Abstract
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.
Highlights
Tissue macrophages exhibit substantial plasticity and can quickly change their function in response to different stimuli found in the local milieu [1], and distinct subsets with characteristic functional activities have been described
In addition to expressing mediators that directly regulate wound repair pathways such as arginase 1 (Arg1), resistin-like molecule alpha (Relm-a), transforming growth factor beta-1 (TGF-b1), vascular endothelial growth factor (VEGF), and insulin-like growth factor-1 (IGF-1) [5], AAMs suppress pro-inflammatory Th1, Th17, and classically activated macrophage (CAMs) responses that contribute to tissue injury [6]
We conclude that during schistosomiasis, distinct populations of alternatively activated macrophages control inflammation and fibrosis: macrophages expressing low levels of lysozyme 2 (Lyz2) express Arg1 and are sufficient to control fibrosis, while more mature Lyz2-expressing macrophages are required for downmodulation of egg-induced inflammation in chronic schistosomiasis
Summary
Tissue macrophages exhibit substantial plasticity and can quickly change their function in response to different stimuli found in the local milieu [1], and distinct subsets with characteristic functional activities have been described. In addition to expressing mediators that directly regulate wound repair pathways such as arginase 1 (Arg1), resistin-like molecule alpha (Relm-a), transforming growth factor beta-1 (TGF-b1), vascular endothelial growth factor (VEGF), and insulin-like growth factor-1 (IGF-1) [5], AAMs suppress pro-inflammatory Th1, Th17, and classically activated macrophage (CAMs) responses that contribute to tissue injury [6]. Herbert and colleagues generated macrophage/neutrophil-specific IL-4Ra-deficient mice (IL-4Raflox/DLysMCre) by expressing Cre recombinase in the regulatory region of the lysozyme M gene expressed in macrophages and neutrophils. They showed AAMs are required to suppress pathogenic Th1/CAM responses during infection with the helminth parasite Schistosoma mansoni [7]. In contrast to IL-4Raflox/DLysMCre mice, mice with a macrophage/neutrophil-specific deletion of Arg (Arg1flox/DLysMCre), an enzyme involved in the conversion of L-arginine into L-
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