Cell Reports
Volume 15, Issue 5, 3 May 2016, Pages 1062-1075
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Article
TNF-Mediated Restriction of Arginase 1 Expression in Myeloid Cells Triggers Type 2 NO Synthase Activity at the Site of Infection

https://doi.org/10.1016/j.celrep.2016.04.001Get rights and content
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Highlights

  • TNF inhibits IL-4-induced Arg1 expression in macrophages and dendritic cells

  • Arg1 is upregulated in macrophages or dendritic cells of L. major-infected TNF−/− mice

  • Arg1 hyperexpression in TNF−/− mice impairs in situ production of leishmanicidal NO

  • Arg1 deletion restores parasite and disease control in otherwise non-healing mice

Summary

Neutralization or deletion of tumor necrosis factor (TNF) causes loss of control of intracellular pathogens in mice and humans, but the underlying mechanisms are incompletely understood. Here, we found that TNF antagonized alternative activation of macrophages and dendritic cells by IL-4. TNF inhibited IL-4-induced arginase 1 (Arg1) expression by decreasing histone acetylation, without affecting STAT6 phosphorylation and nuclear translocation. In Leishmania major-infected C57BL/6 wild-type mice, type 2 nitric oxide (NO) synthase (NOS2) was detected in inflammatory dendritic cells or macrophages, some of which co-expressed Arg1. In TNF-deficient mice, Arg1 was hyperexpressed, causing an impaired production of NO in situ. A similar phenotype was seen in L. major-infected BALB/c mice. Arg1 deletion in hematopoietic cells protected these mice from an otherwise lethal disease, although their disease-mediating T cell response (Th2, Treg) was maintained. Thus, deletion or TNF-mediated restriction of Arg1 unleashes the production of NO by NOS2, which is critical for pathogen control.

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Co-first author

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Co-senior author

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Present address: Biologicals Quality, Novartis Pharma, CH-4002 Basel, Switzerland

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Present address: The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba Queensland 4102, Australia

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Present address: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET) and Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, 20132 Milano, Italy