Sex differences in macrophage differentiation in allergic lung inflammation

过敏性肺部炎症巨噬细胞分化的性别差异

• 批准号: 8760006
• 负责人: NICOLA M HELLER
• 金额: $ 40.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8760006
• 关键词: 15 year old; Adrenal Cortex Hormones; Adult; Agonist; Allergic; Allergic inflammation; Androgen Receptor; Androgens; Animals; Asthma; Biology; Bronchoalveolar Lavage Fluid; Cells; Cessation of life; Characteristics; Data; Estrogen Receptors; Estrogens; Exposure to; Extrinsic asthma; Female; Fibrosis; Gene Expression; Genes; Goals; Gonadal Steroid Hormones; Helminths; Hormones; Hospitalization; Human; Human Characteristics; Immune; Implant; In Vitro; Inflammation; Inflammatory Response; Interleukin-13; Interleukin-4; Lung; Lung Inflammation; Marrow; Mediating; Molecular; Molecular Target; Mus; Ovariectomy; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Play; Population; Prevalence; Recruitment Activity; Research; Respiratory physiology; Role; STAT6 gene; Severities; Sex Characteristics; Signal Transduction; Signal Transduction Induction; Signal Transduction Pathway; Signaling Molecule; Steroid Receptors; Structure of parenchyma of lung; Testing; Time; Translating; Treatment Efficacy; Woman; Women' s Role; Wound Healing; base; bone; cellular targeting; cytokine; human disease; improved; in vivo; macrophage; male; men; monocyte; mouse model; novel; peripheral blood; public health relevance; receptor; receptor expression; response; sex

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.

描述(申请人提供)：15岁以上因哮喘需要住院的患者，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%。主要的哮喘疗法对女性往往无效。动物研究总结了人类疾病：与雄性小鼠相比，雌性小鼠过敏性肺部炎症的特征更严重，而雌激素(E2)会加重肺部炎症。患有哮喘的雌性小鼠和人类的肺都有更多数量的交替激活(或M2)巨噬细胞，这与人类肺功能较差有关。这项建议的广泛目标是了解巨噬细胞性别差异的分子基础及其在过敏性肺部炎症发病机制中的作用。其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(E_2，DHT)及其受体在体内外调节这些差异中的作用。根据我们的初步数据，我们假设(I)女性巨噬细胞表达特有的M2表型基因，与男性细胞相比，对IL-4的反应更强；(Ii)E2促进和抑制IL-4诱导的M2分化。我们将通过确定IL-4受体的表达、IL-4激活的信号转导途径以及在体外诱导不同的小鼠和人巨噬细胞M2基因表达的差异来验证这些假设。我们还将通过荷尔蒙治疗的小鼠过敏性肺部炎症模型，在活体内确定E2和DHT对M2分化、单核细胞募集和巨噬细胞在肺内周转的影响。了解这些性别差异将有助于发现哮喘女性治疗的新靶点，并根据患者的性别为哮喘和过敏性炎症量身定做更有效的个性化治疗。