Incomplete Deletion of IL-4R alpha by LysM Reveals Distinct Subsets of M2 Macrophages Controlling Inflammation and Fibrosis in Chronic

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 naı̈ve resident tissue macrophages from IL-4RaLysM mice almost completely lose IL-4Ra function, a large fraction of macrophages elicited by sterile inflammatory stimuli, Schistosoma mansoni eggs, or S. mansoni infection, fail to excise Il4ra. These F4/80CD11b macrophages, in contrast to resident tissue macrophages, express lower levels of Lyz2 explaining why this population resists LysM-mediated deletion. We show that in response to IL-4 and IL-13, Lyz2IL-4Ra 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 Lyz2IL-4Ra macrophages as the key subset of AAMs mediating the downmodulation of granulomatous inflammation in chronic schistosomiasis. Our observations reveal a limitation on using a LysM 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. Citation: Vannella KM, Barron L, Borthwick LA, Kindrachuk KN, Narasimhan PB, et al. (2014) Incomplete Deletion of IL-4Ra by LysM Reveals Distinct Subsets of M2 Macrophages Controlling Inflammation and Fibrosis in Chronic Schistosomiasis. PLoS Pathog 10(9): e1004372. doi:10.1371/journal.ppat.1004372 Editor: James W. Kazura, Case Western Reserve University, United States of America Received August 29, 2013; Accepted August 1, 2014; Published September 11, 2014 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Disease. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: We have read the journal’s policy and disclose the following potential conflicts: AWC was employed by a commercial company, Biomedical Research Institute. This does not alter our adherence to all PLOS Pathogens policies on sharing data and materials. * Email: [email protected]