Editors' ChoiceInflammation

Chronic Infection, But Limited Inflammation

See allHide authors and affiliations

Science Signaling  01 Jan 2013:
Vol. 6, Issue 256, pp. ec2
DOI: 10.1126/scisignal.2003912

Some pathogens—such as the bacterium that causes tuberculosis, Mycobacterium tuberculosis—can produce chronic infection, and the severity of disease appears to relate more to tissue damage from inflammation than from bacterial burden. Mishra et al. used a mouse infection model in which the bacterial burden was controlled by the addition of streptomycin to study the pathogenesis of tuberculosis infection. Mice genetically deficient in Nos2—encoding inducible nitric oxide synthase (iNOS), the enzyme that produces nitric oxide (NO), in macrophages in response to infection—or in which NO production was pharmacologically inhibited exhibited more severe lung pathology with increased neutrophil infiltration and increased production of the proinflammatory cytokine interleukin-1β (IL-1β) than was observed for wild-type or control mice with the same bacterial burden. The importance of IL-1 signaling in this exacerbated inflammatory response was supported by the lack of such a response in infected mice deficient in the IL-1 receptor that were treated with an iNOS inhibitor. IL-1β is processed from a precursor by macromolecular complexes called inflammasomes, and mice deficient in an essential component of this complex also failed to show the exacerbated inflammatory response in response to infection combined with inhibition of iNOS. Experiments with mice genetically deficient in interferon-γ (IFN-γ) had implicated this cytokine in limiting inflammation in response to infection, and pretreatment of M. tuberculosis–infected macrophages with IFN-γ specifically inhibited the release of IL-1β, but not other cytokines, an effect that was due to altered processing of the IL-1β precursor but not to altered gene expression. Furthermore, IFN-γ only reduced IL-1β processing in response to stimuli or infections that activated the NLRP3-containing inflammasome and not those that activated the AIM2-containing inflammasome. The ability of IFN-γ to inhibit NLRP3-dependent IL-1β production was blocked by deficiency or inhibition of iNOS, which suggested that IFN-γ acted through NO to inhibit the NLRP3 inflammasome. Addition of IFN-γ or an NO donor inhibited the formation of the NLRP3 inflammasome but not the AIM2 inflammasome. NLRP3 and caspase-1, two components of the inflammasome, were S-nitrosylated in macrophages infected with M. tuberculosis and exposed to IFN-γ. Using an inflammasome reconstitution assay, S-nitrosylation of NLRP3, but not caspase-1, inhibited IL-1β processing. Thus, NO appears to have a specific immunosuppressive function in conditions of chronic infection that limits the tissue damage that would otherwise result from a persistently active innate immune response.

B. B. Mishra, V. A. K. Rathinam, G. W. Martens, A. J. Martinot, H. Kornfeld, K. A. Fitzgerald, C. M. Sassetti, Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome–dependent processing of IL-1β. Nat. Immunol. 14, 52–60 (2013). [PubMed]

M. Rayamajhi, E. A. Miao, Just say NO to NLRP3. Nat. Immunol. 14, 12–14 (2013). [PubMed]

Stay Connected to Science Signaling