Arginase-1–Expressing Macrophages Suppress Th2 Cytokine–Driven Inflammation and Fibrosis

PLoS Pathogens

Allen W. Cheever¹  Amber M. Smith²  Peter J. Murray²  Karim C. El Kasmi²  John T. Pesce³  Thirumalai R. Ramalingam³  Mark S. Wilson³  Thomas A. Wynn³  Margaret M. Mentink-Kane³  Robert W. Thompson³ 

[1] Biomedical Research Institute, Rockville, Maryland, United States of America;Departments of Infectious Diseases and Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America;Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America

关键词: Macrophages;    Fibrosis;    Schistosoma mansoni;    T cells;    Cytokines;    Granulomas;    Mouse models;    Inflammation;   

DOI  :  10.1371/journal.ppat.1000371

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Macrophage-specific expression of Arginase-1 is commonly believed to promote inflammation, fibrosis, and wound healing by enhancing L-proline, polyamine, and Th2 cytokine production. Here, however, we show that macrophage-specific Arg1 functions as an inhibitor of inflammation and fibrosis following infection with the Th2-inducing pathogen Schistosoma mansoni. Although susceptibility to infection was not affected by the conditional deletion of Arg1 in macrophages, Arg1−/flox;LysMcre mice died at an accelerated rate. The mortality was not due to acute Th1/NOS2-mediated hepatotoxicity or endotoxemia. Instead, granulomatous inflammation, liver fibrosis, and portal hypertension increased in infected Arg1−/flox;LysMcre mice. Similar findings were obtained with Arg1flox/flox;Tie2cre mice, which delete Arg1 in all macrophage populations. Production of Th2 cytokines increased in the infected Arg1−/flox;LysMcre mice, and unlike alternatively activated wild-type macrophages, Arg1−/flox;LysMcre macrophages failed to inhibit T cell proliferation in vitro, providing an underlying mechanism for the exacerbated Th2 pathology. The suppressive activity of Arg1-expressing macrophages was independent of IL-10 and TGF-β1. However, when exogenous L-arginine was provided, T cell proliferation was restored, suggesting that Arg1-expressing macrophages deplete arginine, which is required to sustain CD4+ T cell responses. These data identify Arg1 as the essential suppressive mediator of alternatively activated macrophages (AAM) and demonstrate that Arg1-expressing macrophages function as suppressors rather than inducers of Th2-dependent inflammation and fibrosis.

【 授权许可】

CC BY