Zhang et al. Journal of Neuroinflammation(2024) 21:159
https://doi.org/10.1186/s12974-024-03152-1

Journal of Neuroinflammation

Open Access

REVIEW

Estrogen-immuno-neuromodulation disorders
in menopausal depression
Yuling Zhang1, Xiying Tan2 and Chaozhi Tang1*
Abstract
A significant decrease in estrogen levels puts menopausal women at high risk for major depression, which remains
difficult to cure despite its relatively clear etiology. With the discovery of abnormally elevated inflammation inmenopausal depressed women, immune imbalance has become a novel focus in the study of menopausal
depression. In this paper, we examined the characteristics and possible mechanisms of immune imbalancecaused by decreased estrogen levels during menopause and found that estrogen deficiency disrupted immune
homeostasis, especially the levels of inflammatory cytokines through the ERα/ERβ/GPER-associated NLRP3/NF-κB
signaling pathways. We also analyzed the destruction of the blood-brain barrier, dysfunction of neurotransmitters,
blockade of BDNF synthesis, and attenuation of neuroplasticity caused by inflammatory cytokine activity, andinvestigated estrogen-immuno-neuromodulation disorders in menopausal depression. Current research suggeststhat drugs targeting inflammatory cytokines and NLRP3/NF-κB signaling molecules are promising for restoring
homeostasis of the estrogen-immuno-neuromodulation system and may play a positive role in the intervention
and treatment of menopausal depression.
Keywords Estrogen, Menopausal depression, Inflammatory cytokine, Blood-brain barrier, Neurotransmitter, BDNF,
Neuroplasticity

Introduction
Depression is a major cause of suicide and mortality worldwide [1, 2]. The vast majority of patients withdepression show insufficient secretion of monoamine
neurotransmitters, making selective serotonin reuptake
inhibitors (SSRIs) the main antidepressant drugs. SSRIs
maintain a high level of 5-hydroxytryptamine (5-HT)in the synaptic cleft, which can effectively alleviate
depressive episodes in the short term [2, 3] but cannot
repair the autonomous regulation of neurotransmitter*Correspondence:
Chaozhi Tang
tcz1980@126.com
1
College of Life Science, Henan Normal University, Xinxiang 453007,
Henan, China
2
Department of Neurology, Xinxiang City First People’s Hospital,
Xinxiang 453000, Henan, China

synthesis, secretion, release and absorption by neurons[4, 5]. Long-term use of SSRIs induces neuronal dysfunction and gradually leads to drug dependence in depressed
patients [5–7]; therefore, tracking the cause of neuronal
dysfunction and developing corresponding treatments
may be the best way to cure depression. With the deterioration of ovarian function, the secretion of estrogenin menopausal women decreases sharply, and the serious
imbalance of endocrine hormone levels results in a highincidence of major depression in menopausal women [8–11]. The relatively clear etiology of menopausal depression provides promising prospects for the investigation ofneuronal dysfunction.
Some early breakthroughs in menopausal depression focused on the link between estrogen and depression [12–14]. Initially, an epidemiological survey of
16,080 women aged 35–60 years led to a preliminary© The Author(s) 2024. 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 the original author(s) andthe source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in thisarticle are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not includedin the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you willneed to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The
Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available
in this article, unless otherwise stated in a credit line to the data.

Zhang et al. Journal of Neuroinflammation(2024) 21:159

understanding of menopausal depression and revealed
that menopausal women had significantly more severe
depressive symptoms, suggesting that changes in estrogen homeostasis are related to the development ofdepression [12]. Further analysis confirmed that estrogencan exert antidepressant effects by regulating the levelof 5-HT and the expression of 5-HT receptors (5-HTR)on presynaptic or postsynaptic membranes [13]. Subsequently, Chhibber et al. reported that decreased estrogen receptor (ER) expression reduces brain-derived
neurotrophic factor (BDNF) levels in the hippocampus,
thereby inhibiting the tropomyosin receptor kinase B(TrkB) signaling pathway, leading to 5-HT2A dysfunction, attenuated synaptic plasticity, and increased susceptibility to depression in menopausal women [14]. To date,abnormalities in signaling pathways caused by estrogen
deficiency have attracted much attention.
Recently, significantly abnormal proportions of T-cell
subsets, activation of microglia, and elevated levels of
inflammatory cytokines in the central nervous systemand peripheral blood were detected during the onset ofmenopausal depression [15–17], and these immune disorders increase the activity of the estrogen-immuno-neuromodulation system, which may be the key to resolving
neuronal dysfunction in menopausal depression. However, due to the involvement of multiple ERs [18–21],
immune responses and regulatory factors [19–27] andnerve signaling molecules [26–30], the disturbanceof signaling pathways in this complex system remains
unclear and has not been comprehensively reviewed inmenopausal depression.
To this end, focusing on the decline of estrogen levels
in menopausal women, we summarize the immune system imbalance and neurological impairments caused by
estrogen deficiency and analyze the detailed process andpossible mechanism of estrogen-immuno-neuromodulation disorders in menopausal depression, with the aim ofproviding scientific directions for further elucidating thepathogenesis of menopausal depression and developing
novel targeted therapeutic drugs.

Immune imbalance in menopause
Characteristic changes in the immune system during
menopause

Characteristic changes in the immune system in menopausal women are the first clue to understanding the disorder of the estrogen-immuno-neuromodulation system
in menopausal depression in order to trace the relevant
signaling pathways from estrogen to specific indicators of
immune imbalance.
An analysis of peripheral blood lymphocyte subsets inmenopausal women and reproductive women revealed
that the total number of lymphocytes in the menopausal women was lower; specifically, the number of B

Page 2 of 19

lymphocytes and CD4+ T cells were significantly lower,
and the ratio of CD4+ to CD8+ T cells was also significantly lower [31]. Further diagnostic findings of serological biochemical factors revealed that the serum levelof interleukin (IL)-4 (a Th2 cytokine) was increased
and the level of interferon (IFN)-γ (a Th1 cytokine) was
decreased in menopausal women, suggesting that the cellular immune activity of the body tended to be attenuatedafter the decrease in estrogen levels [32].
Another important characteristic change in the
immune system of menopausal women is an increased
susceptibility to inflammation. Malutan et al. compared the levels of inflammatory factors in women who
were fertile, perimenopausal, postmenopausal, ovariectomized, or chronically inflammatory and observedthat the levels of the inflammatory factors IL-1β, IL-8
and tumor necrosis factor (TNF)-α were significantly
greater in menopausal women, while the levels of theanti-inflammatory factor IL-20 were lower [33]. Patientswith perimenopausal depression have increased levels
of inflammation [34]. Animal models of perimenopausal
depression exhibit activation of microglia and astrocytes,
as well as increased neuroinflammation and nerve damage [25, 35, 36].
Effect of estrogen on immune imbalance during
menopause

Changes in the immune system in menopausal womenindicate that a decrease in estrogen levels had an important impact on immune homeostasis, leading to thedevelopment of estrogen replacement therapy (ERT).
Estrogens are cholesterol-derived steroid hormones withwide ranges of biological activities that mainly include
estrone (E1), estradiol (17β-estradiol, E2) and estriol(E3). Among them, E2 is the main form of estrogen in
the human body, and its physiological activity is considered to be the strongest [37]. Kumru et al. demonstrated
that E2 could reduce the number of CD8+ T cells to acertain extent, restore the ratio of CD4+ to CD8+ T cells
in peripheral blood to a normal level, and significantly
increase the proportion of CD19+ B cells and the levelof IFN-γ [38]. E2 also had a restorative effect on the proportion of different lymphocyte subsets in menopausal
women, but the number of CD4+ T cells and CD20+ B
cells was still lower than that in reproductive women,
which indicates that estrogen plays an important role inregulating the immune status of menopausal women but
cannot reverse the decline in immune function causedby aging [39]. Estrogen has also been found to have apositive regulatory effect on the preservation of naïve B
cells, which is conducive to the occurrence of a humoral
immune response. In addition, estrogen can decrease thelevel of the proinflammatory cytokine IL-6 in peripheral blood to a certain extent, inhibit the secretion ofZhang et al. Journal of Neuroinflammation(2024) 21:159

inflammatory cytokines by CD4+ T cells, and reduce theinflammatory response in menopausal women [39]. All of
this evidence suggests that estrogen can repair immune
imbalances and maintain immune homeostasis during
menopause.

