Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1β.
Bibhuti B. Mishra,Vijay A. K. Rathinam,Gregory W. Martens,Amanda J. Martinot,Hardy Kornfeld,Katherine A. Fitzgerald,Christopher M. Sassetti,Christopher M. Sassetti +7 more
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TLDR
By exogenously controlling the replication of Mycobacterium tuberculosis in vivo, the requirement for antimicrobial immunity is obviated and it is discovered that both IL-1 production and infection-induced immunopathology were suppressed by lymphocyte-derived interferon-γ (IFN-γ).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.read more
Citations
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Activation and regulation of the inflammasomes
TL;DR: The complex regulatory mechanisms that facilitate a balanced but effective inflammasome-mediated immune response are discussed, and the similarities to another molecular signalling platform — the apoptosome — that monitors cellular health are highlighted.
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Inflammasomes: mechanism of assembly, regulation and signalling
Petr Broz,Vishva M. Dixit +1 more
TL;DR: This Review discusses the recent developments in inflammasome research with a focus on the molecular mechanisms that govern inflammaome assembly, signalling and regulation.
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The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation.
TL;DR: Current understanding of the mechanisms ofNLRP3 inflammasome activation by multiple signaling events, and its regulation by post-translational modifications and interacting partners of NLRP3 are summarized.
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Regulation of inflammasome activation
TL;DR: Genetic studies indicate that mutations in NLRP1, NLRP3, NLRC4, and AIM2 are linked with the development of auto‐inflammatory diseases, enterocolitis, and cancer and transform the understanding of the basic biology and clinical relevance of inflammasomes.
Journal ArticleDOI
Dopamine Controls Systemic Inflammation through Inhibition of NLRP3 Inflammasome
TL;DR: DA and DRD1 signaling prevent NLRP3 inflammasome-dependent inflammation, including neurotoxin-induced neuroinflammation, LPS-induced systemic inflammation, and monosodium urate crystal (MSU)-induced peritoneal inflammation.
References
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Journal ArticleDOI
Cutting Edge: Caspase-1 Independent IL-1β Production Is Critical for Host Resistance to Mycobacterium tuberculosis and Does Not Require TLR Signaling In Vivo
Katrin D. Mayer-Barber,Daniel L. Barber,Kevin Shenderov,Sandra White,Mark S. Wilson,Allen W. Cheever,David G. Kugler,Sara Hieny,Patricia Caspar,Gabriel Núñez,Dirk Schlueter,Richard A. Flavell,Fayyaz S. Sutterwala,Alan Sher +13 more
TL;DR: A major role for IL-1β in host resistance to M. tuberculosis is revealed and it is indicated that during this infection the cytokine can be generated by a mechanism that does not require TLR signaling or caspase-1.
Journal ArticleDOI
Effects of nitric oxide synthase inhibitors on murine infection with Mycobacterium tuberculosis.
TL;DR: Two distinct inhibitors of nitric oxide synthase (aminoguanidine and NG-monomethyl-L-arginine) render similar deleterious effects on tuberculous infection in mice, as assessed by mortality, bacterial burden, and pathological tissue damage, thus confirming the importance of reactive nitrogen intermediates in resistance against M. tuberculosis.
Journal ArticleDOI
Neutrophils are the predominant infected phagocytic cells in the airways of patients with active pulmonary TB.
Seok Yong Eum,Ji Hye Kong,Min Sun Hong,Ye Jin Lee,Jin Hee Kim,Soo Hee Hwang,Sang Nae Cho,Laura E. Via,Clifton E. Barry +8 more
TL;DR: In this paper, the authors show that neutrophils are the predominant cell types infected with Mycobacterium tuberculosis in patients with TB and that these intracellular bacteria appear to replicate rapidly.
Neutrophils are the predominant infected phagocytic cells in the airways of patients with active pulmonary TB
Seok Yong Eum,Ji Hye Kong,Min Sun Hong,Ye Jin Lee,Jin Hee Kim,Soo Hee Hwang,Sang Nae Cho,Laura E. Via,Clifton E. Barry +8 more
TL;DR: Neutrophils are the predominant cell types infected with Mtb in patients with TB and that these intracellular bacteria appear to replicate rapidly, consistent with a role for neutrophils in providing a permissive site for a final burst of active replication of the bacilli prior to transmission.
Journal ArticleDOI
Innate and adaptive interferons suppress IL-1α and IL-1β production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection
Katrin D. Mayer-Barber,Bruno B. Andrade,Daniel L. Barber,Sara Hieny,Carl G. Feng,Patricia Caspar,Sandy Oland,Siamon Gordon,Alan Sher +8 more
TL;DR: The data provide a cellular basis for both the anti-inflammatory effects of IFNs and probacterial functions of type I IFNs during Mtb infection and reveal differential regulation of IL-1 production by distinct cell populations as an additional layer of complexity in the activity ofIL-1 in vivo.