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 in menopausal 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 imbalance caused 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, and investigated estrogen-immuno-neuromodulation disorders in menopausal depression. Current research suggests that 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.
Similar content being viewed by others
Introduction
Depression is a major cause of suicide and mortality worldwide [1, 2]. The vast majority of patients with depression 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 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 [5,6,8,9,10,11]. The relatively clear etiology of menopausal depression provides promising prospects for the investigation of neuronal dysfunction.
Some early breakthroughs in menopausal depression focused on the link between estrogen and depression [12,13,14]. Initially, an epidemiological survey of 16,080 women aged 35–60 years led to a preliminary 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 of depression [12]. Further analysis confirmed that estrogen can exert antidepressant effects by regulating the level of 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 system and peripheral blood were detected during the onset of menopausal depression [15,16,17], 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 [18,19,20,21], immune responses and regulatory factors [19,20,21,22,23,24,25,26,27] and nerve signaling molecules [26,27,28,29,30], the disturbance of signaling pathways in this complex system remains unclear and has not been comprehensively reviewed in menopausal 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 and possible mechanism of estrogen-immuno-neuromodulation disorders in menopausal depression, with the aim of providing scientific directions for further elucidating the pathogenesis of menopausal depression and develo** 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 in menopausal women and reproductive women revealed that the total number of lymphocytes in the menopausal women was lower; specifically, the number of B 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 level of 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 attenuated after 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 observed that 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 the anti-inflammatory factor IL-20 were lower [33]. Patients with 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 women indicate that a decrease in estrogen levels had an important impact on immune homeostasis, leading to the development of estrogen replacement therapy (ERT). Estrogens are cholesterol-derived steroid hormones with wide 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 a certain 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 level of 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 in regulating the immune status of menopausal women but cannot reverse the decline in immune function caused by aging [39]. Estrogen has also been found to have a positive 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 the level of the proinflammatory cytokine IL-6 in peripheral blood to a certain extent, inhibit the secretion of inflammatory cytokines by CD4+ T cells, and reduce the inflammatory 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 caused by estrogen deficiency
The mechanism of immune imbalance caused by estrogen deficiency has not yet been well investigated in menopausal 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 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 mainly on 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 of inflammasome 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 and NLRP3 inflammasome effectors caused by the activation of 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 caused by 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 and TLR4 in the hippocampus of ovariectomized rats and block 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 the expression of ERα and ERβ in the hippocampus and the expression of ERβ in the uterus of ovariectomized mice but did not increase uterine weight, suggesting that SIM may be a safer alternative to hormone replacement 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.
NLRP3 signaling pathways regulated by E2. Estrogen deficiency in ovariectomized mice or rats increases the expression of P2X7R, TLR2 and TLR4 in the hippocampus and further leads to the activation of NLRP3, which promotes the inflammatory cascade and increases the expression of 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 mice can inhibit the expression of P2X7R, TLR2 and TLR4, block these signaling pathways, and reverse the depression and anxiety-like behavior caused by 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 and the 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 this article.)
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, which leads to cognitive impairment and depressive behavior [45, 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 and the detailed pathogenesis of these impairments, providing a comprehensive overview of this complex phenomenon based on the findings of menopausal depression and its related fields. 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 decrease in estrogen levels have shown that the expression of the tight junction protein claudin-5 decreases during menopause and that the permeability of paracellular junctions to sucrose increases, thereby increasing the probability of brain edema and stroke [62, 63]. In the brain tissue of menopausal women or animal models, a decrease in estrogen levels caused an increase in the number of M1 microglia and activated astrocytes, which can secrete a large number of inflammatory cytokines. Therefore, inflammatory cytokines may play an important role in changes in BBB permeability [25, 140]. Tocilizumab, an IL-6 receptor antagonist, can inhibit the activation of hippocampal microglia and astrocytes and the subsequent “inflammatory storm” through the Wnt/β-catenin signaling pathway and restore hippocampal synaptic plasticity [143]. The immune factors IL-1β, IL-10 and IL-33 also play roles in the regulation of neuroplasticity. IL-1β inhibits the expression of the synaptic formation-related molecules synaptophysin (SYP and SYN1), the postsynaptic protein α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA1 subunit, the N-methyl-d-aspartate receptor NR2B subunit and PSD-95 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 of mEPSCs in a dose-dependent manner. In addition, IL-10 can induce postsynaptic compensatory changes such as synaptic expansion, increased mEPSC amplitude, and enhanced 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 to phagocytose the extracellular matrix, which is conducive to the remodeling of synaptic connections between neurons and the functional integration of new neurons and increases the accuracy of fear memory [146]. As a new member of the IL-1 family, IL-33 is considered to play a role similar to that of a warning activator in the positive regulation of synaptic plasticity; however, the detailed mechanism is still unclear. Currently, the primary therapeutic drugs used to treat menopausal depression include fluoxetine, duloxetine, escitalopram, mirtazapine, desvenlafaxine, quetiapine, modafinil and other neuromodulators [143,144,145,146], which are key factors in the onset and progression of depression (Fig. 10). All of these studies have shown that there is a complex regulatory system from estrogen to immune signaling molecules to neurons, which we call the estrogen-immune-neuromodulation system, and estrogen-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 estrogen-immuno-neuromodulation system and may play a positive role in the intervention and treatment of menopausal depression. 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 the targeted treatment of menopausal depression Although the main framework of the estrogen-immune-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 caused by 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 shown that 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 and shows positive and negative regulatory effects [108,109,110] (Fig. 8B). Coincidentally, low levels of IL-33 and other new 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 estrogen levels in menopausal women triggers an imbalance in the estrogen-immune-neuromodulation system, which is the underlying reason why menopausal women are more susceptible to depression. Therefore, accurately understanding the appropriate balance in the nervous system and the regulatory mechanism is key for improving the clinical treatment of menopausal depression.Neurological impairments caused by immune imbalance
BBB destruction
Therapeutic drugs for menopausal depression that target estrogen-immuno-neuromodulation
Data availability
No datasets were generated or analysed during the current study.
References
Wang Y, Cai X, Ma Y, Yang Y, Pan CW, Zhu X, Ke C. Metabolomics on depression: a comparison of clinical and animal research. J Affect Disord. 2024;349:559–68.
Kim JW, Suzuki K, Kavalali ET, Monteggia LM. Ketamine: mechanisms and relevance to treatment of depression. Annu Rev Med. 2024;75:129–43.
