The NLRP12 Inflammasome Recognizes Yersinia pestis

Division of Infectious Diseases and Immunology, UMass Medical School, Worcester, MA 01605, USA.
Immunity (Impact Factor: 19.75). 07/2012; 37(1):96-107. DOI: 10.1016/j.immuni.2012.07.006
Source: PubMed

ABSTRACT 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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    • "Furthermore, NLRP12 also appears to maintain intestinal homeostasis by negatively regulating inflammatory signaling pathways such as NF-kB and MAPK (Zaki et al. 2011; Allen et al. 2012b), and forced coexpression of NLRP12 and ASC results in synergistic activation of caspase-1 and secretion of IL-1b (Wang et al. 2002). In addition , a recent study showed that the NLRP12 inflammasome regulates IL-18 and IL-1b production after Yersinia pestis infection, and NLRP12-deficient mice were more susceptible to bacterial challenge (Vladimer et al. 2012). Like NLRP6, the specific PAMPs or DAMPs that can activate NLPR12, and the precise mechanism of activation, await identification. "
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    • "It functions asYersinia pestis recognition and inflammasome formation for IL-1b and IL-18 maturation for host defense. Meanwhile, it also suppresses colon inflammation and tumorigenesis through negatively regulating the canonical or non-canonical NF-κB signaling (Zaki et al., 2011; Allen et al., 2012; Vladimer et al., 2012). NLRP7 forms infl ammasome during recognition of microbial lipopeptides in human macrophages (Khare et al., 2012). "
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