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

Nature Immunology volume 9, pages 1399–1406 (2008)Cite this article

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.

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Figure 1: Arg1 expression in in vitro mycobacterial infection is regulated by a STAT6-independent, Myd88-dependent pathway.
Figure 2: Central function for the MyD88-C/EBPβ pathway in M. bovis BCG–mediated Arg1 expression.
Figure 3: Specific deletion of Arg1 in macrophages results in higher NO production.
Figure 4: Arg1 deficiency in macrophages increases clearance of M. tuberculosis.
Figure 5: Nitrotyrosine staining of mycobacterial tissues.
Figure 6: Macrophage Arg1 is a susceptibility factor in experimental toxoplasmosis.

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Acknowledgements

We thank I. Förster (Technical University of Munich) for the LysMcre mice; M. Yanagisawa (University of Texas Southwestern) for the Tie2cre mice; P. Ney (St. Jude Children's Research Hospital) for the CMV-cre mice; D. Green (St. Jude Children's Research Hospital) and S. Akira (Osaka University) for the MyD88-deficient mice; S. Morris (University of Pittsburgh) for the antibodies to Arg1; C. Nathan (Weill Medical School of Cornell University) for the antibody to iNOS; S. Smale (University of California, Los Angeles) for the insulated reporter constructs; D. Bush for nitrotyrosine staining of BCG-infected livers; Xenogen for construction of luciferase-bearing pneumococci; Ozgene for microinjection of the targeted Bruce4 cells into C57BL/6 blastocysts and chimera generation; A. DeFreitas for technical assistance; B. Schulman for discussions and generation of Supplementary Figure 6b; and M. Koyanagi and M. Bix for discussion and preliminary infection experiments. Supported by the Sandler Program for Asthma Research (P.J.M.), the National Institutes of Health (AI062921 to P.J.M.; AI27913 to E.I.T.; AI66046 to G.K.; CORE grant P30 CA21765 and the NIAID intramural research program to T.A.W.), the German Research Foundation (SFB620 project A9 to C.B. and U.S.) and the American Lebanese Syrian Associated Charities.

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Author notes

  1. Karim C El Kasmi

    Present address: 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.,

  2. Karim C El Kasmi and Joseph E Qualls: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38015, USA.,

    Karim C El Kasmi, Joseph E Qualls, Amber M Smith, Elaine I Tuomanen & Peter J Murray

  2. Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38015, USA.,

    Karim C El Kasmi, Joseph E Qualls, Amber M Smith, Thirumala-Devi Kanneganti & Peter J Murray

  3. Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.,

    John T Pesce, Robert W Thompson & Thomas A Wynn

  4. Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523, USA.,

    Marcela Henao-Tamayo, Randall J Basaraba & Ian M Orme

  5. Department of Microbiology and Hygiene, Institute of Medical Microbiology and Hygiene University Clinic of Freiburg, 79104 Freiburg, Germany.,

    Till König

  6. Institute of Clinical Microbiology, Immunology and Hygiene University Clinic of Erlangen, 91054 Erlangen, Germany.,

    Ulrike Schleicher & Christian Bogdan

  7. Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute Center, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, USA.,

    Mi-Sun Koo & Gilla Kaplan

  8. Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.,

    Katherine A Fitzgerald

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  1. Karim C El Kasmi
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Contributions

K.C.E.K., J.E.Q. and A.M.S. did most of the experiments. J.T.P. and R.W.T. did the T. gondii experiments. M.H.-T., R.J.B., T.K., U.S., M.-S.K., G.K., E.I.T., I.M.O. and C.B. did the infection and biochemistry experiments. K.A.F. and T.-D.K. contributed key research reagents. P.J.M. created the Arg1 conditional knockout. P.J.M. and A.M.S. bred and backcrossed the mice. T.A.W. and P.J.M. conceived and designed the project and wrote the manuscript.

Corresponding authors

Correspondence to Thomas A Wynn or Peter J Murray.

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El Kasmi, K., Qualls, J., Pesce, J. et al. Toll-like receptor–induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol 9, 1399–1406 (2008). https://doi.org/10.1038/ni.1671

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