The NLRP12 Inflammasome Recognizes Yersinia pestis
Division of Infectious Diseases and Immunology, UMass Medical School, Worcester, MA 01605, USA.Immunity (Impact Factor: 21.56). 07/2012; 37(1):96-107. DOI: 10.1016/j.immuni.2012.07.006
Yersinia pestis, the causative agent of plague, is able to suppress production of inflammatory cytokines IL-18 and IL-1β, which are generated through caspase-1-activating nucleotide-binding domain and leucine-rich repeat (NLR)-containing inflammasomes. Here, we sought to elucidate the role of NLRs and IL-18 during plague. Lack of IL-18 signaling led to increased susceptibility to Y. pestis, producing tetra-acylated lipid A, and an attenuated strain producing a Y. pseudotuberculosis-like hexa-acylated lipid A. We found that the NLRP12 inflammasome was an important regulator controlling IL-18 and IL-1β production after Y. pestis infection, and NLRP12-deficient mice were more susceptible to bacterial challenge. NLRP12 also directed interferon-γ production via induction of IL-18, but had minimal effect on signaling to the transcription factor NF-κB. These studies reveal a role for NLRP12 in host resistance against pathogens. Minimizing NLRP12 inflammasome activation may have been a central factor in evolution of the high virulence of Y. pestis.
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- "Mutations in NLRP12 are associated with a genetic disease, familial cold autoinflammatory syndrome 2 (FCAS2), which closely resembles FCAS1 caused by gain-of-function NLRP3 mutations, and is also alleviated by anti-IL-1 receptor therapy (Borghini et al., 2011; Jéru et al., 2008). Further, NLRP12 was reported to contribute to IL-1 and IL-18 production in response to Yersinia pestis (Vladimer et al., 2012), and IL-1 production during malaria-associated sepsis (Ataide et al., 2014). Several reports implicate NLRP12 in the suppression of NF-B and ERK signalling pathways in murine macrophages, dendritic cells (DCs), or human THP-1 monocytic cells (Allen et al., 2012; Lich et al., 2007; Williams et al., 2005; Zaki et al., 2013, 2011). "
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Article: Inflammasomes[Show abstract] [Hide abstract]
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