Possible mechanisms of immune imbalance causedby estrogen deficiency
The mechanism of immune imbalance caused by estrogen deficiency has not yet been well investigated inmenopausal women [32, 40], but the understanding of
this process is gradually being explored in menopausal
animal models and related cell lines. The effect of estrogen is known to be exerted mainly through its receptors.
ERs consists of classical nuclear receptors (ERα, ERβ
and their subtypes), G protein-coupled estrogen receptor (GPER), ER-X and Gaq-ER, which are specifically
expressed in the cell membrane, cytoplasm and nucleus
of monocytes, macrophages, dendritic cells, neutrophils,
NK cells, CD4+ and CD8+ T cells, regulatory T (Treg)
cells, B cells, microglia, astrocytes, and neurons, among

Fig. 1 NLRP3 signaling pathways regulated by E2. Estrogen deficiency inovariectomized mice or rats increases the expression of P2X7R, TLR2 andTLR4 in the hippocampus and further leads to the activation of NLRP3,
which promotes the inflammatory cascade and increases the expressionof pro-IL-1β and pro-IL-18. Moreover, NLRP3 can lead to caspase-1 activation, which in turn promotes the transformation of pro-IL-1β and pro-IL-18
into mature IL-1β and IL-18, and then, IL-1β facilitates the increase in IBA1
expression and the activation of microglia. Administration of the inflammasome inhibitors VX-765, E2 and ERβ agonists to ovariectomized micecan inhibit the expression of P2X7R, TLR2 and TLR4, block these signaling
pathways, and reverse the depression and anxiety-like behavior causedby estrogen deficiency. RSV inhibits depression-like behavior by increasing
the level of SIRT1 and inhibiting the activation of the NLRP3 inflammasome. SIM can also inhibit the expression of P2X7R, TLR2 and TLR4 andthe activation of the NLRP3 inflammasome and its downstream signaling
pathways in the hippocampus of ovariectomized rats, as well as reduce
the activation of microglia induced by IL-1β, and alleviate depression in
ovariectomized rats. (➝, positive regulation; ⊣, negative regulation. The
meaning of these two indicators is the same across all the figures in thisarticle.)Page 3 of 19

others [18, 20, 22, 41, 42]. When activated by estrogen,different ERs can regulate gene expression directly or in
conjunction with transcription factors or can also regulate cell signal transduction pathways through second
messengers such as cAMP [18, 20, 22, 41]. Recent studies
on the mechanism of immune imbalance caused by estrogen deficiency during menopause have focused mainlyon the regulation of inflammatory signaling pathways by
ERα, ERβ and GPER. Understanding these pathways is
crucial for elucidating the mechanisms of immune imbalance caused by estrogen deficiency and their potential
contribution to menopausal depression.
NLRP3 signaling pathways mediated by the classical ER

Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), the triggering component ofinflammasome formation, is involved in the occurrence and treatment of menopausal depression. Xu et al.
reported that estrogen deficiency increased the expression of purinergic ligand-gated ion channel 7 receptor(P2X7R), toll-like receptor (TLR) 2 and TLR4 in the hippocampus of ovariectomized mice, promoted the inflammatory cascade reaction and the formation of the NLRP3
inflammasome, stimulated nuclear factor-κB (NF-κB),
increased the expression of pro-IL-1β and pro-IL-18,
and finally induced depression and anxiety-like behavior
in mice. Administration of the inflammasome inhibitors
VX-765, E2 and ERβ agonists to ovariectomized mice
blocked these signaling pathways by inhibiting P2X7R,
TLR2 and TLR4 expression, thereby reversing depression
and anxiety-like behaviors caused by estrogen deficiency(Fig. 1) [23]. Resveratrol (RSV), a potential replacement
for E2, can inhibit the activation of NLRP3 and NF-κB in
the hippocampus by increasing the levels of silent information regulator factor 2-related enzyme 1 (sirtuin 1,
SIRT1), thereby restraining the increase in caspase-1 andNLRP3 inflammasome effectors caused by the activationof NLRP3, the conversion of pro-IL-1β to mature IL-1β
and the strong release of IL-1β and IL-18, effectively
combating depression and anxiety-like behaviors causedby estrogen deficiency (Fig. 1) [43]. Menze et al. analyzed
the mechanism of simvastatin (SIM) in neuroprotection
and depression-like behavior resistance and revealed that
SIM can also inhibit the expression of P2X7R, TLR2 andTLR4 in the hippocampus of ovariectomized rats andblock the activation of the NLRP3 inflammasome, thus
decreasing the levels of the proinflammatory cytokines
IL-1β and IL-18 and reducing the expression of ionized
calcium-binding adapter molecule 1 (IBA1) and the activation of microglia. SIM also significantly increased theexpression of ERα and ERβ in the hippocampus and theexpression of ERβ in the uterus of ovariectomized micebut did not increase uterine weight, suggesting that
SIM may be a safer alternative to hormone replacement

Zhang et al. Journal of Neuroinflammation(2024) 21:159

therapy for the management of postmenopausal depression (Fig. 1) [44]. These studies suggest that the NLRP3
inflammasome may become a potential therapeutic target for estrogen deficiency-related affective disorders
such as depression.
NF-κB signaling pathways mediated by the classical ER

NF-κB, an important nuclear transcription factor, can be
regulated by estrogen through multiple signaling pathways. Ovariectomy experiments in animals have demonstrated that the decreased levels of E2 activate NF-κB
signaling pathway in microglia, converting microglia
from the M2 subtype to the M1 subtype and resulting in
the production and secretion of large amounts of inflammatory cytokines such as TNF-α, IL-1β and IL-6, whichleads to cognitive impairment and depressive behavior [45, 46]. Another comparative study showed that E2
supplementation improved depression-like behavior
in aging female mice by reducing NF-κB activation andthe expression of the inflammatory cytokines TNF-α,
IL-1β, and IL-6. Both ERα and SIRT1 antagonists canreverse the effects of E2, suggesting that E2 may protect
aging female mice from depression through the E2/ERα/SIRT1/NF-κB signaling pathway [19] (Fig. 2). By implanting E2 release pellets into ovariectomized middle-aged
female rats, Pratap et al. reported that E2 could decrease
the level of p-NF-κB and increase the expression of themolecular markers phosphorylated extracellular signal regulated protein kinase (p-ERK), phosphorylated

Fig. 2 NF-κB signaling pathways mediated by classical ER. In general,
upon binding to ERα in the membrane, cytoplasm or nucleus, E2 caninhibit the activation of NF-κB by regulating TLR4, MS-KIF18A, ERK, AKT,
CREB, SIRT1 and other signal transduction molecules, thereby decreases
the expression of the proinflammatory cytokines TNF-α, IL-1β and IL-6.
However, supraphysiologic doses of E2 (sE2) abnormally activate NF-κB in
microglia, resulting in increased expression of IBA1, CD86 and the proinflammatory cytokines TNF-α, IL-1β, and IL-6 and decreased expression of
the anti-inflammatory cytokines TGF-β, IL-10, and IL-4. Moreover, E2 canpromote the proliferation, migration and invasion of ER+ breast cancer
cells by activating the PI3K/AKT/NF-κB/TWIST1/CCL2 signaling pathway

