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

TLDR

Macrophage‑specific Arginase‑1 is thought to promote inflammation, fibrosis, and wound healing through increased L‑proline, polyamines, and Th2 cytokine production. In Arg1‑deficient macrophages, elevated Th2 cytokine production and loss of T‑cell proliferation inhibition explain the worsened Th2 inflammation. Arg1‑expressing macrophages suppress Th2‑driven inflammation and fibrosis by depleting arginine, and loss of Arg1 leads to increased pathology and mortality in Schistosoma‑infected mice.

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 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.