeostatic brain function.
Microglia in psychological stress: debatingneuroinflammation

Clinical and preclinical studies conducted over the past
two decades demonstrate that psychological stress influences various neuro-immune pathways [38, 132]. Early
work revealed that both acute and chronic stressors
increase levels of certain pro-inflammatory cytokines
such as IL-1β in the brain [133, 134]. Further studies specifically implicated microglia as the primary source of
these cytokines, and showed that chronic stress alteredmicroglial morphology [133, 135–138]. Collectively
these changes were considered evidence of microglia
activation, and therefore neuroinflammation, caused bypsychological stress. However, as outlined above, neuroinflammation is characterized by macrophage activation,
pro-inflammatory cytokine secretion, leukocyte recruitment, and tissue damage [25]. While there is good evidence that all four of these are present in conditions like
MS, AD, stroke, and bacterial meningitis, it is not clear if
the term neuroinflammation applies to stress-associatedneuro-immune functions.
Recall that the effects of pro-inflammatory cytokines
depend on other factors such as concentration [122].
During neuroinflammation, IL-1β and TNFα concentrations can reach hundreds or even thousands of times
higher than baseline levels, and promote cell death either
by directly triggering apoptotic pathways in target cells,or by enhancing other neuroinflammatory processes
associated with cellular damage [139–144]. While thereis evidence that stress exposure influences IL-1β and
TNFα levels, the magnitude of this effect is considerably
lower by comparison (< 10 times baseline) and occurs in
the absence of overt tissue pathology [41, 133, 135, 145,
146]. It should also be noted that outside the contexts of
injury and disease IL-1β and TNFα secretion in the brain
facilitates synaptic plasticity, which is critical in maintaining homeostasis [124, 131, 147, 148]. As such, modestchanges in pro-inflammatory cytokine expression may
not indicate neuroinflammation and could represent an
altogether different biological process.

Woodburn et al. J Neuroinflammation(2021) 18:258

A common finding reported in stress literature is thepresence of “activated” microglia. As mentioned in the
beginning of this review, the precise definition of macrophage activation is an area of ongoing debate and it is
not clear what precisely constitutes an “activated”, “resting”, or “alternatively activated” macrophage or microglia [25, 30, 32, 33]. In Fig. 1, we provide some common
features of microglia across immunogenic contexts, yeteven these come with a multitude of caveats, as featuresof “activated” microglia in one context may not appear inanother [34, 35, 37]. Further, as mentioned in the previous section, the idea of “activated” microglia presumes
they are quiescent under typical conditions, which is notsupported by recent data [149].
One of the common metrics to assess microglia activation are broad morphological shifts from small soma
with ramified processes in homeostasis, to amoeboid
with thicker and less complicated processes during neuroinflammation [36, 37]. Indeed initial reports indicatedthat stress caused microglia activation largely based onchanges in morphological features [136]. However, evidence suggests that morphological changes in microglia
do not define their functional state. Indeed microglia display dynamic and varied morphologies driven by local
cues and these features may not overlap with assumed
functions. For example, microglia in the developing subventricular zone and cortex display amoeboid morphology, yet the cytokines and growth factors they produce
are essential for neuronal growth and differentiation[150, 151]. Even within the context of chronic stress,changes in microglial morphology vary between brain
region, sex, species, stress paradigm, and stress duration,
without specific biological or behavioral implications[136, 152–156]. In this context, it is not accurate to suggest that morphological changes in microglia alone canprovide insight into their functional state. Moreover, it
should be noted that these morphological analyses havebeen primarily reported in tissue immunolabeled with
IBA-1, which does not fully reproduce microglial complexity. Indeed, studies using mice with a microglia-specific GFP reporter failed to observe such morphologicalchanges after chronic social defeat stress, despite having
more statistical power than previous reports [157]. Thesefindings suggest that chronic stress exposure does notcause microglia activation in a way that resembles theimmunological origins of the term [32, 33, 158].
Other studies have also reported that chronic stresspromotes peripheral leukocyte trafficking in the brain,
but this appears to be dependent on experimental
approaches and context. In particular, studies using G­ FP+
bone marrow (BM)-chimeric mice showed that repeatedsocial defeat (RSD) promotes signaling from microglia
and caused infiltration of peripheral monocytes into

