Regulation of dendritic cells by estrogen receptors during influenza infection

描述(申请人提供)：在流感感染期间，雌激素受体对树突状细胞的调节摘要流感病毒感染在人类人群中导致显著的发病率和死亡率，最近的H1N1大流行强调了了解调节人类对流感病毒免疫反应的生理和环境风险因素的必要性。该项目将确定雌激素受体α(ER1)信号是如何调节小鼠对流感病毒感染的先天免疫反应的。虽然人类和啮齿动物在感染的患病率和严重程度上经常表现出显著的性别差异，但对于这些性别差异发生的分子机制以及它们是否通过性激素对单核细胞和树突状细胞(DC)所阐述的先天免疫反应的影响而被介导，人们知之甚少。在小鼠流感感染过程中，肺和纵隔淋巴结中新形成的炎性和组织树突状细胞的功能重要性最近已被阐明。我们已经证明，雌激素/ER1信号促进GM-CSF驱动的炎症途径，从而导致CD11b+DC的发展。这些DC具有组织和炎症性DC的特征，这在流感感染期间是至关重要的。我们的数据还表明，ER1信号调节成熟DC的激活和功能。在这个项目中，我们将检验一种假设，即在流感感染过程中，DC的新生发育和功能受到ER1信号的调节，以响应正常的内源性雌激素水平。我们将评估ER1信号在体内感染过程中影响DC介导的免疫反应的两种不同机制：(1)调节炎症单核细胞或其他DC前体的从头DC发育；(2)调节成熟DC的功能反应。我们将使用创新的模型来解决这些问题，这些模型包括竞争性ER1+/ER1-/-骨髓嵌合小鼠和ER1缺乏仅限于DC的小鼠。这些新的模型将导致对ER1信号如何响应生理水平的内源性雌激素调节新生DC的发育和男女流感病毒感染期间的功能反应的新见解。 公共卫生相关性：人类和小鼠免疫系统的细胞能够对自然雌激素做出反应。我们试图了解雌激素如何在流感病毒感染期间控制免疫系统的关键调节细胞，称为树突状细胞的发育和功能。这一知识将决定自然雌激素水平如何调节流感感染期间的免疫反应，并有助于阐明为什么男性和女性对病毒感染的易感性不同。

DESCRIPTION (provided by applicant): Regulation of dendritic cells by estrogen receptors during influenza infection Abstract Influenza virus infections result in significant morbidity and mortality in the human population, and the recent H1N1 pandemic underscores the need to understand the physiological and environmental risk factors that regulate the human variation in immune responses to influenza virus. This project will determine how one such physiological factor, estrogen receptor alpha (ER1) signaling, regulates the innate immune response to influenza virus infection in mice. Although humans and rodents often exhibit marked sex differences in the prevalence and severity of infection, little is known about the molecular mechanisms by which these sex differences occur and if they are mediated through effects of sex hormones on the innate immune responses elaborated by monocytes and dendritic cells (DC). The functional importance of newly developed populations of inflammatory and tissue DC in the lung and mediastinal lymph nodes during murine influenza infection has recently been elucidated. We have shown that estradiol/ER1 signaling promotes the GM-CSF-driven inflammatory pathway that leads to development of CD11b+ DC. These DC have features of the tissue and inflammatory DC that are crucial during influenza infection. Our data also show that ER1 signaling modulates the activation and function of mature DC. In this project, we will test the hypothesis that during influenza infection, the de novo development and function of DC are regulated by ER1 signaling in response to normal endogenous levels of estrogens. We will evaluate two distinct mechanisms by which ER1 signaling might influence DC-mediated immune responses during infection in vivo: (1) regulation of de novo DC development from inflammatory monocytes or other DC precursors, and (2) regulation of the functional responses of mature DC. We will address these questions using innovative models that include competitive ER1+/ER1-/- bone marrow chimeric mice and mice in which ER1 deficiency is restricted to DC. These novel models will lead to new insights into how ER1 signaling in response to physiological levels of endogenous estrogens regulates de novo DC development and functional responses during influenza virus infection in both sexes. PUBLIC HEALTH RELEVANCE: Cells of the human and murine immune systems are capable of responding to natural estrogens. We seek to understand how estrogens control the development and function of key regulatory cells of the immune system, termed dendritic cells, during influenza virus infection. This knowledge will determine how natural estrogen levels regulate the immune response during influenza infection and help elucidate why men and women differ in susceptibility to viral infections.