Shaping Microglial Phenotypes Through Estrogen Receptors: Relevance to Sex-Specific Neuroinflammatory Responses to Brain Injury and Disease

Acosta-Martínez, Maricedes

doi:10.1124/jpet.119.264598

Cited by 32 publications

(18 citation statements)

References 150 publications

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“…We recently demonstrated that this difference was driven by signaling through estrogen receptor alpha in myeloid cells, but unexpectedly in males and not females ( 30 ), most likely via conversion of androgens to estrogens and subsequent estrogen receptor activation. Our findings in the present study, demonstrating that the p38α-mediated sex difference is in fact driven by a difference in male microglia, are completely compatible, and further highlight the known role for microglia in sensing endogenous estrogens that may be locally produced in the CNS ( 54 ). Moreover, our upstream regulator analysis of p38α-dependent DEGs in male microglial clusters identified ESR1 as a potential positive regulator ( Figure S7B ).…”

Section: Discussionsupporting

confidence: 85%

p38 MAP Kinase Signaling in Microglia Plays a Sex-Specific Protective Role in CNS Autoimmunity and Regulates Microglial Transcriptional States

et al. 2021

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Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system, representing the leading cause of non-traumatic neurologic disease in young adults. This disease is three times more common in women, yet more severe in men, but the mechanisms underlying these sex differences remain largely unknown. MS is initiated by autoreactive T helper cells, but CNS-resident and CNS-infiltrating myeloid cells are the key proximal effector cells regulating disease pathology. We have previously shown that genetic ablation of p38α MAP kinase broadly in the myeloid lineage is protective in the autoimmune model of MS, experimental autoimmune encephalomyelitis (EAE), but only in females, and not males. To precisely define the mechanisms responsible, we used multiple genetic approaches and bone marrow chimeras to ablate p38α in microglial cells, peripheral myeloid cells, or both. Deletion of p38α in both cell types recapitulated the previous sex difference, with reduced EAE severity in females. Unexpectedly, deletion of p38α in the periphery was protective in both sexes. In contrast, deletion of p38α in microglia exacerbated EAE in males only, revealing opposing roles of p38α in microglia vs. periphery. Bulk transcriptional profiling revealed that p38α regulated the expression of distinct gene modules in male vs. female microglia. Single-cell transcriptional analysis of WT and p38α-deficient microglia isolated from the inflamed CNS revealed a diversity of complex microglial states, connected by distinct convergent transcriptional trajectories. In males, microglial p38α deficiency resulted in enhanced transition from homeostatic to disease-associated microglial states, with the downregulation of regulatory genes such as Atf3, Rgs1, Socs3, and Btg2, and increased expression of inflammatory genes such as Cd74, Trem2, and MHC class I and II genes. In females, the effect of p38α deficiency was divergent, exhibiting a unique transcriptional profile that included an upregulation of tissue protective genes, and a small subset of inflammatory genes that were also upregulated in males. Taken together, these results reveal a p38α-dependent sex-specific molecular pathway in microglia that is protective in CNS autoimmunity in males, suggesting that autoimmunity in males and females is driven by distinct cellular and molecular pathways, thus suggesting design of future sex-specific therapeutic approaches.

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Section: Discussionsupporting

confidence: 85%

p38 MAP Kinase Signaling in Microglia Plays a Sex-Specific Protective Role in CNS Autoimmunity and Regulates Microglial Transcriptional States

et al. 2021

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“…The cause(s) of the sex-related differences in microglia is far from clear with a role for sex hormones being one obvious factor and this influence has been amply demonstrated. Estrogen has profound effects on all immune cells, including microglia; receptor-induced intracellular signaling cascades as well as direct activation of estrogen response elements, which are located on promotors of immune-function genes, both exercise control over production of immune mediators ( Acosta-Martinez, 2020 ). Thus estradiol eliminated the sex-related difference in phagocytic capacity of microglia in neonatal mice ( Nelson et al, 2017 ) and attenuated the LPS-induced changes in microglia from adult male, but not female, rats ( Loram et al, 2012 ).…”

