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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：
10755776
负责人：
Meera Goh Nair
金额：
$ 4.48万
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/10755776
关键词：
3-Dimensional Acute Address Adoptive Cell Transfers Adoptive Transfer Air Back Biological Assay Biology Blocking Antibodies Bone Marrow CD4 Positive T Lymphocytes Cell Communication Cell Separation Cells Chimera organism Chimeric Proteins Coculture Techniques Communicable Diseases 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 Liquid substance Lung Macrophage Measures Mediating Mesenchymal Stem Cells Migration Assay Mucous Membrane Mus Nippostrongylus Parasites Pathogenicity Pathologic Pathology Pathway interactions Persons Protein Secretion Proteins Public Health Pulmonary Inflammation Reagent Recovery Regulation Reporter Resolution Rodent Signal Pathway Signal Transduction Signaling Molecule Soil Sorting Stromal Cells Structure of parenchyma of lung Technology Therapeutic Tissues Visualization airway epithelium arginase cytokine design eosinophil experimental study genetic signature healing helminth infection immunopathology inhibitor insight lung repair migration monocyte mouse model new therapeutic target novel pathogen pathogenic microbe public health relevance resistin response scaffold tissue injury tissue repair transmission process 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.

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