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cAMP-responsive element binding protein (p-CREB),
phosphorylated protein kinase B (p-PKB or AKT), andnitric oxide in the frontal cortex, striatum, and otherbrain areas [24] (Fig. 2). In addition, E2 can inhibit theactivation of microglia and astrocytes and reduce theexpression of proinflammatory cytokines such as TNF-α,
IL-1β and IL-6 through TLR4/NF-κB signaling pathway[22], and our previous studies indicated that the occurrence and exacerbation of depression are closely related
to the NF-κB-related signaling pathway in microglia[27] (Fig. 2). E2 can also activate marrow stromal kinesin family member 18 A (MS-KIF18A) in the cytoplasm
after binding to ERα, and MS-KIF18A further activates
the rapid phosphorylation of ERK, thereby inhibiting theactivation of NF-κB [41] (Fig. 2).
The above results [19, 22, 24, 41, 45–47] support theidea that estrogen inhibits the activation of the NF-κB
signaling pathway and the secretion of inflammatory
cytokines in reproductive women, maintaining immune
homeostasis in the body (especially in the central nervous
system), while during menopause, a decrease in estrogenlevels triggers the activation of NF-κB signaling pathways
and the expression of inflammatory cytokines, resulting
in an immune imbalance in the body, which further promotes neuronal damage and menopausal depression.
Unexpectedly, Li et al. reported that supraphysiologic
doses of E2 can induce neuronal damage and aggravate the depressive behavior of ovariectomized mice byabnormally activating the expression of IBA1 and CD86
in microglia and disrupting brain glycerophospholipid
metabolism through ERα/NF-κB, increasing the expression of the proinflammatory cytokines TNF-α, IL-1β, andIL-6 and decreasing the expression of the anti-inflammatory cytokines TGF-β, IL-10, and IL-4 [48] (Fig. 2).
In addition, studies on the relationship between E2 andbreast cancer showed that E2 can upregulate the transcription factor TWIST1 (a member of the basic helixloop-helix transcription factor family) and NF-κB byactivating the ERα/PI3K (phosphatidylinositol 3-hydroxy
kinase)/AKT/NF-κB signal transduction pathway, thus
positively regulating C-C motif chemokine ligand 2(CCL2) synthesis and autocrine signaling to promote theproliferation, migration and invasion of ER+ breast cancer cells [49] (Fig. 2). These results suggest that the E2/
ERα/NF-κB signaling pathway regulates cellular or bodyinflammation levels with diverse outcomes [19, 22, 24,
41, 47–49]. Whether the reason for this phenomenon isrelated to the dose of E2 or the different ways in which
E2 regulates the central nervous system and peripheral
immune system requires further precise investigation.
Inflammatory signaling pathways mediated by GPER

G protein-coupled receptor (GPR) 30 is a new type ofER, also known as GPER, which is widely distributed inZhang et al. Journal of Neuroinflammation(2024) 21:159

the central nervous system (hippocampus, cortex, hypothalamus, striatum and brain stem) and is associatedwith emotional regulation [50–54]. Estrogen can not
only regulates the NLRP3 and NF-κB signaling pathways
through ERα and ERβ but also regulates inflammationlevels, microglial polarization and astrocyte activity inthe central nervous system through GPER-related signaling pathways to maintain immune homeostasis in thebrain and rescue brain injury, hypomnesia and cognitive
impairment [20, 21, 52, 54–56] (Fig. 3).
Zhao et al. demonstrated that E2 can inhibit theexpression of inflammatory cytokines in microglia
through GPER, and the GPER agonist G1 can promote the anti-inflammatory effect of E2, but GPER
antagonist G15 or GPER knockdown can eliminate
the anti-inflammatory effect of E2 [21]. In addition to
inhibiting the production of TNF-α, IL-1β and IL-6
by microglia, the GPER agonist G1 can also reduce
the expression of CD86, CD11b, macrophage cationicpeptide 1 (MCP-1, also known as CCL2), IBA1, nitricoxide synthase 2 (NOS2), macrophage inflammatory
protein 2 (MIP-2, also known as CXCL2), and NF-κB

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and increase the expression of the anti-inflammatory
factors IL-4, IL-10, arginase 1 (Arg1) and CD206 in
microglia, polarize microglia to the M2 phenotype,and rescue the damage of inflammatory factors to neurons [52, 55, 56]. The mechanism of the GPER agonist
G1 is closely related to the phosphorylation of AKT
and the inhibition of TLR4 [24, 52, 55, 57]. GPER activation can also reduce microglial activation, NLRP3
inflammasome formation, caspase-1 activation mediated by the NLRP3 inflammasome and downstream
IL-1β production and signal transduction, as well as
downstream NF-κB signaling, and strongly upregulate
the expression of the anti-inflammatory factor IL-1RA(an endogenous IL-1 receptor antagonist) mediated by
p-CREB (a transcription factor known to enhance theexpression of IL-1RA) in hippocampal CA1 neurons.
The GPER agonist G1 enhances this anti-inflammatory effect of GPER, while the GPER antagonist G36
reverses this effect [54]. The loss of GPER in astrocytes
can lead to the transformation of astrocytes to the A1
phenotype, increase the expression of TNF-α, IL-6
and IL-1β, increase the accumulation of Serpina3n

Fig. 3 Inflammatory signaling pathways mediated by GPER. E2 can inhibit the expression of TNF-α and IL-1β through GPER, and the GPER agonist G1 canpromote the anti-inflammatory effect of E2. G1 can also reduce the expression of IL-6, CD86, CD11b, MCP-1, IBA1, NOS2, and MIP-2, as well as the activation of NF-κB, and increase the expression of the anti-inflammatory factors IL-4, IL-10, Arg1 and CD206. The mechanism of the GPER agonist G1 is closely
related to the phosphorylation of AKT and the inhibition of TLR4. GPER activation can also reduce NLRP3 inflammasome formation, caspase-1 activation
mediated by the NLRP3 inflammasome and downstream pro-IL-1β transformation into IL-1β, as well as downstream NF-κB signaling, and upregulate theexpression of IL-1RA mediated by p-CREB (IL-1RA enhances the defense of neurons against IL-1β). The GPER agonist G1 enhances this anti-inflammatory
effect of GPER, while the GPER antagonist G36 reverses this effect. Additionally, GPER can decrease the expression of TNF-α, IL-6 and IL-1β, positively regulate PJA1 expression, and decrease the accumulation of Serpina3n through the Gs/cAMP/PKA/CREB signaling pathway. A too high level of E2 can also leadto the overexpression of GPER, Src and MMP-9 in neurons and subsequently activate IL-1β to result in harmful effects on the nervous system. The GPER
antagonist G15 can reverse the damage caused by E2-induced GPER overactivation

Zhang et al. Journal of Neuroinflammation(2024) 21:159

in the cells, damage the function of neurons, and disrupt learning and memory in female mice. Serpina3n
is a molecular marker of neuroinflammation in astrocytes. Praja-1 (PJA1) mediated the effects of astrocytic GPER on learning and memory by binding to
Serpina3n. GPER can positively regulate PJA1 expression by stimulating the G protein (Gs)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/CREB signaling pathway in cultured rat and humanastrocytes [20]. In exosomes isolated from the plasmaof postmenopausal women, the levels of GPER and
PJA1 mRNA were decreased, while the level of Serpina3n in plasma was increased [20]. These results indicate that the astrocyte GPER can regulate learning andmemory through the GPER/PJA1/Serpina3n signaling
pathway in female mice. Although E2 beneficially regulates inflammation in the central nervous system andexerts neuronal protection by binding to its membrane
receptor GPER [20, 21, 52, 54–56], too high of a levelof E2 can also lead to the overexpression of GPER,
sarcoma protein (Src) and matrix metalloproteinase 9(MMP-9) in neurons and subsequently activate IL-1β
to result in harmful effects on the nervous system. The
GPER antagonist G15 can reverse the damage causedby E2-induced GPER overactivation [58] (Fig. 3). Considering the positive regulatory effects of GPER on
neuroinflammation, microglial and astrocyte activation, neuronal damage, and cognitive and memory
impairment, GPER may be a potential therapeutic target for menopausal depression.
As a cell membrane receptor, GPER is more responsive to exogenous estrogen agonist therapeutic drugs,
making its therapeutic mechanism is relatively easier to address and elucidate [59]. Additionally, GPER
expression is notably significant in brain tissues suchas the hippocampus [60, 61]. These factors suggest that
GPER-based antidepressants may be more acceptable
to clinical patients. However, this does not imply that
ERα and ERβ are poor targets. Although the majority of classical estrogen receptors (ERs) are expressedin the nucleus, a small number of these classical ER
subtypes are expressed on the cell membrane. Moreover, the activation of classical ERs can regulate gene
expression more briefly and rapidly. Therefore, further
analysis of the differences in the expression of various ERs in key brain regions associated with depression and the affinity preferences of estrogen alternative
therapeutic drugs for these ERs will help determine themost appropriate ER target for developing antidepressant therapies. In any case, therapeutic drugs targetingkey molecules such as inflammatory cytokines within
the estrogen-immune modulatory signaling pathway
should play an effective role in treating menopausal
depression.