Section: Sex Differences and Microglia: Neurodegenerative Diseasementioning

confidence: 99%

“…Specific age-dependent effects have been reported. For example, the microglial transcriptome, at least in terms of NFκB-regulated genes, was not markedly altered by ovariectomy or 17β-estradiol treatment in young mice ( Villa et al, 2018 ) but in aged mice ovariectomy upregulated inflammatory molecules including TNFα and IL-1β and increased responsiveness to LPS ( Benedusi et al, 2012 ) as recently reviewed ( Villa et al, 2016 ; Lenz and Nelson, 2018 ; Acosta-Martinez, 2020 ).…”

Section: Sex Differences and Microglia: Neurodegenerative Diseasementioning

confidence: 99%

Exploring Sex-Related Differences in Microglia May Be a Game-Changer in Precision Medicine

Lynch

2022

Front. Aging Neurosci.

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One area of microglial biology that has been relatively neglected until recently is sex differences and this is in spite of the fact that sex is a risk factor in several diseases that are characterized by neuroinflammation and, by extension, microglial activation. Why these sex differences exist is not known but the panoply of differences extend to microglial number, genotype and phenotype. Significantly, several of these sex-related differences are also evident in health and change during life emphasizing the dynamic and plastic nature of microglia. This review will consider how age impacts on sex-related differences in microglia and ask whether the advancement of personalized medicine demands that a greater focus is placed on studying sex-related differences in microglia in Alzheimer’s disease, Parkinson’s disease and models of inflammatory stress and trauma in order to make true progress in dealing with these conditions.

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“…Abbreviations: NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, Csf1R colony-stimulating factor 1 receptor, ATP adenosine triphosphate, MHC major histocompatibility complex, E3,5 embryonic day 3.5, CX3CR1 CX3C chemokine receptor 1, LPS lipopolysaccharide, IL-1β interleukin-1beta, IFNγ interferon-γ, GF germ-free, SPF specific-pathogen free unstimulated microglia had similar levels between males and females [67]. It has been documented that estrogen receptors contribute to mediating sex differences of microglia, as evidenced by perinatal activation of estrogen receptor-α being restricted to males during early development [83]. Overall, such differences may subsequently lead to sex-dependent changes and susceptibility to CNS diseases.…”

Section: Weeksmentioning

confidence: 99%

Uncovering sex differences of rodent microglia

Han

Fan

Zhou

et al. 2021

J Neuroinflammation

131

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There are inherent structural and functional differences in the central nervous systems (CNS) of females and males. It has been gradually established that these sex-specific differences are due to a spectrum of genetic, epigenetic, and hormonal factors which actively contribute to the differential incidences, disease courses, and even outcomes of CNS diseases between sexes. Microglia, as principle resident macrophages in the CNS, play a crucial role in both CNS physiology and pathology. However, sex differences of microglia have been relatively unexplored until recently. Emerging data has convincingly demonstrated the existence of sex-dependent structural and functional differences of rodent microglia, consequently changing our current understanding of these versatile cells. In this review, we attempt to comprehensively outline the current advances revealing microglial sex differences in rodent and their potential implications for specific CNS diseases with a stark sex difference. A detailed understanding of molecular processes underlying microglial sex differences is of major importance in design of translational sex- and microglia-specific therapeutic approaches.

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Shaping Microglial Phenotypes Through Estrogen Receptors: Relevance to Sex-Specific Neuroinflammatory Responses to Brain Injury and Disease

Abstract: Shaping microglial phenotypes through estrogen receptors: Relevance to sex-specific neuroinflammatory responses to brain injury and disease

Cited by 32 publications

References 150 publications

p38 MAP Kinase Signaling in Microglia Plays a Sex-Specific Protective Role in CNS Autoimmunity and Regulates Microglial Transcriptional States

p38 MAP Kinase Signaling in Microglia Plays a Sex-Specific Protective Role in CNS Autoimmunity and Regulates Microglial Transcriptional States

Exploring Sex-Related Differences in Microglia May Be a Game-Changer in Precision Medicine

Uncovering sex differences of rodent microglia

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