TNF-Mediated Restriction of Arginase 1 Expression in Myeloid Cells Triggers Type 2 NO Synthase Activity at the Site of Infection

Ulrike Schleicher, Katrin Paduch, Andrea Debus, Stephanie Obermeyer, Till König, Jessica C. Kling, Eliana Ribechini, Diana Dudziak, Dimitrios Mougiakakos, Peter J. Murray, Renato Ostuni, Heinrich Körner, Christian Bogdan

Research output: Contribution to journalArticlepeer-review

Abstract

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. Control of intracellular pathogens requires TNF, but its mechanism of action is incompletely understood. Schleicher et al. show that TNF suppresses Arg1 expression in myeloid cells by decreasing histone acetylation, resulting in enhanced production of NO by NOS2 in situ. Arg1 deletion rescues Leishmania-infected mice from a non-healing infection.

Original languageEnglish
Pages (from-to)1062-1075
Number of pages14
JournalCell Reports
Volume15
Issue number5
DOIs
Publication statusPublished - May 3 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'TNF-Mediated Restriction of Arginase 1 Expression in Myeloid Cells Triggers Type 2 NO Synthase Activity at the Site of Infection'. Together they form a unique fingerprint.

Cite this