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

Abstract

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 Arg1^flox/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. While the function of NOS2 in Th1-type immunity has been investigated extensively, the role of Arg1 in the regulation of Th2-type responses is unclear. Previously, we showed that proline production in AAMs is regulated by Arg1 activity. Because proline is essential for collagen synthesis in myofibroblasts, numerous studies have suggested that Arg1-expressing AAMs regulate wound healing and fibrosis. The development of fibrosis in schistosomiasis is dependent on Th2 cytokines, and mice deficient in IL-4/IL-13 fail to upregulate Arg1. Nevertheless, although Arg1 expression is associated with Th2-dependent fibrosis, the contribution of macrophage-specific Arg1 to the pathogenesis of fibrosis in schistosomiasis was unknown. The studies conducted here with two different strains of mice deficient in macrophage-associated Arg1 demonstrate unequivocally that Arg1-expressing macrophages exhibit both anti-inflammatory and anti-fibrotic activity during Th2-driven inflammatory responses. In schistosomiasis, fibrosis, portal hypertension, and variceal bleeding are the primary pathological changes that characterize the severe hepatosplenic form of the disease in humans. It is widely believed that people who fail to adequately activate immune suppressive mechanisms when chronically infected with S. mansoni are the individuals who ultimately develop severe disease. Our data identify Arg1-expressing macrophages as critical mediators of immune downmodulation in chronic schistosomiasis.