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Neurological impairments caused by immune
imbalance
As discussed above, due to decreased estrogen levels,
menopausal depression is characterized by an immune
imbalance that includes abnormal activity of immune
factors such as TNF-α, IL-1β, IL-6, IL-10, IL-17, IL-33,
and IFN-γ. In this section, we will further focus on neurological impairments caused by immune imbalance andthe detailed pathogenesis of these impairments, providing a comprehensive overview of this complex phenomenon based on the findings of menopausal depression andits related fields.
BBB destruction

The blood-brain barrier (BBB) refers to the isolating
material between brain cells or cerebrospinal fluid (CSF)
and plasma and is mainly composed of capillary endothelial cells with tight junctions, the endothelial basement
membrane and the astrocyte foot plate. Under normal
conditions, the BBB controls the selective permeability
between the components of the plasma and brain tissue
and plays a protective role in brain tissue. Under aging or
pathological conditions, the integrity of the BBB structure changes, and peripheral substances enter brain tissue, leading to dysfunction of brain cells or CSF.
Studies on changes in BBB structure after a decreasein estrogen levels have shown that the expression of thetight junction protein claudin-5 decreases during menopause and that the permeability of paracellular junctions
to sucrose increases, thereby increasing the probabilityof brain edema and stroke [62, 63]. In the brain tissueof menopausal women or animal models, a decrease inestrogen levels caused an increase in the number of M1
microglia and activated astrocytes, which can secretea large number of inflammatory cytokines. Therefore,
inflammatory cytokines may play an important role inchanges in BBB permeability [25, 64–74]. Several subsequent studies have demonstrated that TNF-α, IL-6
and IL-17 can reduce the expression of claudin-5, zona
occludens-1 (ZO-1) and other tight junction proteinsby activating NF-κB signaling pathways in endothelial
cells, destroying the structure of the BBB and promoting
depressive behavior [69, 70]. A large amount of TNF-α
can also induce necrotic apoptosis of endothelial cells,
directly leading to an increase in BBB permeability [71].
Stress-induced depression in humans is accompanied bya decrease in claudin-5 expression and an increase in IL-6
expression. Stress triggers BBB disruption, allowing IL-6
to penetrate the brain and increases the risk of depression in humans [68]. IL-1β can degrade the tight junction
proteins occludin and ZO-1 by enhancing the expressionof MMP-9 in endothelial cells, leading to the destruction of BBB integrity [72]. Moreover, IL-1β can inhibit
the production of hedgehog proteins by astrocytes,

Zhang et al. Journal of Neuroinflammation(2024) 21:159

thereby eliminating the protective effect of astrocytes on
BBB integrity by downregulating the expression of tightjunction proteins. IL-1β can also increase the levels of
the proinflammatory chemokines CCL2, CCL20 and
CXC-chemokine ligand 2 (CXCL2) in astrocytes, whichfurther exacerbates BBB destruction and neuroinflammation after immune cell recruitment [73]. In addition,
during persistent inflammation, active microglia engulf
astrocyte terminals, which directly results in a loss of
BBB integrity [74] (Fig. 4). Our previous studies haveshown that the expression of C-reactive protein (CRP)
is increased in patients with poststroke depression [75].
Cossette et al. reported that CRP can induce endothelial cell activation and that activated endothelial cells can
produce more inflammatory factors, such as CRP, IL-6,
IL-8 and vascular cell adhesion molecule-1 (VCAM-1),
which further aggravate vascular endothelial cell injury.
E2 pretreatment can reduce the production of the above
inflammatory factors and promote vascular repair [76].
Based on the above findings, we hypothesize that someperipheral inflammatory cytokines first attack vascularepithelial cells and decrease the expression of tight junction proteins, leading to an increase in BBB permeability.
Then, these inflammatory cytokines penetrate the BBB toactivate microglia, which in turn secrete more inflammatory cytokines and chemokines and, by inducing necrotic
apoptosis of endothelial cells and triggering phagocytosis

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of the astrocyte footplates, severely exacerbate thedestruction of the BBB. Ultimately, this process leads toneuronal damage and menopausal depression.
Neurotransmitter dysfunction

Neurotransmitters in the central nervous system ofpatients with major depression, including 5-HT [77,78], dopamine (DA) [78], norepinephrine (NE) [78],γ-aminobutyric acid (GABA) [79] and glutamate (Glu)[79] have received increasing amounts of attention. We
next outline the effects of inflammatory cytokines onneurotransmitter dysfunction and the associated pathogenesis in order to enhance the understanding of neurological impairments caused by immune imbalance.
5-HT

5-HT, also called serotonin, is an indoleamine neurotransmitter in brain tissue that can regulate pleasantemotions. TNF-α, IL-1β and IL-6 promote depression
and inhibit the functional activity of serotonergic
neurons.
On the one hand, TNF-α, IL-1β and IL-6 can activate indoleamine 2,3-dioxygenase (IDO), tryptophan
2,3-dioxygenase (TDO) and monoamine oxidase (MAO),
which degrade tryptophan (Trp). IDO and TDO catalyze
the oxidation of Trp to initiate the metabolic cascade,leading to Trp entering the kynurenine (Kyn) metabolicFig. 4 BBB destruction was triggered by immune imbalance during menopause. During menopause, a decrease in estrogen levels causes an increase
in inflammatory cytokines (TNF-α/IL-6/IL-17) in the peripheral blood, which gradually decreases expression of claudin-5, ZO-1 and occludin by activating
the NF-κB signaling pathway and downregulating MMP-9 expression in endothelial cells, thereby increasing the permeability of the BBB. Subsequently,
inflammatory cytokines penetrate the BBB to activate microglia, which in turn secrete more inflammatory cytokines and chemokines (CCL2/CCL20/CXCL2) and recruit more aggressive immune cells, further inducing necrotic apoptosis of endothelial cells, inhibiting hedgehog protein secretion (which
can improve the expression of tight junction proteins in endothelial cells) in astrocytes and triggering the phagocytosis of astrocyte footplates, thereby
severely exacerbating BBB destruction. CRP can induce endothelial cell activation, and activated endothelial cells can produce more CRP, IL-6, IL-8, andVCAM-1, which further aggravate vascular endothelial cell injury. E2 pretreatment can reduce the production of the above inflammatory factors andpromote vascular repair

Zhang et al. Journal of Neuroinflammation(2024) 21:159

Fig. 5 Effects of inflammatory cytokines on 5-HT synthesis, degradation,
reuptake and 5-HTR expression. TNF-α/IL-1β/IL-6 activate IDO and TDO tocatalyze Trp to enter the Kyn metabolic pathway, reduce 5-HT synthesis,
stimulate MAO to promote 5-HT degradation into 5-HIAA, increase the expression of 5-HTT in the presynaptic membrane, aggravate 5-HT reuptake
in the synaptic cleft, inhibit 5-HTR expression in the postsynaptic membrane and attenuate 5-HT efficacy

Fig. 6 Effects of inflammatory cytokines on DA synthesis, packaging,transport, degradation and reuptake. TNF-α and IL-1β can increase ROS
levels and subsequently promote the oxidation of BH4 to XPH2 and BH2,
which further leads to the inactivation of TH and PAH and a reduction in
DA synthesis. TNF-α and IL-1β are also thought to interfere with DA packaging and transport by reducing VMAT expression, and unpackaged DA
is easily degraded to DOPAL and HVA by MAO. Furthermore, DOPAL isoxidized by ALDH to DOPAC, resulting in the massive metabolism of thesynthesized DA. In addition, TNF-α and IL-1β can activate DAT through the
MAPK signaling pathway, increasing the reuptake of DA

pathway and no longer synthesizing 5-HT [80–82]. MAO
catalyzes the degradation of 5-HT to 5-hydroxyindoleacetic acid (5-HIAA). 5-HIAA levels are significantly
associated with depression and anxiety scores in patientswith somatic symptom disorder, and elevated IL-6 levels
exhibit mediating effects [83].
On the other hand, TNF-α, IL-1β and IL-6 can increase
the expression of 5-HT transporters (5-HTT or SERT)in the presynaptic membrane of neurons and promote
5-HT transport from the synaptic cleft to the inner cellbody of neurons, leading to a reduction in 5-HT in thesynaptic cleft and subsequent weakening of the excitatory
potential at the receptor [82, 84]. In addition, inflammatory cytokines also inhibit the expression of 5-HTR,
thereby blocking or attenuating the functional activity ofserotonergic neurons [85] (Fig. 5).
DA

