Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens

Karim C. El Kasmi, University of Colorado
Joseph E. Qualls, St. Jude Children’s Research Hospital
John T. Pesce, National Institutes of Health
Amber M. Smith, St. Jude Children’s Research Hospital
Robert W. Thompson, National Institutes of Health
Marcela Henao-Tamayo, Colorado State University
Randall J. Basaraba, Colorado State University
Till Konig, Hygiene University Clinic of Erlangen
Ulrike Schleicher, Hygiene University Clinic of Erlangen
Mi-Sun Koo, University of Medicine and Dentristry of New Jersey
Gilla Kaplan, University of Medicine and Dentristry of New Jersey
Katherine A. Fitzgerald, University of Massachusetts Medical School
Elaine I. Tuomanen, St. Jude Children’s Research Hospital
Ian M. Orme, Colorado State University
Thirumala-Devi Kanneganti, St. Jude Children’s Research Hospital
Christian Bogdan, Hygiene University Clinic of Erlangen
Thomas A. Wynn, National Institutes of Health
Peter J. Murray, St. Jude Children’s Research Hospital

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.