Wong S, Kwan ATH, Teopiz KM, Le GH, Meshkat S, Ho R, d’Andrea G, Cao B, Di Vincenzo JD, Rosenblat JD, McIntyre RS. A comparison between psilocybin and esketamine in treatment-resistant depression using number needed to treat (NNT): a systematic review. J Affect Disord. 2024;350:698–705.
Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22(3):238–49.
Demireva EY, Suri D, Morelli E, Mahadevia D, Chuhma N, Teixeira CM, Ziolkowski A, Hersh M, Fifer J, Bagchi S, Chemiakine A, Moore H, Gingrich JA, Balsam P, Rayport S, Ansorge MS. 5-HT2C receptor blockade reverses SSRI-associated basal ganglia dysfunction and potentiates therapeutic efficacy. Mol Psychiatry. 2020;25(12):3304–21.
Bravo K, González-Ortiz M, Beltrán-Castillo S, Cáceres D, Eugenín J. Development of the placenta and brain are affected by selective serotonin reuptake inhibitor exposure during critical periods. Adv Exp Med Biol. 2023;1428:179–98.
Hong X, Chen R, Zhang L, Yan L, **n J, Li J, Zha J. Long-term exposure to SSRI citalopram induces neurotoxic effects in zebrafish. Environ Sci Technol. 2022;56(17):12380–90.
Campbell KE, Dennerstein L, Finch S, Szoeke CE. Impact of menopausal status on negative mood and depressive symptoms in a longitudinal sample spanning 20 years. Menopause. 2017;24(5):490–6.
Gordon JL, Girdler SS, Meltzer-Brody SE, Stika CS, Thurston RC, Clark CT, Prairie BA, Moses-Kolko E, Joffe H, Wisner KL. Ovarian hormone fluctuation, neurosteroids, and HPA axis dysregulation in perimenopausal depression: a novel heuristic model. Am J Psychiatry. 2015;172(3):227–36.
Brown L, Hunter MS, Chen R, Crandall CJ, Gordon JL, Mishra GD, Rother V, Joffe H, Hickey M. Promoting good mental health over the menopause transition. Lancet. 2024;403(10430):969–83.
Herson M, Kulkarni J. Hormonal agents for the treatment of depression associated with the menopause. Drugs Aging. 2022;39(8):607–18.
Tangen T, Mykletun A. Depression and anxiety through the climacteric period: an epidemiological study (HUNT-II). J Psychosom Obstet Gynaecol. 2008;29(2):125–31.
Osterlund MK. Underlying mechanisms mediating the antidepressant effects of estrogens. Biochim Biophys Acta. 2010;1800(10):1136–44.
Chhibber A, Woody SK, Karim Rumi MA, Soares MJ, Zhao L. Estrogen receptor β deficiency impairs BDNF-5-HT(2A) signaling in the hippocampus of female brain: a possible mechanism for menopausal depression. Psychoneuroendocrinology. 2017;82:107–16.
Wang H, He Y, Sun Z, Ren S, Liu M, Wang G, Yang J. Microglia in depression: an overview of microglia in the pathogenesis and treatment of depression. J Neuroinflammation. 2022;19(1):132.
Dolotov OV, Inozemtseva LS, Myasoedov NF, Grivennikov IA. Stress-induced depression and alzheimer’s disease: focus on astrocytes. Int J Mol Sci. 2022;23(9):4999.
Wu A, Zhang J. Neuroinflammation, memory, and depression: new approaches to hippocampal neurogenesis. J Neuroinflammation. 2023;20(1):283.
Chakraborty B, Byemerwa J, Krebs T, Lim F, Chang CY, McDonnell DP. Estrogen receptor signaling in the immune system. Endocr Rev. 2023;44(1):117–41.
Jiang X, Chen Z, Yu X, Chen J, Sun C, **g C, Xu L, Liu F, Ni W, Chen L. Lipopolysaccharide-induced depression is associated with estrogen receptor-α/SIRT1/NF-κB signaling pathway in old female mice. Neurochem Int. 2021;148:105097.
Wang X, Jiang Y, Feng B, Ma X, Zhang K, Yang F, Liu Z, Yang L, Yue J, Lu L, Song D, Guo Q, Qi J, Li X, Wang M, Zhang H, Huang J, Zhao M, Liu S. PJA1 mediates the effects of astrocytic GPR30 on learning and memory in female mice. J Clin Invest. 2023;133(18):e165812.
Zhao TZ, Ding Q, Hu J, He SM, Shi F, Ma LT. GPER expressed on microglia mediates the anti-inflammatory effect of estradiol in ischemic stroke. Brain Behav. 2016;6(4):e00449.
Wang J, Hou Y, Zhang L, Liu M, Zhao J, Zhang Z, Ma Y, Hou W. Estrogen attenuates traumatic brain injury by inhibiting the activation of microglia and astrocyte-mediated neuroinflammatory responses. Mol Neurobiol. 2021;58(3):1052–61.
Xu Y, Sheng H, Bao Q, Wang Y, Lu J, Ni X. NLRP3 inflammasome activation mediates estrogen deficiency-induced depression- and anxiety-like behavior and hippocampal inflammation in mice. Brain Behav Immun. 2016;56:175–86.
Pratap UP, Patil A, Sharma HR, Hima L, Chockalingam R, Hariharan MM, Shitoot S, Priyanka HP, ThyagaRajan S. Estrogen-induced neuroprotective and anti-inflammatory effects are dependent on the brain areas of middle-aged female rats. Brain Res Bull. 2016;124:238–53.
Yao G, Bai Z, Niu J, Zhang R, Lu Y, Gao T, Wang H. Astragalin attenuates depression-like behaviors and memory deficits and promotes M2 microglia polarization by regulating IL-4R/JAK1/STAT6 signaling pathway in a murine model of perimenopausal depression. Psychopharmacology. 2022;239(8):2421–43.
Liu B, Zhang Y, Yang Z, Liu M, Zhang C, Zhao Y, Song C. ω-3 DPA protected neurons from neuroinflammation by balancing microglia M1/M2 polarizations through inhibiting NF-κB/MAPK p38 signaling and activating neuron-BDNF-PI3K/AKT pathways. Mar Drugs. 2021;19(11):587.
Tang CZ, Zhang DF, Yang JT, Liu QH, Wang YR, Wang WS. Overexpression of microRNA-301b accelerates hippocampal microglia activation and cognitive impairment in mice with depressive-like behavior through the NF-κB signaling pathway. Cell Death Dis. 2019;10(4):316.
