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Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome–dependent processing of IL-1β

Nature Immunology volume 14, pages 52–60 (2013)Cite this article

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Abstract

Interleukin 1 (IL-1) is an important mediator of innate immunity but can also promote inflammatory tissue damage. During chronic infections such as tuberculosis, the beneficial antimicrobial role of IL-1 must be balanced with the need to prevent immunopathology. By exogenously controlling the replication of Mycobacterium tuberculosis in vivo, we obviated the requirement for antimicrobial immunity and discovered that both IL-1 production and infection-induced immunopathology were suppressed by lymphocyte-derived interferon-γ (IFN-γ). This effect was mediated by nitric oxide (NO), which we found specifically inhibited assembly of the NLRP3 inflammasome via thiol nitrosylation. Our data indicate that the NO produced as a result of adaptive immunity is indispensable in modulating the destructive innate inflammatory responses elicited during persistent infections.

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Figure 1: Lymphocytes, IFN-γ and iNOS modulate the immunopathology of tuberculosis.
Figure 2: The anti-inflammatory activities of NO are independent of its antimycobacterial function.
Figure 3: IL-1R1 and ASC promote the enhanced recruitment of neutrophils observed after inhibition of iNOS.
Figure 4: Activation of macrophages by IFN-γ inhibits the processing of IL-1β.
Figure 5: IFN-γ specifically inhibits activation of the NLRP3 inflammasome.
Figure 6: NO is necessary for IFN-γ-mediated suppression of IL-1β processing.
Figure 7: IFN-γ-induced NO post-translationally inhibits assembly and activation of the NLRP3 inflammasome via thiol nitrosylation.

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Acknowledgements

We thank S. Swain (University of Massachusetts Medical School) for Ifngr1−/− mice; A. Campos-Neto (Forsyth Institute) for M. tuberculosis strain 18b; B. McCormick (University of Massachusetts Medical School) for Salmonella enterica serovar Typhimurium; E. Alnemri (Thomas Jefferson University) for rabbit polyclonal antibody to mouse AIM2; G. Nunez (University of Michigan) for rat monoclonal antibody to ASC; B. McCormick, K. Rock, R. Mishra, A.K. Pandey and J. Lee for scientific insight; and H. Ducharme for animal husbandry. Supported by the US National Institutes of Health (AI064282 to C.M.S.; HL064884 to H.K.; AI083713 to K.A.F.; and U54 AI057159 to V.A.K.R.) and the Howard Hughes Medical Institute (C.M.S.).

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Authors and Affiliations

  1. Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Bibhuti B Mishra & Christopher M Sassetti

  2. Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Vijay A K Rathinam & Katherine A Fitzgerald

  3. Division of Pulmonary, Department of Medicine, Allergy and Critical Care, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Gregory W Martens & Hardy Kornfeld

  4. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA

    Amanda J Martinot

  5. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA

    Christopher M Sassetti

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Contributions

B.B.M. and C.M.S. conceived of the project and designed the experiments; B.B.M. did most of the experiments; V.A.K.R. and G.W.M. did specific experiments; A.J.M. provided veterinary pathology expertise; B.B.M. and C.M.S. wrote the manuscript; H.K. and K.A.F. provided mutant mice, scientific insight and critical review of the manuscript; and C.M.S. oversaw the project.

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Correspondence to Christopher M Sassetti.

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Mishra, B., Rathinam, V., Martens, G. et al. Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome–dependent processing of IL-1β. Nat Immunol 14, 52–60 (2013). https://doi.org/10.1038/ni.2474

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