Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis

John T. Pesce, Thirumalai R. Ramalingam, Margaret M. Mentink-Kane, Mark S. Wilson, Karim C.E. Kasmi, Amber Smith, Robert W. Thompson, Allen W. Cheever, Peter J. Murray, Thomas A. Wynn

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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.

Original languageEnglish (US)
JournalPLoS Pathogens
Volume5
Issue number4
DOIs
StatePublished - Apr 1 2009

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Arginase
Fibrosis
Macrophages
Cytokines
Inflammation
T-Lymphocytes
Arginine
Cell Proliferation
Endotoxemia
Schistosoma mansoni
Polyamines
Portal Hypertension
Infection
Proline
Liver Cirrhosis
Interleukin-10
Wound Healing
Pathology

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Pesce, J. T., Ramalingam, T. R., Mentink-Kane, M. M., Wilson, M. S., Kasmi, K. C. E., Smith, A., ... Wynn, T. A. (2009). Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathogens, 5(4). https://doi.org/10.1371/journal.ppat.1000371

Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. / Pesce, John T.; Ramalingam, Thirumalai R.; Mentink-Kane, Margaret M.; Wilson, Mark S.; Kasmi, Karim C.E.; Smith, Amber; Thompson, Robert W.; Cheever, Allen W.; Murray, Peter J.; Wynn, Thomas A.

In: PLoS Pathogens, Vol. 5, No. 4, 01.04.2009.

Research output: Contribution to journalArticle

Pesce, JT, Ramalingam, TR, Mentink-Kane, MM, Wilson, MS, Kasmi, KCE, Smith, A, Thompson, RW, Cheever, AW, Murray, PJ & Wynn, TA 2009, 'Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis', PLoS Pathogens, vol. 5, no. 4. https://doi.org/10.1371/journal.ppat.1000371
Pesce, John T. ; Ramalingam, Thirumalai R. ; Mentink-Kane, Margaret M. ; Wilson, Mark S. ; Kasmi, Karim C.E. ; Smith, Amber ; Thompson, Robert W. ; Cheever, Allen W. ; Murray, Peter J. ; Wynn, Thomas A. / Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. In: PLoS Pathogens. 2009 ; Vol. 5, No. 4.
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