Xu Y, Sheng H, Tang Z, Lu J, Ni X. Inflammation and increased IDO in hippocampus contribute to depression-like behavior induced by estrogen deficiency. Behav Brain Res. 2015;288:71–8.
Zhuang X, Zhan B, Jia Y, Li C, Wu N, Zhao M, Chen N, Guo Y, Du Y, Zhang Y, Cao B, Li Y, Zhu F, Guo C, Wang Q, Li Y, Zhang L. IL-33 in the basolateral amygdala integrates neuroinflammation into anxiogenic circuits via modulating BDNF expression. Brain Behav Immun. 2022;102:98–109.
Patel RR, Wolfe SA, Bajo M, Abeynaike S, Pahng A, Borgonetti V, D’Ambrosio S, Nikzad R, Edwards S, Paust S, Roberts AJ, Roberto M. IL-10 normalizes aberrant amygdala GABA transmission and reverses anxiety-like behavior and dependence-induced escalation of alcohol intake. Prog Neurobiol. 2021;199:101952.
Giglio T, Imro MA, Filaci G, Scudeletti M, Puppo F, De Cecco L, Indiveri F, Costantini S. Immune cell circulating subsets are affected by gonadal function. Life Sci. 1994;54(18):1305–12.
Priyanka HP, Sharma U, Gopinath S, Sharma V, Hima L, ThyagaRajan S. Menstrual cycle and reproductive aging alters immune reactivity, NGF expression, antioxidant enzyme activities, and intracellular signaling pathways in the peripheral blood mononuclear cells of healthy women. Brain Behav Immun. 2013;32:131–43.
Malutan AM, Dan M, Nicolae C, Carmen M. Proinflammatory and anti-inflammatory cytokine changes related to menopause. Prz Menopauzalny. 2014;13(3):162–8.
Wan Z, Qin X, Tian Y, Ouyang F, Wang G, Wan Q. Long-term consumption of green tea can reduce the degree of depression in postmenopausal women by increasing estradiol. Nutrients. 2023;15(21):4514.
Zare Z, Tehrani M, Zarbakhsh S, Mohammadi M. Protective effects of treadmill exercise on apoptotic neuronal damage and astrocyte activation in ovariectomized and/or diabetic rat prefrontal cortex: molecular and histological aspects. Int J Neurosci. 2022:1–9.
Rana AK, Sharma S, Patial V, Singh D. Lithium therapy subdues neuroinflammation to maintain pyramidal cells arborization and rescues neurobehavioural impairments in ovariectomized rats. Mol Neurobiol. 2022;59(3):1706–23.
Caiazza F, Ryan EJ, Doherty G, Winter DC, Sheahan K. Estrogen receptors and their implications in colorectal carcinogenesis. Front Oncol. 2015;5:19.
Kumru S, Godekmerdan A, Yilmaz B. Immune effects of surgical menopause and estrogen replacement therapy in peri-menopausal women. J Reprod Immunol. 2004;63(1):31–8.
Engelmann F, Rivera A, Park B, Messerle-Forbes M, Jensen JT, Messaoudi I. Impact of estrogen therapy on lymphocyte homeostasis and the response to seasonal influenza vaccine in post-menopausal women. PLoS ONE. 2016;11(2):e0149045.
McCarthy M, Raval AP. The peri-menopause in a woman’s life: a systemic inflammatory phase that enables later neurodegenerative disease. J Neuroinflammation. 2020;17(1):317.
Zusev M, Benayahu D. The regulation of MS-KIF18A expression and cross talk with estrogen receptor. PLoS ONE. 2009;4(7):e6407.
Toran-Allerand CD. Estrogen and the brain: beyond ER-alpha, ER-beta, and 17beta-estradiol. Ann N Y Acad Sci. 2005;1052:136–44.
Liu T, Ma Y, Zhang R, Zhong H, Wang L, Zhao J, Yang L, Fan X. Resveratrol ameliorates estrogen deficiency-induced depression- and anxiety-like behaviors and hippocampal inflammation in mice. Psychopharmacology. 2019;236(4):1385–99.
Menze ET, Ezzat H, Shawky S, Sami M, Selim EH, Ahmed S, Maged N, Nadeem N, Eldash S, Michel HE. Simvastatin mitigates depressive-like behavior in ovariectomized rats: possible role of NLRP3 inflammasome and estrogen receptors’ modulation. Int Immunopharmacol. 2021;95:107582.
Wu B, Song Q, Zhang Y, Wang C, Yang M, Zhang J, Han W, Jiang P. Antidepressant activity of ω-3 polyunsaturated fatty acids in ovariectomized rats: role of neuroinflammation and microglial polarization. Lipids Health Dis. 2020;19(1):4.
Zheng X, Wang J, Bi F, Li Y, **ao J, Chai Z, Li Y, Miao Z, Wang Y. Protective effects of Lycium barbarum polysaccharide on ovariectomy–induced cognition reduction in aging mice. Int J Mol Med. 2021;48(1):121.
Mishra P, Davies DA, Albensi BC. The interaction between NF-κB and estrogen in alzheimer’s disease. Mol Neurobiol. 2023;60(3):1515–26.
Li M, Zhang J, Chen W, Liu S, Liu X, Ning Y, Cao Y, Zhao Y. Supraphysiologic doses of 17β-estradiol aggravate depression-like behaviors in ovariectomized mice possibly via regulating microglial responses and brain glycerophospholipid metabolism. J Neuroinflammation. 2023;20(1):204.
Han R, Gu S, Zhang Y, Luo A, **g X, Zhao L, Zhao X, Zhang L. Estrogen promotes progression of hormone-dependent breast cancer through CCL2-CCR2 axis by upregulation of twist via PI3K/AKT/NF-κB signaling. Sci Rep. 2018;8(1):9575.
Alexander A, Irving AJ, Harvey J. Emerging roles for the novel estrogen-sensing receptor GPER1 in the CNS. Neuropharmacology. 2017;113(Pt B):652–60.
Tang H, Zhang Q, Yang L, Dong Y, Khan M, Yang F, Brann DW, Wang R. GPR30 mediates estrogen rapid signaling and neuroprotection. Mol Cell Endocrinol. 2014;387(1–2):52–8.
Zhang Z, Qin P, Deng Y, Ma Z, Guo H, Guo H, Hou Y, Wang S, Zou W, Sun Y, Ma Y, Hou W. The novel estrogenic receptor GPR30 alleviates ischemic injury by inhibiting TLR4-mediated microglial inflammation. J Neuroinflammation. 2018;15(1):206.
