Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1beta
Department of Medicine, Division of Infectious Diseases and Immunology; Department of Medicine, Division of Pulmonary and Critical Care Medicine; Department of Microbiology and Physiological Systems
Animals; Carrier Proteins; Cells, Cultured; Humans; Immunity, Innate; Inflammasomes; Interferon-gamma; Interleukin-1beta; Mice; Mice, Inbred C57BL; Mice, Knockout; Mycobacterium tuberculosis; Nitric Oxide; Protein Modification, Translational; Protein Multimerization; Signal Transduction; Tuberculosis
Bacterial Infections and Mycoses | Immunology and Infectious Disease | Immunopathology
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-gamma (IFN-gamma). 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.
DOI of Published Version
Nat Immunol. 2013 Jan;14(1):52-60. doi: 10.1038/ni.2474. Epub 2012 Nov 18. Link to article on publisher's site
Mishra, Bibhuti B.; Rathinam, Vijay A. K.; Martens, Gregory W.; Martinot, Amanda J.; Kornfeld, Hardy; Fitzgerald, Katherine A.; and Sassetti, Christopher M., "Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1beta" (2013). University of Massachusetts Medical School Faculty Publications. 239.