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

<div><p>Mice expressing a Cre recombinase from the lysozyme M-encoding locus (<i>Lyz2</i>) have been widely used to dissect gene function in macrophages and neutrophils. Here, we show that while naïve resident tissue macrophages from IL-4Rα^flox/deltaLysM^Cre mice almost completely lose IL-4Rα function, a large fraction of macrophages elicited by sterile inflammatory stimuli, <i>Schistosoma mansoni</i> eggs, or <i>S. mansoni</i> infection, fail to excise <i>Il4rα</i>. These F4/80^hiCD11b^hi macrophages, in contrast to resident tissue macrophages, express lower levels of <i>Lyz2</i> explaining why this population resists LysM^Cre-mediated deletion. We show that in response to IL-4 and IL-13, Lyz2^loIL-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 Lyz2^hiIL-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 LysM^Cre 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.</p>