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

Lookup NU author(s): Dr Lee Borthwick

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This is the final published version of an article that has been published in its final definitive form by Public Library of Science, 2014.

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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 naive resident tissue macrophages from IL-4R alpha(flox/delta) LysM(Cre) mice almost completely lose IL-4R alpha function, a large fraction of macrophages elicited by sterile inflammatory stimuli, Schistosoma mansoni eggs, or S. mansoni infection, fail to excise Il4r alpha. These F4/80(hi) CD11b(hi) macrophages, in contrast to resident tissue macrophages, express lower levels of Lyz2 explaining why this population resists LysM(Cre) -mediated deletion. We show that in response to IL-4 and IL-13, Lyz2(lo) IL-4R alpha(+) 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(hi) IL-4R alpha(+) 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.

Publication metadata

Author(s): Vannella KM, Barron L, Borthwick LA, Kindrachuk KN, Narasimhan PB, Hart KM, Thompson RW, White S, Cheever AW, Ramalingam TR, Wynn TA

Publication type: Article

Publication status: Published

Journal: PLoS Pathogens

Year: 2014

Volume: 10

Issue: 9

Online publication date: 11/09/2014

Acceptance date: 01/08/2014

Date deposited: 01/12/2014

ISSN (print): 1553-7366

ISSN (electronic): 1553-7374

Publisher: Public Library of Science

URL: http://dx.doi.org/10.1371/journal.ppat.1004372

DOI: 10.1371/journal.ppat.1004372

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