Sex differences in macrophage differentiation in allergic lung inflammation

描述（由申请人提供）：15岁以上因哮喘需要住院治疗的患者中，女性的可能性是男性的三倍。2009年，女性占哮喘相关死亡人数的64%。主流的哮喘治疗方法对女性往往无效。动物研究概括了人类疾病：与雄性小鼠相比，雌性小鼠过敏性肺部炎症的标志性特征更严重，雌激素（E2）使肺部炎症恶化。患有哮喘的雌性小鼠和人类的肺部都有更多的选择性活化（或M2）巨噬细胞，这与人类肺功能恶化有关。这项提议的主要目的是了解巨噬细胞性别差异的分子基础及其在过敏性肺炎症发病机制中的作用。具体目的是确定雄性和雌性巨噬细胞M2分化的内在性别差异，以及性激素（E2， DHT）及其受体在体外和体内调节这些差异的作用。根据我们的初步数据，我们假设(i)与男性细胞相比，来自女性的巨噬细胞对IL-4的特异性M2表型基因表达更高；（ii） E2促进和雄激素抑制IL-4诱导的M2分化。我们将通过确定IL-4受体表达、IL-4激活的信号转导途径和M2基因在不同小鼠和人巨噬细胞群体中的体外表达差异来验证这些假设。我们还将利用激素治疗动物的变应性肺部炎症小鼠模型，确定E2和DHT对M2分化、单核细胞募集和巨噬细胞转化的影响。了解这些性别差异将有助于发现治疗哮喘女性的新目标，并根据患者的性别定制更有效、个性化的哮喘和过敏性炎症治疗方法。

DESCRIPTION (provided by applicant): Patients over 15 years old requiring hospitalization for asthma are up to three times more likely to be female than male. Women comprised 64% of the asthma-associated deaths in 2009. Mainstay asthma therapies are often ineffective in women. Animal studies recapitulate the human disease: the hallmark features of allergic lung inflammation are worse in female mice compared to male mice and estrogen (E2) worsens lung inflammation. The lungs of both female mice and humans with asthma have greater numbers of alternatively activated (or M2) macrophages, correlating with worse lung function in humans. The broad objective of this proposal is to understand the molecular basis of sex differences in macrophages and their contribution to pathogenesis in allergic lung inflammation. The Specific Aims are to determine intrinsic sex differences in M2 differentiation in macrophages from male and females and the role of sex hormones (E2, DHT) and their receptors in regulating these differences in vitro and in vivo. Based on our preliminary data, we hypothesize that (i) macrophages from females express characteristic M2 phenotypic genes in response to IL-4 more highly compared to male cells and (ii) that E2 promotes and androgens suppress IL-4-induced M2 differentiation. We will test these hypotheses by defining differences in IL-4 receptor expression, IL-4-activated signal transduction pathways and induction of M2 gene expression in different mouse and human macrophage populations in vitro. We will also determine the effect of E2 and DHT on M2 differentiation, monocyte recruitment and macrophage turnover in the lung in vivo using mouse models of allergic lung inflammation in hormone-treated animals. Understanding these sex differences will help uncover novel targets for therapy in asthmatic women and tailor more effective, personalized therapies for asthma and allergic inflammation based on the sex of the patient.