Brailoiu E, Dun SL, Brailoiu GC, Mizuo K, Sklar LA, Oprea TI, Prossnitz ER, Dun NJ. Distribution and characterization of estrogen receptor G protein-coupled receptor 30 in the rat central nervous system. J Endocrinol. 2007;193(2):311–21.
Bai N, Zhang Q, Zhang W, Liu B, Yang F, Brann D, Wang R. G-protein-coupled estrogen receptor activation upregulates interleukin-1 receptor antagonist in the hippocampus after global cerebral ischemia: implications for neuronal self-defense. J Neuroinflammation. 2020;17(1):45.
Pan MX, Li J, Ma C, Fu K, Li ZQ, Wang ZF. Sex-dependent effects of GPER activation on neuroinflammation in a rat model of traumatic brain injury. Brain Behav Immun. 2020;88:421–31.
Xue Y, Zhang Y, Wu Y, Zhao T. Activation of GPER-1 attenuates traumatic brain injury-induced neurological impairments in mice. Mol Neurobiol. 2024.
Notas G, Kampa M, Castanas E. G protein-coupled estrogen receptor in immune cells and its role in immune-related diseases. Front Endocrinol (Lausanne). 2020;11:579420.
Jiang M, Liu Y, Wu H, Ma Z, Gu X. High estrogen level modifies postoperative hyperalgesia via GPR30 and MMP-9 in dorsal root ganglia neurons. Neurochem Res. 2020;45(7):1661–73.
Prossnitz ER, Barton M. The G protein-coupled oestrogen receptor GPER in health and disease: an update. Nat Rev Endocrinol. 2023;19(7):407–24.
Pemberton K, Rosato M, Dedert C, DeLeon C, Arnatt C, Xu F. Differential effects of the G-protein-coupled estrogen receptor (GPER) on rat embryonic (E18) hippocampal and cortical neurons. eNeuro 2022; 9(4).
DeLeon C, Pemberton K, Green M, Kalajdzic V, Rosato M, Xu F, Arnatt C. Novel GPER agonist, CITFA, increases neurite growth in rat embryonic (E18) hippocampal neurons. ACS Chem Neurosci. 2022;13(8):1119–28.
Sandoval KE, Witt KA. Age and 17β-estradiol effects on blood-brain barrier tight junction and estrogen receptor proteins in ovariectomized rats. Microvasc Res. 2011;81(2):198–205.
Shin JA, Oh S, Ahn JH, Park EM. Estrogen receptor-mediated resveratrol actions on blood-brain barrier of ovariectomized mice. Neurobiol Aging. 2015;36(2):993–1006.
Butler T, Glodzik L, Wang XH, ** K, Li Y, Pan H, Zhou L, Chiang GC, Morim S, Wickramasuriya N, Tanzi E, Maloney T, Harvey P, Mao X, Razlighi QR, Rusinek H, Shungu DC, de Leon M, Atwood CS, Mozley PD. Positron Emission Tomography reveals age-associated hypothalamic microglial activation in women. Sci Rep. 2022;12(1):13351.
Itoh N, Itoh Y, Meyer CE, Suen TT, Cortez-Delgado D, Rivera Lomeli M, Wendin S, Somepalli SS, Golden LC, MacKenzie-Graham A, Voskuhl RR. Estrogen receptor beta in astrocytes modulates cognitive function in mid-age female mice. Nat Commun. 2023;14(1):6044.
Wei X, Li R, Li X, Wang B, Huang J, Mu H, Zhang Q, Zhang Z, Ru Y, Wu X, Qiu Y, Ye Y, Feng Y, Wang S, Chen H, Yi C, Wang J. iPSCs-derived mesenchymal stromal cells mitigate anxiety and neuroinflammation in aging female mice. Int J Biochem Cell Biol. 2023;155:106347.
Rana AK, Sharma S, Kumar R, Singh D. Buckwheat tartary regulates the Gsk-3β/β-catenin pathway to prevent neurobehavioral impairments in a rat model of surgical menopause. Metab Brain Dis. 2023;38(6):1859–75.
Gal Z, Torok D, Gonda X, Eszlari N, Anderson IM, Deakin B, Juhasz G, Bagdy G, Petschner P. Inflammation and blood-brain barrier in depression: interaction of CLDN5 and IL6 gene variants in stress-induced depression. Int J Neuropsychopharmacol. 2023;26(3):189–97.
Voirin AC, Perek N, Roche F. Inflammatory stress induced by a combination of cytokines (IL-6, IL-17, TNF-α) leads to a loss of integrity on bEnd.3 endothelial cells in vitro BBB model. Brain Res. 2020;1730:146647.
Dudek KA, Dion-Albert L, Lebel M, LeClair K, Labrecque S, Tuck E, Ferrer Perez C, Golden SA, Tamminga C, Turecki G, Mechawar N, Russo SJ, Menard C. Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression. Proc Natl Acad Sci U S A. 2020;117(6):3326–36.
Chen AQ, Fang Z, Chen XL, Yang S, Zhou YF, Mao L, **a YP, ** HJ, Li YN, You MF, Wang XX, Lei H, He QW, Hu B. Microglia-derived TNF-α mediates endothelial necroptosis aggravating blood brain-barrier disruption after ischemic stroke. Cell Death Dis. 2019;10(7):487.
Yang F, Zhao K, Zhang X, Zhang J, Xu B. ATP induces disruption of tight junction proteins via IL-1 beta-dependent MMP-9 activation of human blood-brain barrier in vitro. Neural Plast. 2016;2016:8928530.
Wang Y, ** S, Sonobe Y, Cheng Y, Horiuchi H, Parajuli B, Kawanokuchi J, Mizuno T, Takeuchi H, Suzumura A. Interleukin-1β induces blood-brain barrier disruption by downregulating sonic hedgehog in astrocytes. PLoS ONE. 2014;9(10):e110024.
Haruwaka K, Ikegami A, Tachibana Y, Ohno N, Konishi H, Hashimoto A, Matsumoto M, Kato D, Ono R, Kiyama H, Moorhouse AJ, Nabekura J, Wake H. Dual microglia effects on blood brain barrier permeability induced by systemic inflammation. Nat Commun. 2019;10(1):5816.
Tang CZ, Zhang YL, Wang WS, Li WG, Shi JP. Serum levels of high-sensitivity C-reactive protein at admission are more strongly associated with poststroke depression in acute ischemic stroke than homocysteine levels. Mol Neurobiol. 2016;53(4):2152–60.