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selective brain regions. These neuro-immune interactions were associated with reduced exploratory behavior in socially defeated mice [159–161]. However,further studies using LysM-GFP+, ­CCR2RFP, and ­UBCGFP
reporter mice indicate that RSD promotes accumulationof peripheral myeloid cells (i.e., monocytes and granulocytes) in the perivascular space and choroid plexus;
not in the brain parenchyma [157, 159, 162, 163]. These
results suggest that development of the BM-chimera
model enabled extravasation of myeloid cells into thebrain following RSD [157, 159, 162–164]. Despite limited
evidence for leukocyte trafficking in the brain, these studies did find that RSD caused a decline in BBB integrity[157, 165]. These stress-induced changes in the BBB wereassociated with vascular remodeling and the passage ofsignaling peptides, indicating that more subtle processes
are involved during stress as compared to neuroinflammation [163, 165]. It is important to point out that accumulation of peripheral myeloid cells and loss of BBB
integrity has been primarily observed in the RSD model.
These findings are still significant, but it reinforces thefact that the context is critical; RSD is a unique paradigm
as it involves aggressive encounters that can wound subordinate mice, potentially influencing their inflammatory
profile [166–168]. Indeed, other stress models that use
exposure to unstable or aversive environmental conditions (and lack physical confrontations or wounding) do
not cause significant accumulation of peripheral macrophages in the brain [169].
In summary, while it is evident that stress engages
neuro-immune pathways and alters microglia function, these effects are subtle and are not associated withimmune-driven pathology. Despite these modest effects,
neuro-immune interactions still play an important rolein the behavioral and biological effects of chronic stress
exposure. As such, a different framework is needed toaccurately describe neuro-immune responses to stress.
Parainflammation: neuro‑immune adaptations
to homeostatic threats

Historically, neuro-immune interactions have been
framed around existing immunological concepts derived
from models of pathological conditions in which all four
hallmarks of inflammation are present. By contrast, thebehavioral and biological sequelae of chronic stress are
best described as a consequence of prolonged adaptation to homeostatic threats, which, while associated withadverse effects, is not inherently pathological [170, 171].
For example, repeated stress exposure gradually attenuates hypothalamo–pituitary–adrenocortical (HPA) axis
activation in response to a familiar challenge, ultimately
reducing the physiological burden of chronic glucocorticoid secretion [170]. However, adaptation to chronicWoodburn et al. J Neuroinflammation(2021) 18:258

stress also sensitizes HPA activation to new challenges,
which, while appropriate in dangerous situations, canbe disadvantageous in response to innocuous stimuli[170, 172]. Behavioral adaptations to chronic stress canbe understood in a similar way. Recent work shows thatsocial avoidance, the primary outcome of RSD in “susceptible” mice, is a learned behavior that does not generalize outside the aggressor’s strain and can be extinguishedwith repeated exposure in a safe environment [173]. In
other words, “susceptible” mice learn to avoid an aggressor strain in a context that reliably predicts danger. Just
as well, increased immobility in the forced swim test, abehavioral metric used in many other stress paradigms,
might be an adaptive pro-survival behavior, as floating
in an inescapable body of water conserves energy [174].
Nonetheless, these paradigms also alter behaviors such as
sucrose preference, working memory, and effort-related
choice [152, 175–179]. Thus, rather than overt pathophysiology (i.e., relating to disease or injury), chronic
stress effects on brain and behavior can be framed as
adaptations to adverse conditions, which can compromise typical function.

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With this in mind, stress-induced functional changes
in microglia resemble an intermediate tissue state termedparainflammation, in which stressed or malfunctioning cells engage tissue-resident macrophages to restore
homeostasis [132, 180, 181]. In this conceptual framework (Fig. 2.), chronic psychological stress disrupts
homeostatic brain function, provoking changes in microglia function. In coordination with other brain cells,
microglia then facilitate neurobiological adaptations
by initiating immune-related processes (i.e., cytokine
release, phagocytosis). Of note, these microglia-mediatedprocesses occur independent of other peripheral immune
cells and at levels relative to physiological contexts. Ultimately, this may restore brain homeostasis, but may
cause important behavioral and biological consequences.
In support of this, there is growing evidence thatstress-induced changes in microglial function reflect
coordinated interactions between microglia and neurons(and other cells in the brain) rather than dysfunctional
immune processes. For example, chronic unpredictablestress (CUS) and glucocorticoids promote CSF1 signaling
in the PFC, which elicits microglial phagocytosis of neuronal elements in the medial PFC [154, 169]. Ultimately,

