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

Schleicher U, Paduch K, Debus A, Obermeyer S, Koenig T, Kling JC, Ribechini E, Dudziak D, Mougiakakos D, Murray PJ, Ostuni R, Koerner H, Bogdan C (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Cell Reports Elsevier (Cell Press)

Book Volume: 15

Pages Range: 1062-75

Journal Issue: 5

DOI: 10.1016/j.celrep.2016.04.001

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.

Authors with CRIS profile

Ulrike Schleicher Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Katrin Paduch Lehrstuhl für Mikrobiologie und Infektionsimmunologie Stephanie Obermeyer Lehrstuhl für Mikrobiologie und Infektionsimmunologie Diana Dudziak Professur für die Biologie Dendritischer Zellen Dimitrios Mougiakakos Professur für Hämatologie/Onkologie mit dem Schwerpunkt Tumorimmunologie Christian Bogdan Lehrstuhl für Mikrobiologie und Infektionsimmunologie

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Involved external institutions

University of Tasmania (UTAS) AU Australia (AU) European Institute of Oncology / Istituto Europeo di Oncologia (IEO) IT Italy (IT) St. Jude Children’s Research Hospital US United States (USA) (US) Julius-Maximilians-Universität Würzburg DE Germany (DE) Albert-Ludwigs-Universität Freiburg DE Germany (DE)

How to cite

APA:

Schleicher, U., Paduch, K., Debus, A., Obermeyer, S., Koenig, T., Kling, J.C.,... Bogdan, C. (2016). TNF-Mediated Restriction of Arginase 1 Expression in Myeloid Cells Triggers Type 2 NO Synthase Activity at the Site of Infection. Cell Reports, 15(5), 1062-75. https://dx.doi.org/10.1016/j.celrep.2016.04.001

MLA:

Schleicher, Ulrike, et al. "TNF-Mediated Restriction of Arginase 1 Expression in Myeloid Cells Triggers Type 2 NO Synthase Activity at the Site of Infection." Cell Reports 15.5 (2016): 1062-75.

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