DA is a catecholamine neurotransmitter in the brain thatinduces pleasure. Studies have shown that increased levels of TNF-α and IL-1β in CSF are positively correlated

Page 8 of 19

with decreased levels of DA and the severity of dopaminergic neuron damage [86, 87]. The influence of inflammatory cytokines on DA involves synthesis, packaging,metabolism, release and reuptake.
DA synthesis depends on tyrosine hydroxylase (TH),the rate-limiting enzyme that converts tyrosine (Tyr) to
levodopa (L-DOPA). Tyr is derived from phenylalanine(Phe) via phenylalanine hydroxylase (PAH), and TH andPAH require the common cofactor tetrahydrobiopterin(BH4). However, high levels of TNF-α and IL-1β cancause an increase in intracellular reactive oxide species(ROS), which promotes the oxidation of BH4 to dihydroxanthopterin (XPH2) and dihydrobiopterin (BH2), thereby
blocking TH and PAH activity and inhibiting DA synthesis [88] (Fig. 6). E2 treatment can not only decrease theexpression of TNF-α, IL-1β and IL-6 but also improve theproduction of BH4 [89].
TNF-α and IL-1β are also thought to reduce the expression of vesicle monoamine transporter (VMAT), which
are not conducive to DA packaging and transport [90,91] (Fig. 6). Unpackaged DA can be degraded to 3,4-dihydroxyphenzene acetaldehyde (DOPAL) by MAO on the
mitochondrial membrane; the latter is further oxidized
by aldehyde dehydrogenase (ALDH) to 3,4-dihydroxyphenylacetic acid (DOPAC), resulting in the massive
metabolism of the synthesized DA, which cannot bereleased from the presynaptic membrane [92].
In addition, TNF-α can increase the degradation of DA
by extracellular MAO and produce a large amount of themetabolite homovanillic acid (HVA), which is not conducive to the activation of receptors on the postsynaptic
membrane by high concentrations of DA [93] (Fig. 6).
Other studies have shown that TNF-α and IL-1β canactivate 5-HTT and DA transporter (DAT) throughthe receptor-coupled mitogen-activated protein kinase(MAPK) signaling pathway, thereby increasing the reuptake of 5-HT and DA by presynaptic membranes, reducing the transmitter effect, and triggering depressive
behaviors [94–97] (Fig. 6).
NE

NE is a catecholamine neurotransmitter synthesized andsecreted by sympathetic postganglionic neurons and norepinephrine neurons in the brain and is involved in the
dual regulation of the hypothalamic pituitary adrenal(HPA) axis and hypothalamic pituitary gonadal (HPG)
axis. NE is closely related to anxiety and sex hormone
secretion. Studies on the emotional centers and areasof the brain that regulate sex hormone production haveshown that IL-1β can increase NE levels in the central amygdala (CeA), bed nucleus of the stria terminalis(BNST) and paraventricular nucleus (PVN) of the HPA
axis but decrease NE levels in the diagonal band of Broca(DBB), organum vasculosum lamina terminalis (OVLT),Zhang et al. Journal of Neuroinflammation(2024) 21:159

medial preoptic area (MPA), suprachiasmatic nucleus(SCN) and arcuate nucleus (Arc) of the HPG axis [98](Fig. 7). IL-1β differentially regulates NE in different
brain regions to promote the body’s adaptation to systemic immune challenges.
The mechanism by which IL-1β affects NE has been
analyzed mainly through its synthesis and release.
L-DOPA is a precursor substance for NE synthesis, andthe supply of L-DOPA can reverse the effect of IL-1β on
NE in several brain regions of rats. These results suggest that TH, the rate-limiting enzyme of L-DOPA synthesis, may be the key target of IL-1β in regulating NE
synthesis [99, 100]. Similar findings have been observedfor IL-6. IL-6 inhibits TH expression by activating Janus
kinase-signal transducer and activator of transcription(JAK-STAT) 3 and reduces NE synthesis [101]. The antiinflammatory cytokine IL-4 can upregulate the expression of TH and tryptophan hydroxylase (TPH), thereby
reversing the negative regulatory effect of inflammatory
cytokines on neurotransmitters such as NE and 5-HT
and alleviating depressive behavior in rats [102]. The
release of NE is regulated by a variety of transmitters.
The decrease in NE in the MPA region caused by IL-1β is
mainly the result of its activation of GABAergic neurons,
which further exerts inhibitory effects on adrenergic neurons [103] (Fig. 7).
The effects of proinflammatory cytokines on the function of NE also include the regulation of its receptors.
The binding of NE to β2-adrenoceptors on the surface ofastrocytes induces the production of a large number ofnerve growth factors and promotes the growth of neuronal axons, while IFN-γ can activate the MAPK signaling
pathway, inhibit the expression of β2-adrenoceptors inastrocytes and attenuate the regeneration and repair ofaxonal branches induced by NE [104, 105].
GABAGABA is an inhibitory neurotransmitter widely distributed in the brain and spinal cord, and it mainly exists
in interneurons that send out negative feedback signals,

Fig. 7 Effects of immune cytokines on NE synthesis and release. IL-1β can
reduce NE synthesis by inhibiting TH activity and regulating the HPG axis,
increase NE synthesis by regulating the HPA axis, and reduce NE release by
activating GABAergic neurons. IL-6 can also reduce NE synthesis by inhibiting TH activity via the JAK-STAT3 signaling pathway, but the anti-inflammatory cytokine IL-4 can activate TH activity and increase NE synthesis

Page 9 of 19

thereby inhibiting 5-HT, DA and other neurotransmitters, and regulating hormone secretion, muscle contractions, blood pressure, heart rate, feeding, sleep, moodand other physiological activities. Normally, the inhibitory effect of GABAergic neurons helps coordinate thebody’s homeostasis, but abnormal GABA activity canalso lead to a variety of physiological dysfunctions [106].
GABA is primarily synthesized through the decarboxylation of glutamate, a process catalyzed by glutamic aciddecarboxylase (GAD), which is the main rate-limiting
enzyme for GABA synthesis. After synthesized GABA
is released into the synaptic cleft, it first interacts withreceptors on the postsynaptic membrane before being
removed from the synaptic cleft by diffusion effect andactively taken up by glial cells. The ingested GABA istransformed into Glu through transamination, and thelatter is further transformed into glutamine (Gln, an
amide of glutamate) under the catalysis of glutaminesynthetase (GS). As Gln regurgitates to neurons, it istransformed again into Glu by glutaminase (Glut), which
is subsequently transformed into new GABA under theaction of GAD. Studies have shown that IL-33 has anegative regulatory effect on GABA synthesis. LPS treatment of mice can lead to the overexpression of IL-33 inamygdala astrocytes. After being captured by IL-1Rs on
neurons in the CeA, IL-33 can activate NF-κB and downregulate the expression of BDNF directly or indirectly
through the MAPK signaling pathway, which further
decreases the GAD expression region and GABA synthesis in the medial prefrontal cortex (mPFC), resulting
in an attenuated inhibitory effect on GABAergic neuronal circuitry between the mPFC and CeA, and ultimately
leading to anxiety-like behaviors related to excitatoryneurotoxicity in the mice [29, 107] (Fig. 8A).
IL-1β, another ligand of IL-1R, can regulate GABA
release in the CeA. The frequency and amplitude ofminiature inhibitory postsynaptic currents (mIPSCs) in
GABAergic neurons change regularly with increasing or
decreasing IL-1β levels, indicating that IL-1β has a bidirectional regulatory effect on GABA release from thepresynaptic membrane. This forward or reverse regulatory effect is different in various clusters of GABAergic
neurons in the CeA region [108, 109]. An endogenous
antagonist of IL-1β can competitively bind to IL-1R but
generally does not cause downstream signals. However,its regulatory effect on spontaneous inhibitory postsynaptic currents (sIPSCs) of GABAergic neurons in the
CeA region was opposite to that of IL-1β. These results
indicate that IL-1β can also indirectly affect the action
potential of presynaptic neurons to induce GABA release[109, 110] (Fig. 8B, C).
IL-6 has also been reported to have a regulatory effecton GABAergic neurons, mainly by reducing the densityof functional GABA receptor A (GABAAR), increasingZhang et al. Journal of Neuroinflammation(2024) 21:159

