TNF-mediated restriction of arginase 1 expression in myeloid cells triggers type 2 NO synthase activity at the site of infection

Schleicher, Ulrike, Paduch, Katrin, Debus, Andrea, Obermeyer, Stephanie, Koenig, Till, Kling, Jessica C., Ribechini, Eliana, Dudziak, Diana, Mougiakakos, Dimitrios, Murray, Peter J., Ostuni, Renato, Koerner, Heinrich and Bogdan, Christian (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: 1062-1075. doi:10.1016/j.celrep.2016.04.001


Author Schleicher, Ulrike
Paduch, Katrin
Debus, Andrea
Obermeyer, Stephanie
Koenig, Till
Kling, Jessica C.
Ribechini, Eliana
Dudziak, Diana
Mougiakakos, Dimitrios
Murray, Peter J.
Ostuni, Renato
Koerner, Heinrich
Bogdan, Christian
Title TNF-mediated restriction of arginase 1 expression in myeloid cells triggers type 2 NO synthase activity at the site of infection
Journal name Cell Reports   Check publisher's open access policy
ISSN 2211-1247
Publication date 2016-05-03
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.celrep.2016.04.001
Open Access Status DOI
Volume 15
Issue 5
Start page 1062
End page 1075
Total pages 14
Place of publication New York, NY, United States
Publisher Elsevier
Collection year 2017
Language eng
Formatted 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.
Keyword Tumor necrosis factor (TNF)
Leishmania major
Myeloid cells
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute Publications
 
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