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

By J. Pesce, T. Ramalingam, Margaret M. Mentink-Kane, M. Wilson, K. E. El Kasmi, A. Smith, Robert W. Thompson, A. Cheever, P. Murray, TA Wynn. PLoS Pathogens, 2009

821 citations recorded by the source corpus.

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.

Subfields: Immunology, Parasitology

View Paper: https://www.semanticscholar.org/paper/7441bf5a984c906932882f034c038a8409d27e53

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In Immunology

1. F. Tacke
2. P. Italiani
3. D. Boraschi
4. Luke Barron
5. G. Harry
6. C. McPherson
7. Rubén Orihuela
8. Xiangming Zou

In Parasitology

1. TA Wynn

Citations in the corpus

• Metabolism via Arginase or Nitric Oxide Synthase: Two Competing Arginine Pathways in Macrophages (2014, background): “Suppression of T cell activation, proliferation, and/or differentiation by macrophage arginase I was shown in vivo in murine disease models dominated by M2 macrophages, like schistosomiasis (80, 83) or leishmaniasis (92).”
• Nitric oxide and redox mechanisms in the immune response (2011, background): “[231] recently demonstrated a NO-independent role for AG1 in alternatively activated macrophages in mice chronically infected with the”
• Macrophage Polarization in Inflammatory Diseases (2014, background): “A study using myeloid cell restricted Arg1 deficiency Schistosoma mansoni infection model suggested that Arg1 appeared to be a key mediator for the development of helminth infestation through restraining both unrestricted Th2-mediated fibrotic pathology and intestinal damage associated with increase”
• Integrating mechanisms of pulmonary fibrosis (2011, background): “Th2 cytokine-stimulated macrophages that express the enzyme arginase-1 also exhibit potent antifibrotic activity (Pesce et al., 2009).”
• Macrophage heterogeneity in liver injury and fibrosis. (2014, background): “Of note, alternatively activated arginase-expressing macrophages are capable of constraining liver fibrosis in an archetypical Th2 inflammation model and it is feasible that they also derive from local precursors [35].”
• From Monocytes to M1/M2 Macrophages: Phenotypical vs. Functional Differentiation (2014, background): “M2-produced ornithine can promote cell proliferation and repair through polyamine and collagen synthesis, fibrosis and other tissue remodeling functions (167), while M1-produced NO is an important effector molecule with microbicidal activity and cell proliferation inhibitory capacity (168).”
• Microglial M1/M2 polarization and metabolic states (2016, background): “The M2 phenotype has also been considered as the ‘default’ polarization of resident macrophages (Murray and Wynn, 2011) with the production of ornithine to promote cell proliferation and repair through polyamine and collagen synthesis, fibrosis and tissue remodelling functions (Pesce et al., 2009).”