RELMalpha-expressing macrophages mediate host disease tolerance in mucosal infection

RELMα表达巨噬细胞介导粘膜感染中宿主疾病耐受性

• 批准号: 10028145
• 负责人: Meera Goh Nair
• 金额: $ 66.85万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-20 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10028145
• 关键词: 3-Dimensional; Acute; Address; Adoptive Cell Transfers; Adoptive Transfer; Air; Biological Assay; Biology; Blocking Antibodies; Bone Marrow; CD4 Positive T Lymphocytes; Cell Communication; Cells; Cellular Structures; Chimera organism; Chimeric Proteins; Coculture Techniques; Complement; Data; Disease; Epithelial Cells; Equilibrium; Gene Expression; Helminths; Hematopoietic; Heterogeneity; Hookworm Infections; Hookworms; Human; Immune; Immune response; Immunity; Impairment; Infection; Inflammation; Inflammatory; Injury; Integrins; Knockout Mice; Liquid substance; Lung; Lung Inflammation; Measures; Mediating; Mesenchymal Stem Cells; Migration Assay; Mucous Membrane; Mus; Nippostrongylus; Parasites; Pathogenicity; Pathologic; Pathology; Pathway interactions; Proteins; Public Health; Reagent; Recovery; Regulation; Reporter; Resolution; Rodent; Signal Pathway; Signal Transduction; Soil; Stromal Cells; Structure of parenchyma of lung; System; Technology; Therapeutic; Tissues; airway epithelium; base; cytokine; design; eosinophil; experimental study; genetic signature; healing; helminth infection; immunopathology; inhibitor/antagonist; insight; lung repair; macrophage; migration; monocyte; mouse model; new therapeutic target; novel; pathogen; pathogenic microbe; public health relevance; resistin; response; scaffold; tissue injury; tissue repair; wound healing

The optimal host response to microbial pathogens requires balancing effective pathogen killing with limiting tissue pathology caused by the pathogen or by the host’s own immune response. This host disease tolerance phenomenon is especially critical in infections with helminths, which are macroparasites that can cause severe tissue damage and inflammation. Using a mouse model of hookworm infection with Nippostrongylus brasiliensis (Nb), we identify Resistin-like molecule (RELM)a as a highly secreted protein that protects the host from potentially fatal infection-induced lung tissue damage at the expense of optimal hookworm killing. Our central hypothesis is that RELMa is a host disease tolerance mechanism that shifts the balance from helminth killing to resolution of inflammation and tissue healing. RELMa is expressed by immune cells such as macrophages and non-immune cells such as epithelial cells (EC). In preliminary data utilizing bone marrow chimeras and macrophage co-cultures, we identified that RELMa- expressing alternatively activated macrophages (AAMac) are less efficient at Nb killing, but instead dampen lung inflammation and promote tissue repair. Further, we generate unique Arginase1/RELMa AAMac dual reporters, that reveal AAMac heterogeneity and implicate RELMa+ AAMacs as a new wound healing macrophage subset. Based on these findings, the focus of this proposal is to combine novel cell-specific RELMa KO/reporter mice with functional co-culture assays and new RELMa reagents to delineate RELMa function in macrophage- helminth interactions and mucosal tissue healing. In Aim 1, we will employ cell-specific RELMa KO/reporter mice and adoptive cell transfers to delineate the contribution of RELMa derived from innate cells (AAMac or eosinophils) or EC to Nb immunity and tissue healing. In Aim 2, we will investigate RELMa regulation of macrophage-Nb interaction using AAMac dual reporter mice, RELMa fusion proteins and blocking antibodies, and optimized co-culture assays. In Aim 3, we will employ 3D lung scaffold and EC air-liquid interface co-cultures with AAMacs and mesenchymal stem cells to determine how RELMa-expressing AAMacs and ECs interact with the lung stroma and aid lung tissue recovery. We anticipate that a better understanding of the beneficial versus pathogenic effects of RELMa in helminth infection could guide therapeutic strategies to enhance anti-helminth immunity while limiting pathologic inflammation and promoting tissue healing. Our findings provide new insight into alternatively activated macrophage biology and macrophage-stromal cell interactions, which could be broadly applicable to resolving mucosal tissue injury and inflammation that are of significant public health concern.

宿主对微生物病原体的最佳反应需要平衡有效的病原体杀灭 限制由病原体或宿主自身免疫反应引起的组织病理学。 这种宿主疾病耐受现象在蠕虫感染中尤其重要， 是大型寄生虫，可导致严重的组织损伤和炎症。使用鼠标 利用巴西日本圆线虫（Nippostrongylus brasiliensis，Nb）感染钩虫的模型，我们鉴定了抵抗素样 分子（RELM）作为一种高度分泌的蛋白质，保护宿主免受潜在的致命伤害。 感染引起的肺组织损伤，以最佳的钩虫杀灭为代价。我们的中央 一种假说认为，抗宿主抗体是一种宿主疾病耐受机制， 杀灭蠕虫以消除炎症和组织愈合。免疫球蛋白表达 细胞如巨噬细胞和非免疫细胞如上皮细胞（EC）。初步 利用骨髓嵌合体和巨噬细胞共培养的数据，我们确定了巨噬细胞- 表达交替激活的巨噬细胞（AAMac）在Nb杀伤方面效率较低，但 而是抑制肺部炎症并促进组织修复。此外，我们还生成了独特的 精氨酸酶1/AMAc双报告基因，揭示了AAMac的异质性， AMAc + AMAc作为新的伤口愈合巨噬细胞亚群。根据这些发现， 该建议的重点是将联合收割机新的细胞特异性的MAPKO/报告基因小鼠与功能性的MAPKO/报告基因小鼠结合， 共培养试验和新的抗肿瘤试剂，以描述巨噬细胞中的抗肿瘤功能， 蠕虫相互作用和粘膜组织愈合。在目标1中，我们将使用细胞特异性的RNA， KO/报告基因小鼠和过继细胞转移，以描述来源于 先天性细胞（AAMac或嗜酸性粒细胞）或EC对Nb免疫和组织愈合。在目标2中，我们将 使用AAMac双报告小鼠研究了巨噬细胞-Nb相互作用的EARMA调节， ADMMa融合蛋白和封闭抗体，以及优化的共培养测定。在目标3中，我们 将采用3D肺支架和EC气液界面与AAMacs共培养， 间充质干细胞，以确定表达AAMacs和EC如何与细胞相互作用。 肺间质和辅助肺组织恢复。我们预计，更好地了解 蠕虫感染中的有益作用与致病作用可以指导治疗 增强抗蠕虫免疫力同时限制病理性炎症的策略， 促进组织愈合。我们的发现为替代激活的巨噬细胞提供了新的见解 生物学和巨噬细胞-基质细胞相互作用，这可以广泛适用于解决 粘膜组织损伤和炎症是重要公共健康问题。