Estrogen Receptor-Dependent Regulation of Dendritic Cell Development and Function.
Estrogen Receptor-Dependent Regulation of Dendritic Cell Development and Function.
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DOI：
10.3389/fimmu.2017.00108
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发表时间：
2017
影响因子：
7.3
通讯作者：
Guéry JC
中科院分区：
文献类型：
--
作者：
Laffont S;Seillet C;Guéry JC
自身免疫、传染病和癌症对妇女和男子的影响不同。因为她们往往比男性产生更强烈的适应性免疫反应，所以女性对某些传染病的易感性较低，但患自身免疫的风险也较高。性别依赖性因子对免疫应答的调节可能涉及几种非冗余机制。然而，一个特殊的研究领域涉及性类固醇激素在先天免疫细胞，特别是树突状细胞（DC）生物学中的作用。近年来，我们对DC群体谱系起源的理解有所扩展，并且已经鉴定了形成外周DC亚群的谱系提交转录因子。祖细胞和成熟DC亚群都表达雌激素受体（ER），这是配体依赖性转录因子。这表明，雌激素可能有助于通过调节DC生物学的免疫力的性别差异。在这里，我们回顾了最近的文献，并强调雌激素依赖性ERα激活调节特定DC亚群的发育或功能反应的证据。GM-CSF诱导的DC分化的体外模型表明，CD 11 c + CD 11bint Ly 6cneg细胞依赖于雌激素激活ERα来发育，并获得激活初始CD 4 + T淋巴细胞的能力，并对CD 40刺激产生强烈的促炎细胞因子应答。在该模型中，雌激素信号传导与GM-CSF结合对于促进巨噬细胞-DC祖细胞中的早期干扰素调节因子（Irf）-4表达及其随后分化为IRF-4 hi CD 11 c + CD 11bint Ly 6cneg细胞（与cDC 2亚群密切相关）是必需的。Flt 3L诱导的DC分化模型反过来表明，ERα信号传导促进常规DC（cDC）和浆细胞样DC（pDC）的发育，这些DC响应TLR刺激具有更高的促炎细胞因子产生能力。同样地，细胞内在ER信号传导在体内积极调节小鼠pDC中TLR驱动的I型干扰素（IFN）的产生。雌激素的这种作用可能有助于女性pDC在由TLR 7配体引发的I型IFN的产生方面比男性pDC更熟练。总之，证据支持雌激素信号传导调节小鼠和人类cDC和pDC发育和/或效应子功能的重要方面的观点。
Autoimmunity, infectious diseases and cancer affect women and men differently. Because they tend to develop more vigorous adaptive immune responses than men, women are less susceptible to some infectious diseases but also at higher risk of autoimmunity. The regulation of immune responses by sex-dependent factors probably involves several non-redundant mechanisms. A privileged area of study, however, concerns the role of sex steroid hormones in the biology of innate immune cells, especially dendritic cells (DCs). In recent years, our understanding of the lineage origin of DC populations has expanded, and the lineage-committing transcription factors shaping peripheral DC subsets have been identified. Both progenitor cells and mature DC subsets express estrogen receptors (ERs), which are ligand-dependent transcription factors. This suggests that estrogens may contribute to the reported sex differences in immunity by regulating DC biology. Here, we review the recent literature and highlight evidence that estrogen-dependent activation of ERα regulates the development or the functional responses of particular DC subsets. The in vitro model of GM-CSF-induced DC differentiation shows that CD11c+ CD11bint Ly6cneg cells depend on ERα activation by estrogen for their development, and for the acquisition of competence to activate naive CD4+ T lymphocytes and mount a robust pro-inflammatory cytokine response to CD40 stimulation. In this model, estrogen signaling in conjunction with GM-CSF is necessary to promote early interferon regulatory factor (Irf)-4 expression in macrophage-DC progenitors and their subsequent differentiation into IRF-4hi CD11c+ CD11bint Ly6cneg cells, closely related to the cDC2 subset. The Flt3L-induced model of DC differentiation in turn shows that ERα signaling promotes the development of conventional DC (cDC) and plasmacytoid DC (pDC) with higher capability of pro-inflammatory cytokine production in response to TLR stimulation. Likewise, cell-intrinsic ER signaling positively regulates the TLR-driven production of type I interferons (IFNs) in mouse pDCs in vivo. This effect of estrogens likely contributes to the greater proficiency of women’s pDCs than men’s as regards the production of type I IFNs elicited by TLR7 ligands. In summary, evidence is emerging in support of the notion that estrogen signaling regulates important aspects of cDC and pDC development and/or effector functions, in both mice and humans.