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

基本信息

批准号：
10385759
负责人：
Meera Goh Nair
金额：
$ 67.3万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
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/10385759
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 Chimera organism Chimeric Proteins Coculture Techniques Complement Cre lox recombination system 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 Measures Mediating Mesenchymal Stem Cells Migration Assay Mucous Membrane Mus Nippostrongylus Parasites Pathogenicity Pathologic Pathology Pathway interactions Persons Proteins Public Health Pulmonary Inflammation Reagent Recovery Regulation Reporter Resolution Rodent Signal Pathway Signal Transduction Soil Stromal Cells Structure of parenchyma of lung Technology Therapeutic Tissues airway epithelium base cytokine design eosinophil experimental study genetic signature healing helminth infection immunopathology inhibitor 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

项目摘要

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.

对微生物病原体的最佳宿主反应需要平衡有效的病原体杀死通过病原体或宿主自身免疫反应引起的限制组织病理学。这种宿主疾病耐受现象在蠕虫感染中尤其重要，是造成严重组织损伤和IND炎症的大型岩石。钩虫感染的模型，用巴西乳核（NB），我们识别抗蛋白样分子（relm）A作为高度分泌的蛋白质，可从潜在致命的感染引起的肺组织损害以最佳的钩虫杀死假设是，Relma是一种宿主疾病的耐受性机制，可转移出来蠕虫杀死炎症和组织健康。巨噬细胞和非免疫细胞（例如上皮细胞）（EC）利用骨髓嵌合体和巨噬细胞共培养的数据，我们确定表达替代激活的巨噬细胞（AAMAC）在NB杀戮方面的效率较低，但取而代之的是肺部炎症并进一步促进组织。精氨酸酶1/Relma AAMAC双重记者，Revel AAMAC异质性并暗示基于发现，Relma+ AAMAC作为新的伤口标题。该提案的重点是将新颖的细胞特异性Relma KO/Reporter小鼠与功能相结合共培养分析和新试剂，以描绘巨噬细胞中的复发功能在AIM 1中进行蠕虫相互作用和粘膜组织愈合 KO/记者小鼠和收养细胞转移，以描述从 Inate细胞（AAMAC或嗜酸性粒细胞）或EC至NB免疫和组织健康2，在AIM 2中，我们将使用AAMAC双重报道小鼠研究巨噬细胞-NB相互作用的Relma调节，中级融合蛋白和阻断抗体，并在AIM 3中进行了优化的共培养测定。将使用3D肺脚手架和EC EC空气界面与AAMACS和间充质干细胞确定反对反应的AAMAC和EC如何与肺基质和有助于肺组织恢复。 Relma在掌舵感染中的有益与病原体作用可以引导治疗增强抗螺旋免疫力的策略，同时限制病理发炎和促进组织愈合。生物学和巨噬细胞细胞相互作用，可用于解决粘膜组织损伤和炎症引起了重大公共卫生的关注。