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
Source: PubMed


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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    ABSTRACT: NOD-like receptors (NLR) are a family of cytosolic pattern recognition receptors that include many key drivers of innate immune responses. NLRP12 is an emerging member of the NLR family that is closely related to the well-known inflammasome scaffold, NLRP3. Since its discovery, various functions have been proposed for NLRP12, including the positive regulation of dendritic cell (DC) and neutrophil migration and the inhibition of NF-κB and ERK signalling in DC and macrophages. We show here that NLRP12 is poorly expressed in murine macrophages and DC, but is strongly expressed in neutrophils. Using myeloid cells from WT and Nlrp12(-/)(-) mice, we show that, contrary to previous reports, NLRP12 does not suppress LPS- or infection-induced NF-κB or ERK activation in myeloid cells, and is not required for DC migration in vitro. Surprisingly, we found that Nlrp12 deficiency caused increased rather than decreased neutrophil migration towards the chemokine CXCL1 and the neutrophil parasite Leishmania major, revealing NLRP12 as a negative regulator of directed neutrophil migration under these conditions.
    Immunobiology 10/2015; DOI:10.1016/j.imbio.2015.10.001 · 3.04 Impact Factor
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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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    ABSTRACT: Inflammasomes are large cytosolic multiprotein complexes that assemble in response to detection of infection- or stress-associated stimuli and lead to the activation of caspase-1-mediated inflammatory responses, including cleavage and unconventional secretion of the leaderless proinflammatory cytokines IL-1β and IL-18, and initiation of an inflammatory form of cell death referred to as pyroptosis. Inflammasome activation can be induced by a wide variety of microbial pathogens and generally mediates host defense through activation of rapid inflammatory responses and restriction of pathogen replication. In addition to its role in defense against pathogens, recent studies have suggested that the inflammasome is also a critical regulator of the commensal microbiota in the intestine. Finally, inflammasomes have been widely implicated in the development and progression of various chronic diseases, such as gout, atherosclerosis, and metabolic syndrome. In this perspective, we discuss the role of inflammasomes in infectious and noninfectious inflammation and highlight areas of interest for future studies of inflammasomes in host defense and chronic disease.
    Cold Spring Harbor perspectives in biology 10/2014; 6(12). DOI:10.1101/cshperspect.a016287 · 8.68 Impact Factor
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    • "Interestingly, these diseases are associated with increased caspase-1 activity, are sensitive to therapeutics targeting IL-1β (anakinra), and appear to be independent of NF-κB activation (57–59). However, the ability of NLRP12 to form a functional inflammasome under physiological situations and in the context of human disease appears to occur only under highly specific conditions and is an area of current investigation (60, 61). Indeed, several studies have evaluated NLRP12 inflammasome formation ex vivo and using Nlrp12−/− mice under a variety of conditions and have directly shown that this NLR does not regulate IL-1β/IL-18 maturation (62–69). "
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    ABSTRACT: Aberrant inflammation is an enabling characteristic of tumorigenesis. Thus, signaling cascades that alter inflammatory activation and resolution are of specific relevance to disease pathogenesis. Pattern recognition receptors (PRRs) are essential mediators of the host immune response and have emerged as critical elements affecting multiple facets of tumor pathobiology. The nucleotide-binding domain and leucine-rich repeat containing (NLR) proteins are intracellular PRRs that sense microbial and non-microbial products. Members of the NLR family can be divided into functional sub-groups based on their ability to either positively or negatively regulate the host immune response. Recent studies have identified a novel sub-group of non-inflammasome forming NLRs that negatively regulate diverse biological pathways associated with both inflammation and tumorigenesis. Understanding the mechanisms underlying the function of these unique NLRs will assist in the rationale design of future therapeutic strategies targeting a wide spectrum of inflammatory diseases and cancer. Here, we will discuss recent findings associated with this novel NLR sub-group and mechanisms by which these PRRs may function to alter cancer pathogenesis.
    Frontiers in Immunology 04/2014; 5:169. DOI:10.3389/fimmu.2014.00169
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