RELM-alpha regulation of hookworm-induced lung inflammation

RELM-α 对钩虫引起的肺部炎症的调节

• 批准号: 8438459
• 负责人: Meera Goh Nair
• 金额: $ 35.72万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438459
• 关键词: Acute; Address; Asthma; B-Lymphocytes; Basophilia; Basophils; Bone Marrow; Cell Lineage; Cells; Characteristics; Chimera organism; Chitinase; Chronic; Chronic Obstructive Airway Disease; Coculture Techniques; Data; Disease; Epithelial Cells; Exhibits; Exposure to; Family; Feedback; Gene Expression Profile; Helminth Antigens; Helminths; Hookworm Infections; Hookworms; Hypersensitivity; Immune; Immune response; Immunity; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-13; Interleukin-4; Knowledge; Lung; Lung Inflammation; Macrophage Activation; Mammals; Mediating; Modeling; Molecular; Mus; Nippostrongylus; Orthologous Gene; Parasites; Pathogenesis; Pathway interactions; Play; Prevalence; Proteins; Public Health; Regulation; Role; Signal Transduction; Soil; Source; Stimulus; System; T-Lymphocyte; Testing; Th2 Cells; Tissues; Transgenic Mice; base; cell type; cytokine; design; eosinophil; in vivo; in vivo Model; macrophage; member; notch protein; novel; prevent; resistin; response; therapeutic target; therapy design

DESCRIPTION (provided by applicant): Helminth infections provoke a T helper type 2 (Th2) cell response, which is critical for protective immunity. Although it is clear that Th2 cells play an essential role in limiting parasite burden, these same responses also cause chronic helminth-induced inflammation. Moreover, Th2 cytokine responses are also involved in the detrimental inflammation associated with allergy, asthma and chronic obstructive pulmonary disease (COPD). Therefore, a better understanding of how Th2 cell responses are regulated could offer new opportunities to design treatments both to promote anti-parasite immunity and limit Th2 cytokine-associated inflammatory disorders. The secreted protein RELMa was recently identified as a potent immuno-regulatory molecule that could limit inflammation in multiple helminth infection models. In this proposal, we will employ a model of hookworm infection-induced lung inflammation to delineate how RELMa expression is regulated, and to determine the downstream targets of RELMa-mediated inhibition of lung inflammation. Our preliminary data demonstrate that infection with Nippostrongylus brasiliensis (Nb) promotes chronic lung inflammation that is associated with RELMa expression by epithelial cells, alternatively activated macrophages and eosinophils. Further, RELMa-deficient (Retnla-/-) mice exhibited exacerbated chronic lung inflammation, and increased macrophage and Th2 cytokine responses. However, the factors that promote RELMa expression and the cell lineage-restricted requirements for RELMa-mediated tissue protection are unknown. Additionally, the downstream factors and cell-types mediating exacerbated lung inflammation in Retnla-/- mice are undefined. In Aim 1, the combined approaches of cell-specific deletions, bone marrow chimeras and cell transfers will be employed to identify the cell types and cell-derived factors that promote RELMa expression, and the mechanism through which RELMa limits Nb-induced chronic lung inflammation. Knowledge of what regulates RELMa expression, and how RELMa mediates tissue protection, could provide new opportunities to harness the biologic function of RELMa for therapies to treat or prevent lung inflammation. In our preliminary data investigating how Nb-induced RELMa expression in the lung is initiated, a previously unrecognized pathway of macrophage-basophil cross-regulation was uncovered, in which basophils induce macrophage recruitment and expression of RELMa. Further, RELMa provides a negative feedback regulation to limit basophil function. Based on these findings, Aim 2 will employ both Nb infection and an in vivo model of lung basophilia to examine how basophils mediate macrophage activation and expression of RELMa. Finally, a novel macrophage-basophil co-culture system will be employed to delineate the molecular mechanisms of basophil-macrophage cross-regulation. Given the emergence of basophils as critical innate cells in Th2 cytokine responses, investigating how basophil:macrophage interactions are regulated could increase our understanding of how to manipulate Th2 cytokine-dependent immunity and inflammation.

描述（由申请人提供）：蠕虫感染引起了T辅助型2（TH2）细胞反应，这对于保护性免疫至关重要。尽管很明显，Th2细胞在限制寄生虫负担中起着至关重要的作用，但这些相同的反应也会引起慢性蠕虫引起的炎症。此外，Th2细胞因子反应还参与与过敏，哮喘和慢性阻塞性肺疾病（COPD）相关的有害炎症。因此，更好地了解如何调节Th2细胞反应可以为设计治疗既促进抗寄生虫免疫力并限制Th2细胞因子相关炎症性疾病提供新的机会。最近将分泌的蛋白质伴侣确定为有效的免疫调节分子，可以限制多种蠕虫感染模型中的炎症。在此提案中，我们将采用钩虫感染诱导的肺部炎症模型来描述如何调节Relma表达，并确定Relma介导的肺部炎症抑制的下游靶标。我们的初步数据表明，对nippostrongylus brasiliensis（NB）的感染促进了慢性肺炎症，这与上皮细胞与Relma表达相关，替代激活了巨噬细胞和嗜酸性粒细胞。此外，缺乏疾病（RETNLA - / - ）小鼠表现出恶化的慢性肺部炎症，巨噬细胞增加和Th2细胞因子反应增加。但是，尚不清楚促进复发表达和细胞谱系限制性的细胞谱系要求的因素。此外，介导的Retnla - / - 小鼠中介导加重的肺部炎症的下游因子和细胞类型是不确定的。在AIM 1中，将采用细胞特异性缺失，骨髓嵌合体和细胞转移的组合方法来识别促进RELMA表达的细胞类型和细胞衍生因子，以及Relma限制NB诱导的慢性肺炎症的机制。了解哪种调节相关表达的信息，以及Relma如何介导组织保护，可以为利用疗法的生物学功能提供新的机会，以治疗或预防肺部炎症。在我们的初步数据中，研究了NB诱导的肺中的Relma表达是如何启动的，以前未被认可的巨噬细胞 - 嗜碱性交叉调节的途径被发现，其中嗜碱性噬菌体诱导巨噬细胞募集和Relma的表达。此外，Relma提供了负反馈调节以限制嗜碱性粒细胞功能。基于这些发现，AIM 2将同时采用NB感染和肺嗜碱性嗜碱性体内模型来检查嗜碱性粒细胞如何介导巨噬细胞的激活和相同的表达。最后，将采用一种新型的巨噬细胞 - 嗜碱性共培养系统来描述嗜碱性粒细胞 - 巨噬细胞交叉调节的分子机制。鉴于嗜碱性粒细胞作为Th2细胞因子反应中关键的先天细胞的出现，研究嗜碱性粒细胞：巨噬细胞相互作用的调节如何可以增加我们对如何操纵Th2细胞因子依赖性免疫和炎症的理解。