TNF-Mediated Restriction of Arginase 1 Expression in Myeloid Cells Triggers Type 2 NO Synthase Activity at the Site of Infection.
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.
Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany; Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, 91054 Erlangen, Germany.
Ulrike
U
Schleicher
Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany.
Katrin
K
Paduch
Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany.
Andrea
A
Debus
Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany.
Stephanie
S
Obermeyer
Abteilung Mikrobiologie und Hygiene, Institut für Medizinische Mikrobiologie und Hygiene, Albert-Ludwigs-Universität Freiburg, 79104 Freiburg, Germany.
Till
T
König
Menzies Institute for Medical Research Tasmania, Hobart, Tasmania 7000, Australia.
Jessica C
JC
Kling
Institute of Virology and Immunobiology, University of Würzburg, 97078 Würzburg, Germany.
Eliana
E
Ribechini
Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, 91054 Erlangen, Germany; Laboratory of DC Biology, Department of Dermatology, FAU Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany.
Diana
D
Dudziak
Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, 91054 Erlangen, Germany; Department of Internal Medicine 5, Hematology and Oncology, FAU Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany.
Dimitrios
D
Mougiakakos
Departments of Infectious Diseases and Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Peter J
PJ
Murray
Department of Experimental Oncology, European Institute of Oncology (IEO), 20139 Milan, Italy.
Renato
R
Ostuni
Menzies Institute for Medical Research Tasmania, Hobart, Tasmania 7000, Australia.
Heinrich
H
Körner
Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany; Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address: christian.bogdan@uk-erlangen.de.
Christian
C
Bogdan
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001119:Arginase / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002452:Cell Count; D003713:Dendritic Cells / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D018320:Leishmania major; D007896:Leishmaniasis / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D050800:STAT6 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D015415:Biomarkers; D006657:Histones; D050800:STAT6 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; D001119:Arginase