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Fig. 8 Effects of inflammatory cytokines on GABA synthesis (A) and release (B, C). (A) GABA is primarily synthesized by Glu, and GAD is the main ratelimiting enzyme for GABA synthesis. The binding of IL-33 to IL-1R first activates MAPK and further activates the NF-κB signaling pathway to inhibit BDNF
synthesis, leading to a decrease in GAD expression and GABA synthesis. (B, C) IL-1β can regulate different GABAergic neurons, resulting in decreased orincreased GABA release and corresponding decreases or increases in the number of IPSCs. TNF-α/IL-1β/IL-6 can also decrease the expression of postsynaptic GABAAR and attenuate GABA-induced IPSC. However, IL-10 promotes GABA release from GABAergic neurons and enhances IPSC through the MAPK/
PI3K signaling pathway

the probability of GABAAR leaving the plasma membraneor decreasing the probability of GABAAR insertion into
the plasma membrane. Therefore, the effect of GABA is
attenuated, and the inhibitory or excitatory balance ofpostsynaptic neurons is disrupted [111]. The regulatory
effect of TNF-α on GABA is also related to its receptor.
Studies have shown that TNF-α binds to TNF-R1, activates the MAPK, PI3K, protein phosphatase 1 and dynein
GTPase 1 signaling pathways, downregulates the levels of
the α1, α2, β2, β3 and γ2 subunits of GABAAR on the cell
membrane surface, and rapidly and sustainably decreases
inhibitory synaptic strength in hippocampal GABAergic
neurons of adult rat and mouse [112]. The mixed administration of IL-1β, TNF-α and GM-CSF to mice also
showed that proinflammatory cytokines can increase thedysfunction of GABAAR by increasing the conversion of
the GABAAR α1-subunit, accelerating the attenuation of
GABA IPSC, and weakening its neuroinhibitory effect[113] (Fig. 8B).
Recent studies have shown that IL-10 can regulate therelease of GABA from presynaptic neurons in the amygdala through the MAPK and PI3K pathways or indirectly
affect the release of GABA from presynaptic neurons
induced by action potentials, thereby alleviating anxietylike behaviors. One study also revealed that the regulatory effect of IL-10 on GABA release in the amygdala ofmice with alcohol addiction was comprehensively weakened, and the level of GABA release in the amygdala ofmice with alcohol addiction increased after the remission of alcohol addiction, suggesting that the key mechanism involved in the effect of alcohol addiction is thedysfunction of IL-10 on GABA regulation. Therefore,
IL-10 can be used as a diagnostic indicator for alcohol
addiction and can be applied in the treatment of alcohol
addiction through the regulation of GABA release [30](Fig. 8C).
Glu

Glu, also known as alpha-amino glutaric acid, is the mostabundant amino acid neurotransmitter in the central
nervous system. As the precursor of GABA production in
the brain, Glu release causes the excitation of postsynaptic neurons, and together with GABA, Glu regulates thebalance between excitation and inhibition in the brain[114]. Glu in neurons can be produced by glucose bypass
metabolism through tricarboxylic acid (TCA) cycle.
After release, Glu is ingested by excitatory amino acidtransporters (EAATs) of astrocytes and synthesized into
Gln for storage. Gln from astrocytes is then transported
to neurons, where it is metabolized back into Glu in
response to Glut (Figs. 8A and 9). Insufficient Glu leads
to decreased excitability of neurons, and excessive releaseof Glu leads to hyperexcitability poisoning of postsynaptic neurons [114]. Abnormal Glu synthesis and release
are believed to be related to memory disorders, cognitive impairment, schizophrenia, depression, epilepsy andother neurological and psychiatric diseases [79].
Studies on the regulation and mechanism of inflammatory cytokines in glutamatergic neurons have focused
mainly on the effect of inflammatory cytokines on Glu
uptake by glial cells. For example, activated microglia release large amounts of IL-1β, which can lead toZhang et al. Journal of Neuroinflammation(2024) 21:159

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Fig. 9 Effects of inflammatory cytokines on Glu synthesis, release and uptake. TNF-α and IL-1β can promote the synthesis and release of Glu, activate
mGluR and AMPAR on the postsynaptic membrane, and cause mEPSC enhancement and neuronal excitotoxicity in postsynaptic neurons. Moreover,microglia-derived IL-1β can inhibit the expression of EAAT, reduce the transfer of Glu from the synaptic cleft to astrocytes, and aggravate the hyperexcitedstimulation of postsynaptic neurons by Glu. In addition, astrocytes absorb less Glu, transform and generate less Gln, and transport less Gln to glutamatergic neurons, a process that would balance Glu release from glutamatergic neurons to a certain extent

a decrease in EAAT activity and Glu uptake in astrocytes. The excessive presence of glutamate in the synaptic cleft leads to sustained activation of Ca2+-permeable
α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid
receptor (AMPAR) in postsynaptic neurons, resulting in
hyperexcitability [115, 116] (Fig. 9). Similar results havebeen demonstrated in mouse models of multiple sclerosis (MS), where IL-1β decreases EAAT expression in
cerebellar astrocytes and enhances the effect of Glu in
Purkinje cells. The duration of the miniature excitatory
postsynaptic currents (mEPSCs) is increased, resulting
in hyperexcitability poisoning of postsynaptic neurons[117] (Fig. 9). However, in the treatment of glaucomatous
retinal detachment, IL-1 plays a positive regulatory rolein Glu uptake by glial cells. The binding of IL-1 to IL-1Rin Muller cells can activate the P38 MAPK pathway andincrease the expression of caspase 11, which can promote actin fiber depolymerization mediated by cofilin.
As a result, actin-loaded Na+/K+-ATPase is more localized to the cell membrane, and the Na+ in Muller cells istransported to the outside of the cell. However, the glutamate transporter (GLAST) on the cell membrane needs
to transfer three Na+ ions in coordination with each Glu
ingested, so Na+/K+-ATPase increases the efficiency of
Glu ingestion through GLAST [118].
In addition, Shim et al. treated normal and TNFR1shRNA-transfected Bergmann glial cells with TNF-α
and found that TNF-α promoted the release of Glu from
Bergmann cells to the synaptic cleft of Purkinje cells. It
also enhanced the excitability of postsynaptic neurons byactivating metabotropic glutamate receptor 1 (mGluR1)[119] (Fig. 9). It has also been shown that inflammatory
cytokines can directly regulate the synthesis and releaseof Glu by neurons. When exploring the neurotoxicity of
TNF-α and IL-1β, Ye et al. reported that both could leadto simultaneous increases in intracellular and extracellular Glu content in human cortical neuron cells supplemented with Gln in culture medium, and Glut was nolonger localized only in the mitochondrial membrane,
but also in other intracellular or extracellular regions.
These results indicate that TNF-α and IL-1β can cause
neuronal excitatory intoxication by promoting the synthesis and release of Glu [120] (Fig. 9). In contrast, Zhou
et al. reported that IL-1β can upregulate the degradationof the synaptophysin protein by the E3 ligase siah1 via
the ERK signaling pathway and subsequently inhibit therelease of Glu, which impaired the learning and memory
ability of rats [121].
BDNF deficiency and dysfunction

BDNF typically exists as a dimer protein, with eachmonomer being a secreted, mature polypeptide composed of 119 amino acid residues. BDNF is predominantly expressed in the central nervous system and exerts
significant neurotrophic effects. It is the most abundantneurotrophic factor in the adult brain, particularly in the
hippocampus and cerebral cortex, where it plays crucial roles in axon growth, myelination, synaptogenesis,
and synaptic plasticity [122–124]. Compared to otherneurotrophic factors, BDNF has garnered considerable attention in depression research due to its involvement in neuronal repair during depression remission[124–127]. BDNF’s significance in this context has led toa focus on its mechanisms of action and interactions with
inflammatory factors, which can impact neural activities through various neurotrophic pathways. Given its
importance, BDNF will be used as a representative neurotrophic factor to discuss the effects and mechanisms
of inflammatory factors on neural activities mediatedby neurotrophic factors. Blood samples and depression

