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: 9302827
• 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/9302827
• 关键词: 15 year old; Adrenal Cortex Hormones; Adult; Agonist; Allergic; Allergic inflammation; Androgen Receptor; Androgens; Animals; Asthma; Biology; Bone Marrow; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cells; Cessation of life; Characteristics; Data; Estrogen Receptor alpha; Estrogen Receptor beta; 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; Inflammatory Response; Interleukin 4 Receptor; Interleukin-13; Interleukin-4; Lung; Lung Inflammation; Mediating; Modeling; Molecular; Molecular Target; Mus; Ovariectomy; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Play; Population; Prevalence; Pulmonary Inflammation; Recruitment Activity; Research; Respiratory physiology; Role; STAT6 gene; Severities; Sex Characteristics; Signal Induction; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Steroid Receptors; Structure of parenchyma of lung; Testing; Time; Translating; Treatment Efficacy; Woman; Women' s Role; Wound Healing; asthmatic; base; cellular targeting; cytokine; differential expression; human disease; improved; in vivo; macrophage; male; men; monocyte; mouse model; new therapeutic target; novel; peripheral blood; personalized medicine; 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（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3倍。2009年，女性占哮喘相关死亡人数的64%。主流哮喘疗法对女性往往无效。动物研究概括了人类疾病：与雄性小鼠相比，雌性小鼠的过敏性肺部炎症的标志性特征更严重，雌激素（E2）抑制了肺部炎症。患有哮喘的雌性小鼠和人类的肺部都有更多的交替激活（或M2）巨噬细胞，这与人类肺功能较差有关。本研究的主要目的是了解巨噬细胞性别差异的分子基础及其在变应性肺炎发病机制中的作用。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中的作用。基于我们的初步数据，我们假设：（i）与男性细胞相比，女性巨噬细胞对IL-4的反应更高，表达特征性M2表型基因;（ii）E2促进IL-4诱导的M2分化，雄激素抑制IL-4诱导的M2分化。我们将通过定义IL-4受体表达、IL-4激活的信号转导通路和体外不同小鼠和人巨噬细胞群体中M2基因表达的诱导差异来测试这些假设。我们还将确定E2和DHT对M2分化的影响，单核细胞募集和巨噬细胞周转在体内肺使用小鼠模型的过敏性肺部炎症的激素治疗的动物。 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定制更有效的个性化治疗。