Cossette É, Cloutier I, Tardif K, DonPierre G, Tanguay JF. Estradiol inhibits vascular endothelial cells pro-inflammatory activation induced by C-reactive protein. Mol Cell Biochem. 2013;373(1–2):137–47.
Lan XY, Yu H, Chen QJ, Zhai S, Zhang CF, Li F, Wang CZ, Yuan CS. Effect of liquiritin on neuroendocrine-immune network in menopausal rat model. Phytother Res. 2020;34(10):2665–74.
Cao LH, Qiao JY, Huang HY, Fang XY, Zhang R, Miao MS, Li XM. PI3K-AKT signaling activation and icariin: the potential effects on the perimenopausal depression-like rat model. Molecules. 2019;24(20):3700.
Duman RS, Sanacora G, Krystal JH. Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron. 2019;102(1):75–90.
Zhang K, Liu R, Gao Y, Ma W, Shen W. Electroacupuncture relieves LPS-induced depression-like behaviour in rats through IDO-mediated tryptophan-degrading pathway. Neuropsychiatr Dis Treat. 2020;16:2257–66.
Joaquim HPG, Costa AC, Gattaz WF, Talib LL. Kynurenine is correlated with IL-1β in plasma of schizophrenia patients. J Neural Transm (Vienna). 2018;125(5):869–73.
Correia AS, Vale N. Tryptophan metabolism in depression: a narrative review with a focus on serotonin and kynurenine pathways. Int J Mol Sci. 2022;23(15):8493.
Park B, Lee S, Jang Y, Park HY. Affective dysfunction mediates the link between neuroimmune markers and the default mode network functional connectivity, and the somatic symptoms in somatic symptom disorder. Brain Behav Immun. 2024;118:90–100.
Qiu X, Lu P, Zeng X, ** S, Chen X. Study on the mechanism for SIRT1 during the process of exercise improving depression. Brain Sci. 2023;13(5):719.
Atmaca HT. Expression of serotonin 2A, 2 C, 6 and 7 receptor and IL-6 mRNA in experimental toxoplasmic encephalitis in mice. Heliyon. 2019;5(11):e02890.
Lian TH, Guo P, Zhang YN, Li JH, Li LX, Ding DY, Li DN, Zhang WJ, Guan HY, Wang XM, Zhang W. Parkinson’s disease with depression: the correlations between neuroinflammatory factors and neurotransmitters in cerebrospinal fluid. Front Aging Neurosci. 2020;12:574776.
Dong L, Zheng YM, Luo XG, He ZY. High inflammatory tendency induced by malignant stimulation through imbalance of CD28 and CTLA-4/PD-1 contributes to dopamine neuron injury. J Inflamm Res. 2021;14:2471–82.
Vancassel S, Fanet H, Castanon N, De Monchaux C, Cussotto S, Capuron L. Tetrahydrobiopterin modulates the behavioral neuroinflammatory response to an LPS challenge in mice. Brain Behav Immun. 2022;105:139–48.
Sprouse J, Sampath C, Gangula P. 17β-Estradiol suppresses gastric inflammatory and apoptotic stress responses and restores nNOS-mediated gastric emptying in streptozotocin (STZ)-induced diabetic female mice. Antioxid (Basel). 2023;12(3):758.
Singh G, Mittra N, Singh C. Tempol and silymarin rescue from zinc-induced degeneration of dopaminergic neurons through modulation of oxidative stress and inflammation. Mol Cell Biochem. 2023;478(8):1705–18.
Lee HJ, Choe K, Park JS, Khan A, Kim MW, Park TJ, Kim MO. O-cyclic phytosphingosine-1-phosphate protects against motor dysfunctions and glial cell mediated neuroinflammation in the Parkinson’s disease mouse models. Antioxid (Basel). 2022;11(11):2107.
Graves SM, **e Z, Stout KA, Zampese E, Burbulla LF, Shih JC, Kondapalli J, Patriarchi T, Tian L, Brichta L, Greengard P, Krainc D, Schumacker PT, Surmeier DJ. Dopamine metabolism by a monoamine oxidase mitochondrial shuttle activates the electron transport chain. Nat Neurosci. 2020;23(1):15–20.
Erbaş O, Taşkıran D. Sepsis-induced changes in behavioral stereotypy in rats; involvement of tumor necrosis factor-alpha, oxidative stress, and dopamine turnover. J Surg Res. 2014;186(1):262–68.
Wu Y, Na X, Zang Y, Cui Y, **n W, Pang R, Zhou L, Wei X, Li Y, Liu X. Upregulation of tumor necrosis factor-alpha in nucleus accumbens attenuates morphine-induced rewarding in a neuropathic pain model. Biochem Biophys Res Commun. 2014;449(4):502–7.
Zhu CB, Lindler KM, Owens AW, Daws LC, Blakely RD, Hewlett WA. Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters. Neuropsychopharmacology. 2010;35(13):2510–20.
Morón JA, Zakharova I, Ferrer JV, Merrill GA, Hope B, Lafer EM, Lin ZC, Wang JB, Javitch JA, Galli A, Shippenberg TS. Mitogen-activated protein kinase regulates dopamine transporter surface expression and dopamine transport capacity. J Neurosci. 2003;23(24):8480–8.
Felger JC, Mun J, Kimmel HL, Nye JA, Drake DF, Hernandez CR, Freeman AA, Rye DB, Goodman MM, Howell LL, Miller AH. Chronic interferon-α decreases dopamine 2 receptor binding and striatal dopamine release in association with anhedonia-like behavior in nonhuman primates. Neuropsychopharmacology. 2013;38(11):2179–87.
Sirivelu MP, MohanKumar PS, MohanKumar SM. Interleukin-1 beta simultaneously affects the stress and reproductive axes by modulating norepinephrine levels in different brain areas. Life Sci. 2012;91(17–18):878–84.
Sirivelu MP, Shin AC, Perez GI, MohanKumar PS, MohanKumar SM. Effect of L-dopa on interleukin-1 beta-induced suppression of luteinizing hormone secretion in intact female rats. Hum Reprod. 2009;24(3):718–25.
Nagatsu T, Nakashima A, Watanabe H, Ito S, Wakamatsu K, Zucca FA, Zecca L, Youdim M, Wulf M, Riederer P, Dijkstra JM. The role of tyrosine hydroxylase as a key player in neuromelanin synthesis and the association of neuromelanin with Parkinson’s disease. J Neural Transm (Vienna). 2023;130(5):611–25.
Li R, Hou J, Xu Q, Liu QJ, Shen YJ, Rodin G, Li M. High level interleukin-6 in the medium of human pancreatic cancer cell culture suppresses production of neurotransmitters by PC12 cell line. Metab Brain Dis. 2012;27(1):91–100.
