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Mechanism of CX3CR1+ macrophage-mediated resolution of eosinophilic allergic lung inflammation

CX3CR1巨噬细胞介导的嗜酸性过敏性肺部炎症消退机制

基本信息

批准号：
10625350
负责人：
Gye Young Park
金额：
$ 56.56万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-10 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625350
关键词：
Active Sites Adopted Allergens Allergic Allergic inflammation Alveolar Macrophages Apoptotic Asthma Binding Biological Assay Bronchial Provocation Tests CCL26 gene CX3CL1 gene Cell Death Cell physiology Cells Characteristics Complement 1q Cytometry Data Eosinophilia Excision Extrinsic asthma Family Functional disorder Gene Expression Profile Gene Expression Profiling Healthcare Homeostasis Human In Vitro Infiltration Inflammation Inflammatory Institutional Review Boards Investigation Ligands Liquid substance Longevity Lung Macrophage Macrophage Activation Mediating Modeling Molecular Morphology Mus Organ Pathogenesis Pathway interactions Patients Phagocytes Phase Phenotype Play Prevention Process Protocols documentation Pulmonary Inflammation Refractory Reporter Research Resolution Role Series Site Societies Source Structure of parenchyma of lung Techniques Testing Time Tissues Transcript Transgenic Mice airway inflammation asthma model asthmatic care burden cell type chemokine conditional knockout eosinophil experimental study gain of function improved in vivo in vivo Model inflammatory lung disease insight mouse model novel pulmonary function receptor recruit response sialic acid binding Ig-like lectin single-cell RNA sequencing targeted treatment translation to humans translational study

项目摘要

Title: Mechanism of CX3CR1+ macrophage-mediated resolution of eosinophilic allergic lung inflammation Abstract: Recent studies show that tissue-resident macrophages participate in not only the initiation of inflammation but also in the resolution and prevention of local inflammation. To precisely determine the subsets of macrophages engaged in resolving lung inflammation and gain insight into their functions, we adopted new techniques of mass cytometry and single-cell RNA-seq (sc-RNA-seq) to analyze human and mouse macrophages in the lung. Our supporting data showed that alveolar macrophages (AMs) are phenotypically diverse and highly dynamic in response to allergen challenge. Based on the sc-RNA-seq data, AMs can be clustered into a few groups at a steady status. Among these groups, a subset of CX3CR1-expressing AMs (CX3CR1+ AMs) are unique in terms of their phenotype and patterns of gene expression, compared to classical resident AMs which are CX3CR1 negative. In patients with allergic asthma and a mouse model of asthma, we found that CX3CR1+ AMs are markedly increased in BAL by allergen challenge. The CX3CR1+ AMs express not only the macrophage but also eosinophil markers such as human Siglec-8. Further investigation with the CX3CR1- reporter and Epx-cre (a.k.a. Eo-cre) reporter mice reveals that CX3CR1+ macrophages engulf eosinophils at a steady state and in allergic lung inflammation. Depletion of CX3CR1+ macrophages in mouse models resulted in spontaneous tissue eosinophilia at a steady status and prolonged tissue eosinophilia in allergic lung inflammation. Based on this data, we hypothesized that the newly recruited CX3CR1+ AM subset promote the clearance of tissue eosinophils and facilitates the resolution of allergic lung inflammation. In aim 1, we will focus on the cellular dynamics of CX3CR1+ macrophages in allergic lung inflammation. Regarding the molecular mechanism of CX3CR1+ mediated-eosinophil clearance, we examined the potential ligands for CX3CR1 – CX3CL1 and CCL26. We discovered that CCL26 plays a key role in activating CX3CR1+ macrophages, whereas CX3CL1 is indispensable. Our sc-RNA-seq data revealed that CX3CR1+ AM subset is the sole source of the transcript of C1q - a key molecule for efferocytosis. In in-vitro setting, CCL26 triggers CX3CR1+ macrophages to secrete C1q in a CX3CR1 receptor-mediated manner. Furthermore, C1q and CCL26 are increased in BAL by allergen challenge in patients with allergic asthma. This data suggests CCL26 activates CX3CR1+ macrophages to facilitate efferocytosis via C1q secretion. In aim 2, we will examine the detailed mechanisms of CX3CR1+ macrophage activation through CCL26-mediated C1q secretion. Finally, we will extend the study to translational human research using the IRB-approved protocol for the segmental provocation with an allergen to evaluate the human relevance of the above proposed experiments. The proposed study is based on our strong supporting data on the new roles of CX3CR1+ macrophages in the resolution of allergic lung inflammation. This study will lead to a better understanding of the resolution process of allergic asthma.

题目：CX3CR1+巨噬细胞介导的嗜酸性粒细胞变应性肺部炎症的消退机制