Zhang et al. Journal of Neuroinflammation(2024) 21:159

scale scores from elderly patients with depression showthat the levels of TNF-α and BDNF are negatively correlated, and the ratio of TNF-α to BDNF is consistent
with the Montgomery-Asberg Depression Rating Scale(MADRS) [128]. Other studies have confirmed that TNFα, IL-1β and IL-6 reduce the expression of BDNF in thebrain [129, 130], which further attenuates the activation of PI3K/Akt and MAPK P38, downstream signaling
molecules of TrkB (transmembrane receptor of BDNF
on neurons), leading to structural damage and dysfunction of neurons [26, 131, 132]. These results suggest that
inflammatory cytokines can induce BDNF deficiency anddysfunction.
Furthermore, BDNF/TrkB signaling often occurs at theend of axons, and BDNF and TrkB can first form endosomes through endocytosis and then undergo retrograde
transport to the cell body, leading to ERK5 phosphorylation and subsequent downstream effects. Carlos et al.
cultured the cell body and axon compartments of primary neurons to explore the mechanism by which IL-1β
affects BDNF and found that IL-1β attenuated the densityof BDNF endosomes in various regions of neurons andthat BDNF endosomes accumulated only in the terminal
region of axons. Subsequent investigations confirmedthat IL-1β induces the ubiquitination of BDNF endosomes, and these ubiquitinated endosomes are discarded
after sorting by the cell transport system, and the failureof retrograde transport blocked the downstream signal
activation of BDNF [133, 134]. In addition, in a study
showing that IL-1β affects long-term potentiation (LTP)in the dendritic spines of hippocampal neurons, IL-1βinhibited the phosphorylation of insulin receptor substrate 1, a protein that links the activation of the BDNF
receptor TrkB to downstream signaling pathways regulating CREB, Arc and cofilin, thereby blocking the effectof BDNF, attenuating P38 MAPK activation and actin
fiber polymerization, and interfering with memory consolidation [135].
Neuroplasticity attenuation

Neuroplasticity mainly refers to the regulation and rearrangement of neuronal genesis, differentiation and apoptosis, among which the plasticity of neuronal synapses
is the most commonly studied target in disease development and repair. Synaptic plasticity mainly includes
short-term synaptic plasticity and long-term synaptic
plasticity. Short-term synaptic plasticity includes facilitation, inhibition and enhancement. Long-term synaptic
plasticity is primarily manifested as LTP and long-term
depression (LTD). In menopause model mice subjected
to bilateral ovariectomy, neuronal plasticity in the hippocampus, hypothalamus and amygdala was altered, synaptic transmission and LTP of neurons were significantly

Page 12 of 19

weakened, and mice exhibited obvious spatial memory
deficits and depressive behaviors [136].
Inflammatory cytokines levels during menopause play
important roles in regulating synaptic plasticity. It has
been reported that a high concentration of TNF (1 µg/mL) can impair the plasticity of hippocampal CA1 pyramidal neurons in mice without affecting baseline synaptictransmission or previously established LTP. In contrast,a low concentration of TNF (1 ng/mL) promotes LTP inneurons, and the release of intracellular Ca2+ can preventthe negative effect of a high concentration of TNF on
synaptic plasticity, but when Ca2+ stores are depleted, theability of a low concentration of TNF to promote synaptic plasticity is lost [137]. Recent studies have shown that
the MAPK signaling pathway may mediate the inhibitory
effect of TNF-α on hippocampal LTP [138].
IL-6 also interferes with synaptic plasticity. The paired
pulse current (presynaptic and postsynaptic) in mPFC
neurons was measured by the patch clamp technique in
IL-6 signal-blocking and wild-type social failure chronic
stress model mice. The ratio of current generated by
N-methyl-D-aspartate receptor (NMDAR) and AMPAR
in stress-tolerant wild-type mice was significantly lower
than that in IL-6 signal-blocking mice, and the ratioof current generated by AMPA and GABAAR in stresssensitive wild-type mice was also significantly lower thanthat in IL-6 signal-blocking mice, indicating that IL-6
drives the negative rearrangement of synaptic plasticity in mPFC neurons during the formation of social failure behaviors [139]. IL-6 has also been shown to play a
key role in synaptic plasticity dysfunction in amygdala
neurons in mice with peripheral nerve injury-induced
depressive behavior. IL-6 activates the palmitoylatedtransferase DHHC3 through the PI3K signaling pathway
and promotes the palmitoylation of postsynaptic density
protein-95 (PSD-95), which binds to the postsynaptic
membrane Glu receptor 1 and aspartate receptor subunit NR2B, impinging on amygdala neurons from therest of the brain, resulting in depression-like behavior
in mice [140]. Tocilizumab, an IL-6 receptor antagonist,
can inhibit the activation of hippocampal microglia andastrocytes and the subsequent “inflammatory storm”
through the Wnt/β-catenin signaling pathway and restore
hippocampal synaptic plasticity [141].
Additionally, INF-γ is involved in the regulation ofneuroplasticity, which can lead to synaptic structural
instability by reshaping the morphology of neurons in
the nucleus accumbens, thus affecting opioid-induced
addictive withdrawal behavior [142]. INF-γ can induce anacute increase in the amplitude of IPSCs in GABAergic
neurons in a postsynaptic protein kinase C (PKC)-dependent manner and an acute increase in the frequency of
IPSCs in GABAergic neurons in an inducible nitric oxide
synthase- and soluble guanylate cyclase-dependent

Zhang et al. Journal of Neuroinflammation(2024) 21:159

Page 13 of 19

Fig. 10 Estrogen-immune-neuromodulation disorders promote menopausal depression. A significant decrease in estrogen levels in menopausal
women disrupts the homeostasis of the estrogen-immune-neuromodulation system, which first leads to immune imbalance, then induces nervous
disorders, and finally gradually causes depression in menopausal women. Current research on immune imbalance has focused mainly on microglia,
astrocytes, proinflammatory factors such as TNF-α, IL-1β, and IL-6, and anti-inflammatory factors such as IL-4 and IL-10. The investigation of neurological impairments involves BBB permeability, neurotransmitter activity, BDNF synthesis and neuronal plasticity. All these advances provide clues for thetargeted treatment of menopausal depression

manner. IFN-γ was observed to shift short-term synaptic
plasticity toward facilitation [143].
The immune factors IL-1β, IL-10 and IL-33 also playroles in the regulation of neuroplasticity. IL-1β inhibits the expression of the synaptic formation-related
molecules synaptophysin (SYP and SYN1), the postsynaptic
proteinα-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptor GluA1 subunit, theN-methyl-d-aspartate receptor NR2B subunit and PSD95 through histone deacetylase 4 (HDAC4), thus regulating the transcriptional inhibitor MeCP2 SUMO, resulting
in LTP deficits and decreased synaptic plasticity [144].
IL-10 has been found to significantly enhance synaptic transmission and synaptic plasticity in hippocampal glutamatergic neurons, increasing the frequency ofmEPSCs in a dose-dependent manner. In addition, IL-10
can induce postsynaptic compensatory changes such as
synaptic expansion, increased mEPSC amplitude, andenhanced Ca2+ responsiveness to the AMPA agonist
5-fluorouracil alanine in primary cultured hippocampal
glial synapses [145].

The regulation of neuroplasticity by IL-33 was discovered in the study of the mechanism of memory consolidation. Both memory accuracy and the expression of
IL-33 decreased simultaneously in aged mice, and IL-33
administration significantly alleviated age-related dendritic spine regression. IL-33 can also guide microglia tophagocytose the extracellular matrix, which is conduciveto the remodeling of synaptic connections between neurons and the functional integration of new neurons andincreases the accuracy of fear memory [146]. As a newmember of the IL-1 family, IL-33 is considered to play arole similar to that of a warning activator in the positive
regulation of synaptic plasticity; however, the detailed
mechanism is still unclear.