Park HJ, Shim HS, An K, Starkweather A, Kim KS, Shim I. IL-4 inhibits IL-1β-induced depressive-like behavior and central neurotransmitter alterations. Mediators Inflamm. 2015; 2015:941413.
Sirivelu MP, Burnett R, Shin AC, Kim C, MohanKumar PS, MohanKumar SM. Interaction between GABA and norepinephrine in interleukin-1beta-induced suppression of the luteinizing hormone surge. Brain Res. 2009;1248:107–14.
Day JS, O’Neill E, Cawley C, Aretz NK, Kilroy D, Gibney SM, Harkin A, Connor TJ. Noradrenaline acting on astrocytic β₂-adrenoceptors induces neurite outgrowth in primary cortical neurons. Neuropharmacology. 2014;77:234–48.
Ryan KM, Boyle NT, Harkin A, Connor TJ. Dexamethasone attenuates inflammatory-mediated suppression of β(2)-adrenoceptor expression in rat primary mixed glia. J Neuroimmunol. 2020;338:577082.
Milanez MIO, Silva AM, Perry JC, Faber J, Nishi EE, Bergamaschi CT, Campos RR. Pattern of sympathetic vasomotor activity induced by GABAergic inhibition in the brain and spinal cord. Pharmacol Rep. 2020;72(1):67–79.
Vainchtein ID, Chin G, Cho FS, Kelley KW, Miller JG, Chien EC, Liddelow SA, Nguyen PT, Nakao-Inoue H, Dorman LC, Akil O, Joshita S, Barres BA, Paz JT, Molofsky AB, Molofsky AV. Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science. 2018;359(6381):1269–73.
Bajo M, Varodayan FP, Madamba SG, Robert AJ, Casal LM, Oleata CS, Siggins GR, Roberto M. IL-1 interacts with ethanol effects on GABAergic transmission in the mouse central amygdala. Front Pharmacol. 2015;6:49.
Patel RR, Khom S, Steinman MQ, Varodayan FP, Kiosses WB, Hedges DM, Vlkolinsky R, Nadav T, Polis I, Bajo M, Roberts AJ, Roberto M. IL-1β expression is increased and regulates GABA transmission following chronic ethanol in mouse central amygdala. Brain Behav Immun. 2019;75:208–19.
Bajo M, Herman MA, Varodayan FP, Oleata CS, Madamba SG, Harris RA, Blednov YA, Roberto M. Role of the IL-1 receptor antagonist in ethanol-induced regulation of GABAergic transmission in the central amygdala. Brain Behav Immun. 2015;45:189–97.
Pribiag H, Stellwagen D. TNF-α downregulates inhibitory neurotransmission through protein phosphatase 1-dependent trafficking of GABA(A) receptors. J Neurosci. 2013;33(40):15879–93.
Garcia-Oscos F, Salgado H, Hall S, Thomas F, Farmer GE, Bermeo J, Galindo LC, Ramirez RD, D’Mello S, Rose-John S, Atzori M. The stress-induced cytokine interleukin-6 decreases the inhibition/excitation ratio in the rat temporal cortex via trans-signaling. Biol Psychiatry. 2012;71(7):574–82.
Giacco V, Panattoni G, Medelin M, Bonechi E, Aldinucci A, Ballerini C, Ballerini L. Cytokine inflammatory threat, but not LPS one, shortens GABAergic synaptic currents in the mouse spinal cord organotypic cultures. J Neuroinflammation. 2019;16(1):127.
Andersen JV, Schousboe A, Verkhratsky A. Astrocyte energy and neurotransmitter metabolism in Alzheimer’s disease: integration of the glutamate/GABA-glutamine cycle. Prog Neurobiol. 2022;217:102331.
Charles-Messance H, Blot G, Couturier A, Vignaud L, Touhami S, Beguier F, Siqueiros L, Forster V, Barmo N, Augustin S, Picaud S, Sahel JA, Rendon A, Grosche A, Tadayoni R, Sennlaub F, Guillonneau X. IL-1β induces rod degeneration through the disruption of retinal glutamate homeostasis. J Neuroinflammation. 2020;17(1):1.
Chen Y, Li X, **ong Q, Du Y, Luo M, Yi L, Pang Y, Shi X, Wang YT, Dong Z. Inhibiting NLRP3 inflammasome signaling pathway promotes neurological recovery following hypoxic-ischemic brain damage by increasing p97-mediated surface GluA1-containing AMPA receptors. J Transl Med. 2023;21(1):567.
Mandolesi G, Musella A, Gentile A, Grasselli G, Haji N, Sepman H, Fresegna D, Bullitta S, De Vito F, Musumeci G, Di Sanza C, Strata P, Centonze D. Interleukin-1β alters glutamate transmission at purkinje cell synapses in a mouse model of multiple sclerosis. J Neurosci. 2013;33(29):12105–21.
Namekata K, Harada C, Kohyama K, Matsumoto Y, Harada T. Interleukin-1 stimulates glutamate uptake in glial cells by accelerating membrane trafficking of Na+/K+-ATPase via actin depolymerization. Mol Cell Biol. 2008;28(10):3273–80.
Shim HG, Jang SS, Kim SH, Hwang EM, Min JO, Kim HY, Kim YS, Ryu C, Chung G, Kim Y, Yoon BE, Kim SJ. TNF-α increases the intrinsic excitability of cerebellar Purkinje cells through elevating glutamate release in Bergmann Glia. Sci Rep. 2018;8(1):11589.
Ye L, Huang Y, Zhao L, Li Y, Sun L, Zhou Y, Qian G, Zheng JC. IL-1β and TNF-α induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase. J Neurochem. 2013;125(6):897–908.
Zhou Q, Lin L, Li H, Li Y, Liu N, Wang H, Jiang S, Li Q, Chen Z, Lin Y, ** H, Deng Y. Intrahippocampal injection of IL-1β upregulates Siah1-mediated degradation of synaptophysin by activation of the ERK signaling in male rat. J Neurosci Res. 2023;101(6):930–51.
Albini M, Krawczun-Rygmaczewska A, Cesca F. Astrocytes and brain-derived neurotrophic factor (BDNF). Neurosci Res. 2023;197:42–51.
Li Y, Li F, Qin D, Chen H, Wang J, Wang J, Song S, Wang C, Wang Y, Liu S, Gao D, Wang ZH. The role of brain derived neurotrophic factor in central nervous system. Front Aging Neurosci. 2022;14:986443.
