Regulation of dendritic cells by estrogen receptors during influenza infection

流感感染期间雌激素受体对树突状细胞的调节

• 批准号: 8038623
• 负责人: Susan Kovats
• 金额: $ 24.45万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8038623
• 关键词: Accounting; Address; Adjuvant; Adult; Affect; Antigen Presentation; Antiviral Response; Biology; Bone Marrow; Cells; Competence; Cytokine Activation; Data; Dendritic Cells; Development; Endocrine; Environment; Environmental Risk Factor; Equilibrium; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Exhibits; Female; Gonadal Steroid Hormones; Granulocyte-Macrophage Colony-Stimulating Factor; Hormone Receptor; Human; ITGAM gene; ITGAX gene; Immune; Immune response; Immune system; Immunization; Infection; Inflammatory; Influenza; Influenza A Virus, H1N1 Subtype; Interferon Regulatory Factor 4; Interferon Type I; Knowledge; Lead; Ligands; Lung; Mediastinal lymph node group; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Myelogenous; Organ; Outcome; Pathway interactions; Physiological; Population; Predisposition; Prevalence; Process; Production; Receptor Signaling; Regulation; Relative (related person); Rodent; Rodent Model; Severities; Sex Bias; Sex Characteristics; Signal Transduction; Testing; Tissues; Toll-like receptors; Variant; Virus; Virus Diseases; Woman; Work; abstracting; cell mediated immune response; cytokine; in vivo; influenzavirus; innovation; insight; lymph nodes; male; men; monocyte; mortality; novel; pandemic disease; progenitor; response; sex; transcription factor

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.

描述（由申请人提供）：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导致人类显着发病和死亡，最近的H1N1大流行强调需要了解调节人类对流感病毒免疫反应变化的生理和环境危险因素。该项目将确定雌激素受体α（ER1）信号这一生理因素如何调节小鼠对流感病毒感染的先天免疫反应。尽管人类和啮齿动物在感染的患病率和严重程度方面经常表现出明显的性别差异，但人们对这些性别差异发生的分子机制以及它们是否是通过性激素对单核细胞和树突状细胞（DC）产生的先天免疫反应的影响来介导的了解甚少。最近阐明了小鼠流感感染期间肺和纵隔淋巴结中新产生的炎症和组织 DC 群体的功能重要性。我们已经证明雌二醇/ER1 信号传导促进 GM-CSF 驱动的炎症途径，从而导致 CD11b+ DC 的发育。这些 DC 具有在流感感染期间至关重要的组织和炎症 DC 的特征。我们的数据还表明 ER1 信号传导调节成熟 DC 的激活和功能。在这个项目中，我们将测试以下假设：在流感感染期间，DC 的从头发育和功能受到 ER1 信号传导的调节，以响应正常的内源性雌激素水平。我们将评估 ER1 信号传导可能影响体内感染期间 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 前体从头 DC 发育，以及（2）调节成熟 DC 的功能反应。我们将使用创新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 缺陷仅限于 DC 的小鼠。这些新颖的模型将带来新的见解，以了解在两性流感病毒感染期间，ER1信号如何响应内源性雌激素的生理水平来调节DC的从头发育和功能反应。 公共卫生相关性：人类和鼠类免疫系统的细胞能够对天然雌激素做出反应。我们试图了解雌激素在流感病毒感染期间如何控制免疫系统关键调节细胞（称为树突状细胞）的发育和功能。这些知识将确定天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。