Incomplete Deletion of IL-4Rα by LysMCre Reveals Distinct Subsets of M2 Macrophages Controlling Inflammation and Fibrosis in Chronic Schistosomiasis

PLoS Pathogens

Thirumalai R. Ramalingam¹  Luke Barron²  Lee A. Borthwick²  Thomas A. Wynn²  Prakash Babu Narasimhan²  Robert W. Thompson²  Allen W. Cheever²  Kevin M. Vannella²  Sandra White²  Kevin M. Hart²  Kristen N. Kindrachuk³ 

[1] Biomedical Research Institute, Rockville, Maryland, United States of America;Program in Tissue Immunity and Repair, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America;Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom

关键词: Macrophages;    Fibrosis;    Schistosoma mansoni;    Inflammation;    Gene expression;    Schistosomiasis;    Inflammatory diseases;    White blood cells;   

DOI  :  10.1371/journal.ppat.1004372

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Mice expressing a Cre recombinase from the lysozyme M-encoding locus (Lyz2) have been widely used to dissect gene function in macrophages and neutrophils. Here, we show that while naïve resident tissue macrophages from IL-4Rαflox/deltaLysMCre mice almost completely lose IL-4Rα function, a large fraction of macrophages elicited by sterile inflammatory stimuli, Schistosoma mansoni eggs, or S. mansoni infection, fail to excise Il4rα. These F4/80hiCD11bhi macrophages, in contrast to resident tissue macrophages, express lower levels of Lyz2 explaining why this population resists LysMCre-mediated deletion. We show that in response to IL-4 and IL-13, Lyz2loIL-4Rα+ macrophages differentiate into an arginase 1-expressing alternatively-activated macrophage (AAM) population, which slows the development of lethal fibrosis in schistosomiasis. In contrast, we identified Lyz2hiIL-4Rα+ macrophages as the key subset of AAMs mediating the downmodulation of granulomatous inflammation in chronic schistosomiasis. Our observations reveal a limitation on using a LysMCre mouse model to study gene function in inflammatory settings, but we utilize this limitation as a means to demonstrate that distinct populations of alternatively activated macrophages control inflammation and fibrosis in chronic schistosomiasis.

【 授权许可】

CC BY