Article abstract
Nature Immunology 9, 1399 - 1406 (2008)
Published online: 2 November 2008 | doi:10.1038/ni.1671
Toll-like receptor–induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens
Karim C El Kasmi1,2,9,10, Joseph E Qualls1,2,10, John T Pesce3, Amber M Smith1,2, Robert W Thompson3, Marcela Henao-Tamayo4, Randall J Basaraba4, Till König5, Ulrike Schleicher6, Mi-Sun Koo7, Gilla Kaplan7, Katherine A Fitzgerald8, Elaine I Tuomanen1, Ian M Orme4, Thirumala-Devi Kanneganti2, Christian Bogdan6, Thomas A Wynn3 & Peter J Murray1,2
Abstract
Toll-like receptor (TLR) signaling in macrophages is required for antipathogen responses, including the biosynthesis of nitric oxide from arginine, and is essential for immunity to Mycobacterium tuberculosis, Toxoplasma gondii and other intracellular pathogens. Here we report a 'loophole' in the TLR pathway that is advantageous to these pathogens. Intracellular pathogens induced expression of the arginine hydrolytic enzyme arginase 1 (Arg1) in mouse macrophages through the TLR pathway. In contrast to diseases dominated by T helper type 2 responses in which Arg1 expression is greatly increased by interleukin 4 and 13 signaling through the transcription factor STAT6, TLR-mediated Arg1 induction was independent of the STAT6 pathway. Specific elimination of Arg1 in macrophages favored host survival during T. gondii infection and decreased lung bacterial load during tuberculosis infection.
- Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38015, USA.
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38015, USA.
- Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
- Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523, USA.
- Department of Microbiology and Hygiene, Institute of Medical Microbiology and Hygiene University Clinic of Freiburg, 79104 Freiburg, Germany.
- Institute of Clinical Microbiology, Immunology and Hygiene University Clinic of Erlangen, 91054 Erlangen, Germany.
- Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute Center, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, USA.
- Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
- Present address: Department of Pediatrics, Division of Gastroenterology and Hepatology, University of Colorado at Denver and Health Sciences Center, Anschutz Medical Campus, Colorado 80045, USA.
- These authors contributed equally to this work.
Correspondence to: Peter J Murray1,2 e-mail: peter.murray@stjude.org
Correspondence to: Thomas A Wynn3 e-mail: twynn@niaid.nih.gov
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