Therapeutic drugs for menopausal depression thattarget estrogen-immuno-neuromodulation
Currently, the primary therapeutic drugs used to treat
menopausal depression include fluoxetine, duloxetine,
escitalopram, mirtazapine, desvenlafaxine, quetiapine,modafinil and other neuromodulators [147–153]. However, these drugs do not address the decline in ovarianZhang et al. Journal of Neuroinflammation(2024) 21:159

Page 14 of 19

Table 1 Therapeutic drugs/agents for menopausal depression targeting the estrogen-immune-neuromodulation signaling pathway
Drugs/Agents
E2
ER-β selective
ligand C-1
Vivelle-Dot

Targets
ERα, ERβERβ

Subjects
Ovariectomized rats
Ovariectomized miceER

G03C, G03F

ER, PR

E2 + progesterone

ER, PR

Tibolone

ER, PR, AR

RSV

SIRT1

Women with past perimenopausal depression
and women with nohistory of depression
Women in Denmark
aged 45 years and over
Euthymic perimenopausal and early postmenopausal women
Perimenopausal
women with depressive
symptoms
Ovariectomized miceSIM

Astragalin

HydroxymethylOvariectomized rats
glutaryl coenzyme
A reductase
UnclearOvariectomized miceErxian decoction

UnclearOvariectomized miceω-3 polyunsaturated fatty acidN-3 polyunsaturated fatty acid
Fagopyrum tataricum seed extract
Acer tegmentosum

UnclearOvariectomized rats

UnclearOvariectomized rats

UnclearOvariectomized rats

UnclearOvariectomized rats

Saikosaponin A

UnclearChaihu-GuizhiGanjiang tang

Unclear36-week-old rats withchronic unpredictablemild stress
Perimenopausal andpostmenopausal
women with mooddisorderEfficacy
Synergized with escitalopram to exert anti-menopausal depression effects [154]
Reduced depressive-like behavior and also avoided uterine obesity in ovariectomized mice [155]
Reduced the recurrence and incidence of depression [156]Decreased the risk of depression for women aged 54 or older when were administered locally [157]
Effectively prevented the development of clinically significant depressive symptoms [158]
Exhibited exciting innovations for the treatment of menopausal depression
through tissue-selective activation of ER, PR or AR [159]
Ameliorated depression- and anxiety-like behaviors by inhibiting the activationof NLRP3 and NF-κB in the hippocampus [43]Alleviated depressive behavior in ovariectomized rats by inhibiting the activationof microglia and NLRP3 inflammasome, and the expression of P2X7R, TLR2 andTLR4 [44]Attenuated depression‑like behaviors by regulating the IL‑4R/JAK1/STAT6 signaling pathway [25]Relieved perimenopausal depression by regulating the levels of BDNF, Bcl-2, ER
and IL-6 [160]
Exerted antidepressant and neuroprotective activities through suppressing microglial M1 polarization and inhibiting proinflammatory cytokines expression [45]Decreased the levels of IL-6 and TNF-α and improved depressive behaviors inpostmenopausal depression rats [161]Inhibited the occurrence of depression-like behavior in ovariectomized rats bydecreasing the expression of IL-1β and IL-2 [67]Effectively decreased behavioral depression-like responses by downregulating
the expression of c-Fos and IL-1β [162]
Exerted the antidepressant-like effects by regulating the levels of IL-1β, IL-6 andTNF-α in the hippocampus [163]
Reduced plasma IL-6 and soluble IL-6 receptor concentrations and improved
depressed mood [164]PR, progesterone receptor; AR, androgenic receptor

function and estrogen levels in menopausal women, so
their therapeutic effect on menopausal depression is not
ideal. Consequently, ERT has gained attention as a potential treatment. E2, ERβ selective ligand C-1, Vivelle-Dot,
G03C, G03F, E2 + progesterone and tibolone have beenused to treat model animals or menopausal depression
patients [154–159]. Additionally, immune imbalances inmenopausal women are also of interest to researchers,
and immunomodulatory drugs and agents, such as RSV,SIM, astragalin, Erxian decoction, omega-3 (ω-3, also
called N-3) polyunsaturated fatty acid, Fagopyrum tataricum seed extract, Acer tegmentosum, Saikosaponin A and
Chaihu-Guizhi-Ganjiang tang, have been used to treat
menopausal depression model animals or perimenopausal and postmenopausal women with mood disorders

and shown good curative efficacy. However, the targets ofmost of these drugs and agents remain unclear [25, 43–
45, 67, 160–164]. Here, we summarize the names, known
targets, subjects and efficacy of these therapeutic drugs
and agents to provide a reference for further evaluation,
improvement or clinical trial research (Table 1).

Conclusion and future directions
In conclusion, a significant decrease in estrogen levels
disrupts immune homeostasis, particularly the levels of
the immune factors TNF-α, IL-1β, IL-4, IL-6, IL-10 and
IL-18 through the ERα/ERβ/GPER-associated NLRP3/
NF-κB signaling pathway, which involves many signaling molecules, such as TLR2, TLR4, P2X7R, SIRT1,
CREB, MS-KIF18A, PI3K, AKT, Gs, cAMP, PKA, PJA1,

Zhang et al. Journal of Neuroinflammation(2024) 21:159

Serpina3n, Src, and MMP-9 [19–24, 41, 43, 44, 47–49, 52,
54–56, 58]. Subsequently, the increase of inflammatory
cytokine levels causes BBB destruction [25, 62–74, 165],
the dysfunction of neurotransmitters such as 5-HT [80–85], DA [86–97], NE [98–105], GABA [29, 30, 106–113]
and Glu [79, 114–121], BDNF deficiency and dysfunction[26, 128–135], and attenuation of neuroplasticity [136–146], which are key factors in the onset and progressionof depression (Fig. 10). All of these studies have shownthat there is a complex regulatory system from estrogento immune signaling molecules to neurons, which wecall the estrogen-immune-neuromodulation system, andestrogen-immune-neuromodulation disorders cause susceptibility to depression in menopausal women (Fig. 10).
Therefore, drugs targeting inflammatory cytokines and
NLRP3/NF-κB signaling pathway-associated molecules
are promising for restoring homeostasis of the estrogenimmuno-neuromodulation system and may play a positive role in the intervention and treatment of menopausal
depression.
Although the main framework of the estrogenimmune-neuromodulation system is understood, many
details involving this regulatory system remain unclear.
For example, studies on the downstream signaling molecules of ERs and the stimulating factors of the NLRP3/
NF-κB signaling pathway are very extensive, and few
studies on the activation of NLRP3 and NF-κB causedby estrogen deficiency have clarified the interactions
between various molecules step by step, which has limited the development of targeted antidepressants. In
addition, there are some opposing and unified equilibrium points in the estrogen-immune-neuromodulation
system. Multiple studies focusing on IL-1β have shownthat IL-1β can not only decrease NE synthesis by disrupting the HPG system, GABA neurons and the expression of TH but also promote an increase in NE synthesis
through the HPA system [98, 99, 103] (Fig. 7). IL-1β acts
on different GABA neuron clusters in the amygdala andshows positive and negative regulatory effects [108–110](Fig. 8B). Coincidentally, low levels of IL-33 and othernew members of the IL-1 family show a positive regulatory effect on neuroplasticity, while high levels of IL-33
lead to a decrease in BDNF synthesis [29, 107] (Fig. 8A),
disrupting the construction of neural synapses. Our
understanding is that under normal circumstances, different elements of the body control a physiological activity in an appropriate state through mutual restriction
and coordination, so different doses of stimulus factors
affected by time and space are critical to maintaining or
upsetting the balance. The dramatic decrease in estrogenlevels in menopausal women triggers an imbalance inthe estrogen-immune-neuromodulation system, whichis the underlying reason why menopausal women are
more susceptible to depression. Therefore, accurately

Page 15 of 19

understanding the appropriate balance in the nervous
system and the regulatory mechanism is key for improving the clinical treatment of menopausal depression.

Supplementary Information

The online version contains supplementary material available at https://doi.
org/10.1186/s12974-024-03152-1.
Supplementary Material 1
Acknowledgements
Not applicable.
Author contributions
Y.Z. and X.T. wrote the original draft. C.T supervised, reviewed and edited themanuscript. C.T also participated in funding acquisition. All authors read andapproved the final manuscript.
Funding
This research was supported by the Henan Provincial Science and Technology
Research Projects (No. 232102210110 and 242102310555) to CT.
Data availability
No datasets were generated or analysed during the current study.

Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Received: 20 April 2024 / Accepted: 11 June 2024

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