Fig. 2 Contrast between neuroinflammation and parainflammation. Neuroinflammation (left) describes immune-driven pathology which occurs in
the course of disease, injury, or infection in the brain. This tissue state can be identified by four common molecular and cellular hallmarks illustrated
on the left. These are: (1) high levels of pro-inflammatory cytokines, (2a) microglia and (2b) peripheral macrophage activation, (3) infiltration of
peripheral leukocytes (e.g., bone-derived monocytes, T cells) to the parenchyma, and tissue damage such as (4a) BBB breakdown and (4b) neuron
death. Neuro-immune systems can also be engaged by homeostatic challenges (i.e., psychological stress), leading to an intermediate tissue statetermed parainflammation (right). While a formal definition of parainflammation is yet to be widely accepted in neuroscience, neuro-immune
interactions previously reported in parainflammatory contexts are shown on the right. These include: (1) microglial recruitment of bone-derived
monocytes to the perivascular space, (2) changes in cytokine signaling between neurons and microglia, (3) microglia-mediated neuronal
remodeling, and (4) diffusion of small signaling peptides across the BBB

Woodburn et al. J Neuroinflammation(2021) 18:258

this neuronal remodeling by microglia contributes tosynapse loss in the medial PFC and associated stressinduced behavioral changes [169, 182]. Interestingly, ourrecent work suggests that while synapse loss persists overthe course of chronic stress, microglia-mediated neuronal remodeling diminishes over time, indicating that
this is a coordinated process and that spine loss is maintained by other mechanisms [152].
Further support for the concept of parainflammationin stress research comes from emerging evidence thatstress-induced changes in microglia correspond to stressinduced changes in neuronal activity. Previous work
showed that repeated restraint stress increased microglial proliferation in the hippocampus; however, this was
blocked by treatment with the glucocorticoid receptor
antagonist RU486 or the NMDA receptor antagonist
MK801 prior to restraint [183]. Other studies demonstrated that acute stress exposure increased c-Fos labeling in neurons within the periaqueductal gray (PAG),
and that microglia adjacent to c-Fos positive neurons
displayed morphological changes [184]. Furthermore,this was distinct from morphological changes caused by
LPS treatment, as LPS altered microglial morphology in
the PAG regardless of c-Fos labeling on nearby neurons,
indicating that microglia respond to different stimuli inthese contexts. Experiments conducted in our own lab
also hint that neuronal activity drives microglial function
in stress. We found that treatment with diazepam limited
FosB staining in the medial PFC, which corresponded toattenuated stress effects on microglia-mediated neuronal
remodeling, dendritic spine density, CSF1 signaling,
and behavior [155]. This is in line with research in othermodel systems suggesting that CSF1 is released by hyperexcitable neurons, although this remains to be directly
tested in the context of chronic stress [185, 186].
Because parainflammation is an adaptive process, it isimportant to consider these changes within the greatercontext of the stress model. Seminal work in stress neurobiology demonstrated that while acute stress drives
glutamate signaling in the PFC and hippocampus of maleanimals, this reverses as stress exposure becomes chronic[179, 187–189]. It has previously been hypothesized that,while this change is not without consequences, it ultimately reflects a metabolic shift to meet the homeostaticchallenges of stress [170, 171, 190–194].
In essence, glucocorticoids released during initial stress
exposure cause long-lasting potentiation of AMPA andNMDA receptor currents in pyramidal neurons, leading to increased surface expression of these receptors
and improvements in working memory [187–189, 195].
However, excess or prolonged glucocorticoid and glutamate stimulation can exacerbate excitotoxic insults byincreasing intracellular ­Ca2+, and high glucocorticoid