Wang CS, Kavalali ET, Monteggia LM. BDNF signaling in context: from synaptic regulation to psychiatric disorders. Cell. 2022;185(1):62–76.
Zhang JC, Yao W, Hashimoto K. Brain-derived neurotrophic factor (BDNF)-TrkB signaling in inflammation-related depression and potential therapeutic targets. Curr Neuropharmacol. 2016;14(7):721–31.
Correia AS, Cardoso A, Vale N. BDNF unveiled: exploring its role in major depression disorder serotonergic imbalance and associated stress conditions. Pharmaceutics. 2023;15(8):2081.
Baek DC, Kang JY, Lee JS, Lee EJ, Son CG. Linking alterations in estrogen receptor expression to memory deficits and depressive behavior in an ovariectomy mouse model. Sci Rep. 2024;14(1):6854.
Loef D, Vansteelandt K, Oudega ML, van Eijndhoven P, Carlier A, van Exel E, Rhebergen D, Sienaert P, Vandenbulcke M, Bouckaert F, Dols A. The ratio and interaction between neurotrophin and immune signaling during electroconvulsive therapy in late-life depression. Brain Behav Immun Health. 2021;18:100389.
Feng X, Ma X, Li J, Zhou Q, Liu Y, Song J, Liu J, Situ Q, Wang L, Zhang J, Lin F. Inflammatory pathogenesis of post-stroke depression. Aging and disease.; 2024.
Zhang YM, Wei RM, Feng YZ, Zhang KX, Ge YJ, Kong XY, Li XY, Chen GH. Sleep deprivation aggravates lipopolysaccharide-induced anxiety, depression and cognitive impairment: the role of pro-inflammatory cytokines and synaptic plasticity-associated proteins. J Neuroimmunol. 2024;386:578252.
Wu Y, Zhu Z, Lan T, Li S, Li Y, Wang C, Feng Y, Mao X, Yu S. Levomilnacipran improves lipopolysaccharide-induced dysregulation of synaptic plasticity and depression-like behaviors via activating BDNF/TrkB mediated PI3K/Akt/mTOR signaling pathway. Mol Neurobiol. 2023.
Gao R, Ali T, Liu Z, Li A, Hao L, He L, Yu X, Li S. Ceftriaxone averts neuroinflammation and relieves depressive-like behaviors via GLT-1/TrkB signaling. Biochem Biophys Res Commun. 2024;701:149550.
Carlos AJ, Tong L, Prieto GA, Cotman CW. IL-1β impairs retrograde flow of BDNF signaling by attenuating endosome trafficking. J Neuroinflammation. 2017;14(1):29.
Bronfman FC, Escudero CA, Weis J, Kruttgen A. Endosomal transport of neurotrophins: roles in signaling and neurodegenerative diseases. Dev Neurobiol. 2007;67(9):1183–203.
Tong L, Prieto GA, Kramár EA, Smith ED, Cribbs DH, Lynch G, Cotman CW. Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-1β via p38 mitogen-activated protein kinase. J Neurosci. 2012;32(49):17714–24.
Yan YD, Chen YQ, Wang CY, Ye CB, Hu ZZ, Behnisch T, Huang ZL, Yang SR. Chronic modafinil therapy ameliorates depressive-like behavior, spatial memory and hippocampal plasticity impairments, and sleep-wake changes in a surgical mouse model of menopause. Transl Psychiatry. 2021;11(1):116.
Maggio N, Vlachos A. Tumor necrosis factor (TNF) modulates synaptic plasticity in a concentration-dependent manner through intracellular calcium stores. J Mol Med (Berl). 2018;96(10):1039–47.
Yang Q, Zhang Y, Zhang L, Li X, Dong R, Song C, Cheng L, Shi M, Zhao H. Combination of tea polyphenols and proanthocyanidins prevents menopause-related memory decline in rats via increased hippocampal synaptic plasticity by inhibiting p38 MAPK and TNF-α pathway. Nutr Neurosci. 2022;25(9):1909–27.
Esquivel-Rendón E, Vargas-Mireles J, Cuevas-Olguín R, Miranda-Morales M, Acosta-Mares P, García-Oscos F, Pineda JC, Salgado H, Rose-John S, Atzori M. Interleukin 6 dependent synaptic plasticity in a social defeat-susceptible prefrontal cortex circuit. Neuroscience. 2019;414:280–96.
Liu L, Dai L, Xu D, Wang Y, Bai L, Chen X, Li M, Yang S, Tang Y. Astrocyte secretes IL-6 to modulate PSD-95 palmitoylation in basolateral amygdala and depression-like behaviors induced by peripheral nerve injury. Brain Behav Immun. 2022;104:139–54.
Xu D, Xu Y, Gao X, Yan M, Zhang C, Wu X, **a Q, Ge J. Potential value of Interleukin-6 as a diagnostic biomarker in human MDD and the antidepressant effect of its receptor antagonist tocilizumab in lipopolysaccharide-challenged rats. Int Immunopharmacol. 2023;124Pt B:110903.
Zhu Y, Yan P, Wang R, Lai J, Tang H, **ao X, Yu R, Bao X, Zhu F, Wang K, Lu Y, Dang J, Zhu C, Zhang R, Dang W, Zhang B, Fu Q, Zhang Q, Kang C, Chen Y, Chen X, Liang Q, Wang K. Opioid-induced fragile-like regulatory T cells contribute to withdrawal. Cell. 2023;186(3):591–e606523.
Döhne N, Falck A, Janach GMS, Byvaltcev E, Strauss U. Interferon-γ augments GABA release in the develo** neocortex via nitric oxide synthase/soluble guanylate cyclase and constrains network activity. Front Cell Neurosci. 2022;16:913299.
Li Puma DD, Colussi C, Bandiera B, Puliatti G, Rinaudo M, Cocco S, Paciello F, Re A, Ripoli C, De Chiara G, Bertozzi A, Palamara AT, Piacentini R, Grassi C. Interleukin 1β triggers synaptic and memory deficits in herpes simplex virus type-1-infected mice by downregulating the expression of synaptic plasticity-related genes via the epigenetic MeCP2/HDAC4 complex. Cell Mol Life Sci. 2023;80(6):172.
Nenov MN, Konakov MV, Teplov IY, Levin SG. Interleukin-10 facilitates glutamatergic synaptic transmission and homeostatic plasticity in cultured hippocampal neurons. Int J Mol Sci. 2019;20(13):3375.