Page 9 of 16

levels have profound effects on metabolism by depleting available energy and inhibiting cellular growth [170,192, 193]. Thus, over time it may become beneficial tolimit the signals associated with acute stress in theseregions. Keeping with this, chronic stress is associatedwith decreased AMPA and NMDA receptor expression,
blunted EPSCs in excitatory pyramidal neurons, andimpairments in working memory [179, 196]. Previous
reports are also largely consistent in documenting morphological changes such as dendritic retraction and lossof apical spines in pyramidal neurons after chronic stress
exposure, which would make them less susceptible to theeffects of excessive ­Ca2+ [197–201].
Given this context, the changes in microglial function
arising from chronic stress are quintessentially parainflammatory processes. In this framework, acute stress
exposure increases excitatory neurotransmission in a
subset of brain regions [187, 188]. Microglia detect thisshift in neuronal activity, and may modulate it throughincreased (but much lower than pathological levels)
cytokine secretion [124, 135, 145, 202]. As stress exposure continues, activity-dependent signals from neurons,
such as CSF1, increase and direct neighboring microglia
to modulate neuronal activity through structural remodeling of neurons or release of neuromodulators [169].
These parainflammatory mechanisms are also accompanied by cell autonomous mechanisms in neurons, such as
dendritic retraction and degradation of glutamate receptors, which maintain this neuronal phenotype [179, 197,
200, 203]. Collectively, these coordinated neuron–microglia interactions mitigate the effects of uncontrolled glutamate signaling and promote behavioral adaptations toadverse conditions. As an inadvertent result however,these changes may also promote longer-term behavioral
and physiological consequences. Thus, while parainflammatory mechanisms are not associated with overt tissue
pathology (as is the case in neuroinflammation), some
aspects can be considered maladaptive.
Clinical implications

This is a semantic argument, but it is significant, as stressmodels are often used to inform our understanding of
psychiatric conditions such as major depressive disorder(MDD). Indeed, preclinical work attributing stress effects
to neuroinflammation and microglia activation are frequently cited by clinical studies claiming a similar etiology for MDD. These clinical reports indicate that someindividuals with MDD have higher blood cytokine levels
than controls, while others report increased PET detection of translocator protein (TSPO) during depressive
episodes, which is interpreted as an indication of microglia activation and neuroinflammation [204, 205]. WhileWoodburn et al. J Neuroinflammation(2021) 18:258

this work provides evidence of altered immune signaling
in MDD, much like the basic research discussed in thisreview, these measures do not necessarily indicate thatneuroinflammation or immune dysregulation underlies
the etiology of MDD.
Indeed, mild infections or experimentally induced
inflammation with LPS increase blood concentrationsof inflammatory cytokines to much higher levels, suggesting that peripheral immune signaling in MDD differs from that observed during inflammation [206–208].
Similarly, although TSPO has been used as a proxy for
microglia activation, the functional consequences ofincreased TSPO are not entirely understood [209]. In
fact, PET imaging studies conducted in patients with MS
show no difference in TSPO expression between activated macrophages in white matter lesions and those innormal appearing white matter or in healthy controls[210]. Other studies have indicated additional confounds
to consider in TSPO studies, namely that TSPO tracers are bound by vascular endothelia and TSPO levels
show maximal intensity after the resolution of inflammation [211, 212]. Further, preclinical studies indicate that
TSPO expression is also increased in neurons, not microglia, after periods of heightened neurotransmission [213].
These findings suggest that the utility of TSPO in assessing microglia activation is limited by its lack of cellular
and temporal specificity. The role of neuroinflammation
in MDD was further challenged by recent clinical studies that showed microglia from individuals with MDD
have increased expression of transcripts and proteinsassociated with homeostatic functions, rather than markers of inflammation [214].
Our focus on this literature is not intended to dismiss
a potential relationship between MDD and inflammation
outright. There is strong evidence to suggest that genuine inflammatory responses can disrupt mood in patientswith chronic illness or comorbid inflammatory diseases[215–217]. In addition, recent findings demonstratethat there are differences in circulating immune factors
and cells in subsets of MDD patients [218]. Considering the evidence however, it seems unlikely that MDD
or the psychological effects of stress can be consideredtruly neuroinflammatory conditions on their own. And
although neuro-immune interactions have clearly been
implicated in MDD, they appear to reflect an intermediate immune state rather than classic inflammation. Our
understanding of immune function in MDD is still developing and further research is needed to fully appreciate
its complexity. As such, hypotheses that reduce multidimensional diagnoses like MDD to pathological immune
function are not likely to advance treatments for patients.
This necessitates the use of conceptual frameworks that
integrate parainflammatory neuro-immune interactions

Page 10 of 16

within a larger biopsychosocial context, as has been donein other areas of neuroscience and psychiatry [219–221].