Nguyen PT, Dorman LC, Pan S, Vainchtein ID, Han RT, Nakao-Inoue H, Taloma SE, Barron JJ, Molofsky AB, Kheirbek MA, Molofsky AV. Microglial remodeling of the extracellular matrix promotes synapse plasticity. Cell. 2020;182(2):388–e403315.
Zhou J, Wang X, Feng L, **ao L, Yang R, Zhu X, Shi H, Hu Y, Chen R, Boyce P, Wang G. Venlafaxine vs. fluoxetine in postmenopausal women with major depressive disorder: an 8-week, randomized, single-blind, active-controlled study. BMC Psychiatry. 2021;21(1):260.
Joffe H, Soares CN, Petrillo LF, Viguera AC, Somley BL, Koch JK, Cohen LS. Treatment of depression and menopause-related symptoms with the serotonin-norepinephrine reuptake inhibitor duloxetine. J Clin Psychiatry. 2007;68(6):943–50.
Li S, Li ZF, Wu Q, Guo XC, Xu ZH, Li XB, Chen R, Zhou DY, Wang C, Duan Q, Sun J, Luo D, Li MY, Wang JL, **e H, Xuan LH, Su SY, Huang DM, Liu ZS, Fu WB. A Multicenter, Randomized, Controlled trial of electroacupuncture for perimenopause women with mild-moderate depression. Biomed Res Int. 2018; 2018:5351210.
Joffe H, Groninger H, Soares CN, Nonacs R, Cohen LS. An open trial of mirtazapine in menopausal women with depression unresponsive to estrogen replacement therapy. J Womens Health Gend Based Med. 2001;10(10):999–1004.
Kornstein SG, Clayton AH, Bao W, Guico-Pabia CJ. A pooled analysis of the efficacy of desvenlafaxine for the treatment of major depressive disorder in perimenopausal and postmenopausal women. J Womens Health (Larchmt). 2015;24(4):281–90.
Soares CN, Thase ME, Clayton A, Guico-Pabia CJ, Focht K, Jiang Q, Kornstein SG, Ninan PT, Kane CP. Open-label treatment with desvenlafaxine in postmenopausal women with major depressive disorder not responding to acute treatment with desvenlafaxine or escitalopram. CNS Drugs. 2011;25(3):227–38.
Soares CN, Frey BN, Haber E, Steiner M. A pilot, 8-week, placebo lead-in trial of quetiapine extended release for depression in midlife women: impact on mood and menopause-related symptoms. J Clin Psychopharmacol. 2010;30(5):612–15.
Ibrahim WW, Safar MM, Khattab MM, Agha AM. 17β-Estradiol augments antidepressant efficacy of escitalopram in ovariectomized rats: neuroprotective and serotonin reuptake transporter modulatory effects. Psychoneuroendocrinology. 2016;74:240–50.
Sasayama D, Sugiyama N, Yonekubo S, Pawlak A, Murasawa H, Nakamura M, Hayashi M, Ogawa T, Moro M, Washizuka S, Amano N, Hongo K, Ohnota H. Novel oestrogen receptor β-selective ligand reduces obesity and depressive-like behaviour in ovariectomized mice. Sci Rep. 2017;7(1):4663.
Schmidt PJ, Ben Dor R, Martinez PE, Guerrieri GM, Harsh VL, Thompson K, Koziol DE, Nieman LK, Rubinow DR. Effects of estradiol withdrawal on mood in women with past perimenopausal depression: a randomized clinical trial. JAMA Psychiatry. 2015;72(7):714–26.
Wium-Andersen MK, Jørgensen TSH, Halvorsen AH, Hartsteen BH, Jørgensen MB, Osler M. Association of hormone therapy with depression during menopause in a cohort of Danish women. JAMA Netw Open. 2022;5(11):e2239491.
Gordon JL, Rubinow DR, Eisenlohr-Moul TA, **a K, Schmidt PJ, Girdler SS. Efficacy of transdermal estradiol and micronized progesterone in the prevention of depressive symptoms in the menopause transition: a randomized clinical trial. JAMA Psychiatry. 2018;75(2):149–57.
Kulkarni J, Gavrilidis E, Thomas N, Hudaib AR, Worsley R, Thew C, Bleeker C, Gurvich C. Tibolone improves depression in women through the menopause transition: a double-blind randomized controlled trial of adjunctive tibolone. J Affect Disord. 2018;236:88–92.
Zhang L, Li J, Chen Q, Di L, Li N. Erxian decoction, a famous Chinese medicine formula, ameliorate depression- like behavior in perimenopausal mice. Endocr Metab Immune Disord Drug Targets. 2021;21(12):2203–12.
Choi JE, Borkowski K, Newman JW, Park Y. N-3 PUFA improved post-menopausal depression induced by maternal separation and chronic mild stress through serotonergic pathway in rats-effect associated with lipid mediators. J Nutr Biochem. 2021;91:108599.
Park HJ, Shim HS, Park S, Shim I. Antidepressant effect and neural mechanism of Acer tegmentosum in repeated stress-induced ovariectomized female rats. Anim Cells Syst (Seoul). 2020;24(4):205–13.
Chen XQ, Chen SJ, Liang WN, Wang M, Li CF, Wang SS, Dong SQ, Yi LT, Li CD. Saikosaponin A attenuates perimenopausal depression-like symptoms by chronic unpredictable mild stress. Neurosci Lett. 2018;662:283–9.
Ushiroyama T, Ikeda A, Sakuma K, Ueki M. Chai-Hu-Gui-Zhi-Gan-Jiang-Tang regulates plasma interleukin-6 and soluble interleukin-6 receptor concentrations and improves depressed mood in climacteric women with insomnia. Am J Chin Med. 2005;33(5):703–11.
Nusslock R, Alloy LB, Brody GH, Miller GE. Annual research review: neuroimmune network model of depression: a developmental perspective. J Child Psychol Psychiatry. 2024.
Acknowledgements
Not applicable.
Funding
This research was supported by the Henan Provincial Science and Technology Research Projects (No. 232102210110 and 242102310555) to CT.
Author information
Authors and Affiliations
Contributions
Y.Z. and X.T. wrote the original draft. C.T supervised, reviewed and edited the manuscript. C.T also participated in funding acquisition. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
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) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of 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.
About this article
Cite this article
Zhang, Y., Tan, X. & Tang, C. Estrogen-immuno-neuromodulation disorders in menopausal depression. J Neuroinflammation 21, 159 (2024). https://doi.org/10.1186/s12974-024-03152-1
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s12974-024-03152-1