Conclusion
As research on the involvement of neuro-immune systems in chronic stress expands, it is imperative that ourmodels and conceptual frameworks be adapted to relevant data. Initial studies used existing disease-based
terms to define stress-associated changes in microglial
function. However, preclinical research demonstrates
that neuro-immune responses to stress are distinct from
CNS disease, injury, or infection and should not be characterized as neuroinflammation [25, 41]. The neurobiological changes that occur with chronic stress reflect
adaptations required to meet the homeostatic demandsof an unstable environment. We suggest that, before
concluding a given neuro-immune interaction is evidence of neuroinflammation, investigators first consider
whether the hallmarks of inflammation are also present.
These include: substantially increased cytokine concentrations, macrophage activation, parenchymal infiltration of peripheral immune cells, and pathological tissue
damage [25]. We also urge stress researchers to consider
how observed neuro-immune changes compare to othermodel systems within and beyond that context. It is also
worth considering if these changes are entirely detrimental, or if they might reflect an adaptive, or even beneficial(i.e., eustress) response to unstable conditions [222, 223].
Distinction between pathological (inflammation) andadaptive (parainflammation) functions of neuro-immune
interactions are necessary if we hope to one day leverage them for therapeutic purposes. To this end, technologies such as single-cell RNA-Seq and time-of-flightmass cytometry can lend important insights, as theseapproaches enables researchers to understand the heterogeneity of cellular populations and can identify molecularpatterns to distinguish various functional states [73, 224,
225]. This is particularly relevant to tissue-resident macrophages, such as microglia, as they display a remarkable
degree of functional plasticity [31]. Given these technicaladvances and appreciation for the spectrum of microglia
function, we propose that it is time to shift the conceptual framework used to describe neuro-immune function
in non-disease contexts, such as stress. Indeed, there issubstantial evidence that neuro-immune interactions inchronic stress resemble parainflammation; an intermediate immune state where immune responses are directed
toward reestablishing homeostasis [181]. In the end, thisframework will enable researchers to more accurately
describe the functional role of microglia in various contexts; and we are hopeful this leads to new therapeuticstrategies involving microglia.

Woodburn et al. J Neuroinflammation(2021) 18:258

Abbreviations
A1R: Adenosine A1 receptor; ADP: Adenosine diphosphate; AMPA: α-Amino3-hydroxy-5-methyl-4-isoxazolepropionic acid; Aβ: Amyloid beta; ATP:
Adenosine triphosphate; BBB: Blood–brain barrier; BDNF: Brain-derived
neurotrophic factor; BM: Bone marrow; CCR2: C–C Motif Chemokine Receptor
2; CNS: Central nervous system; CR3: Compliment receptor 3; CSF1: Colony
stimulating factor 1; CSF1R: Colony stimulating factor 1 receptor; CUS: Chronic
unpredictable stress; CX3CL1: C-X3-C motif chemokine ligand 1; CX3CR1:
C-X3-C motif chemokine receptor 1; CXCL16: C-X-C motif chemokine ligand 6;
D1: Dopamine 1 receptor; dLGN: Dorsal lateral geniculate nucleus; EAE: Experimental autoimmune encephalomyelitis; EGFP: Enhanced green fluorescentprotein; HPA: Hypothalamo–pituitary–adrenocortical; IFN-γ: Interferon gamma;
IL-1β: Interleukin 1 beta; IL-10: Interleukin 10; IL-1ra: IL-1 receptor antagonist;
IL-6: Interleukin 6; IL-33: Interleukin 33; LPS: Lipopolysaccharide; LTP: Long-term
potentiation; MDD: Major depressive disorder; mEPSC: Miniature excitatory
postsynaptic current; MHC: Major histocompatibility complex; MHV: Mouse
hepatitis virus; MS: Multiple sclerosis; NMDA: N-Methyl-D-aspartate; PAG:
Periaqueductal gray; PET: Positron emission tomography; PFC: Prefrontal
cortex Poly-IC: Polyinosinic:polycytidylic acid; P2Y12: Purinergic receptor P2Y,
G-protein coupled, 12; RGC​: Retinal ganglion cells; ROS: Reactive oxygen
species; RSD: Repeated social defeat; TREM2: Triggering receptor expressed on
myeloid cells 2; TSPO: Translocator protein; TNF-α: Tumor necrosis factor alpha;
UBC: Ubiquitin C.
Acknowledgements
Not applicable
Authors’ contributions
ESW defined the topic of review. SCW and ESW prepared the manuscript.
SCW created the figures. JLB aided in manuscript review and figure design. All
authors read and approved the final manuscript.
Funding
Authors are supported by funds from the National Institutes of Health(F32-MH123051; R21-MH120614; R01-MH-123545).
Availability of data and materials
Not applicable.

Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Received: 5 August 2021 Accepted: 28 October 2021

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