Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin

Boyden, Eric D.; Dietrich, William F.

doi:10.1038/ng1724

Cited by 781 publications

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“…This trait difference has been mapped to a locus on chromosome 11 named Ltxs1, and was recently associated with NALP1b gene. 99 The NALP1 locus in mouse contains three paralogues, NALP1a, NALP1b and NALP1c (Table 1). NALP1b is highly polymorphic in mouse, and susceptibility to LeTx seems to be associated with a functional NALP1b allele and caspase-1 activation.…”

Section: Nalp1 and Susceptibility To Anthraxmentioning

confidence: 99%

“…NALP1b is highly polymorphic in mouse, and susceptibility to LeTx seems to be associated with a functional NALP1b allele and caspase-1 activation. 99 Murine NALP1b does not contain a PYD; hence, it is not clear whether it requires ASC or dimerization with another NALP for caspase-1 recruitment. However, NALP1b possesses a CARD and a region related to CARDINAL.…”

Section: Nalp1 and Susceptibility To Anthraxmentioning

confidence: 99%

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Inflammatory caspases and inflammasomes: master switches of inflammation

2006

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Fifteen years have passed since the cloning and characterization of the interleukin-1b-converting enzyme (ICE/caspase-1), the first identified member of a family of proteases currently known as caspases. Caspase-1 is the prototypical member of a subclass of caspases involved in cytokine maturation termed inflammatory caspases that also include caspase-4 caspase -5, caspase -11 and caspase -12. Efforts to elucidate the molecular mechanisms involved in the activation of these proteases have uncovered an important role for the NLR family members, NALPs, NAIP and IPAF. These proteins promote the assembly of multiprotein complexes termed inflammasomes, which are required for activation of inflammatory caspases. This article will review some evolutionary aspects, biochemical evidences and genetic studies, underlining the role of inflammasomes and inflammatory caspases in innate immunity against pathogens, autoinflammatory syndromes and in the biology of reproduction. Inflammatory CaspasesThe history of caspases began with the identification of an aspartate-specific protease activity involved in the conversion of the 31 kDa proIL-1b precursor to its active 17 kDa biologically active form, 1,2 and the identification of caspase-1 as the protease responsible for proIL-1b maturation. 3,4 The subsequent discovery of ced-3, that shares similarities with caspase-1 and which is involved in programmed cell death (PCD) in Caenorhabditis elegans, suggested that caspases might play fundamental roles in apoptosis. 5 As reviewed in the papers accompanying this issue of Cell Death and Differentiation, the role of apoptotic caspases in C. elegans and in vertebrates is crucial and deal with many facets of cell biology, development and diseases. In this review, we will focus on a subset of caspases present only in vertebrates and known as inflammatory caspases.Inflammatory caspases (also known as group I caspases) are encoded by three main genes in humans caspase-1, caspase-4 and caspase-5 and three main genes in mouse, caspase-1, caspase-11 and caspase-12. 6,7 In mammals, these caspases are characterized by the presence of a CARD domain at the N-terminus (Figure 1a). Human, chimp and mouse inflammatory caspases share significant similarity and are organized in a single locus (Figure 1c). Phylogenetic analysis of the conserved CARD domain suggests that the inflammatory caspases can be separated in evolutionaryrelated clusters (Figure 1b). The caspase-1 cluster contains caspase-1 and four other genes encoding decoy caspases: cop, inca1, inca2 and iceberg. These decoy caspase-1-like genes are absent in the mouse genome, suggesting that they have arisen recently by duplication of caspase-1. Although human and mouse caspase-1 are likely orthologues, sequence analysis suggests that human caspase-4 and caspase-5 have originated from a duplication of caspase-11. 7 However, the human caspase-12 gene, which in the chimp genome contains an SHG box important for it enzymatic activity, 8 evolved towards an enzymatically inactive form at some stage...

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Section: Nalp1 and Susceptibility To Anthraxmentioning

confidence: 99%

Section: Nalp1 and Susceptibility To Anthraxmentioning

confidence: 99%

Inflammatory caspases and inflammasomes: master switches of inflammation

2006

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“…[39][40][41][42][43] Interestingly, NLRP3 also contributes to the ability of dendritic cells and macrophages to detect endogenous danger molecules released by dying cells. NLRP3 can signal the presence of adenosine triphosphate (ATP), crystals of monosodium urate (MSU) or calcium pyrophosphate crystals, 39,44 and other large particulates of non-microbial origin, such as alum, silica and asbestos ( Figure 2).…”

Section: Genetics Of the Inflammasomes In Human Pathologiesmentioning

confidence: 99%

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

2011

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Nucleotide-binding oligomerization domain (NOD)-containing protein-like receptors (NLRs) are a recently discovered class of innate immune receptors that play a crucial role in initiating the inflammatory response following pathogen recognition. Some NLRs form the framework for cytosolic platforms called inflammasomes, which orchestrate the early inflammatory process via IL-1b activation. Mutations and polymorphisms in NLR-coding genes or in genetic loci encoding inflammasome-related proteins correlate with a variety of autoinflammatory diseases. Moreover, the activity of certain inflammasomes is associated with susceptibility to infections as well as autoimmunity and tumorigenesis. In this review, we will discuss how identifying the genetic characteristics of inflammasomes is assisting our understanding of both autoinflammatory diseases as well as other immune system-driven disorders.

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“…NLRP2 is less well studied, but it is considered to inhibit the NLRP3-ASC interaction [36,37]. NLRP1 does not require the mediation of ASC for the activation of Caspase-1 [38], it can also activate Caspase-5 [39], and can be activated by the anthrax lethal toxin, causing cell death [40]. NLRP6 is as a critical regulator of proinflammatory signal transduction, particularly by activating NF-κB and Caspase-1 [41].…”

Section: Introductionmentioning

confidence: 99%

Aggregatibacter actinomycetemcomitans targets NLRP3 and NLRP6 inflammasome expression in human mononuclear leukocytes

Belibasakis

Johansson

2012

Cytokine

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Periodontitis is an inflammatory condition that destroys the tooth-supporting tissues, as a result of local bacterial infection. Aggregatibacter actinomycetemcomitans is a Gram-negative facultative anaerobic species, highly associated with aggressive periodontitis. Periodontal inflammation is dominated by cytokines of the Interleukin (IL)-1 family. Prior to their secretion by mononuclear cells, IL-1 cytokines are processed by intracellular protein complexes, known as "inflammasomes", which can sense the bacterial challenge. The aim of this study was to investigate which inflammasomes are regulated in mononuclear cells in response to A. actinomycetemcomitans. The D7SS strain and its derivative leukotoxin and cytolethal distending toxin knock-out mutant strains were used to infect human mononuclear cells at a 1:10 cell: bacteria ratio, for 3 h. The expression of various inflammasome components in the cells was investigated by TaqMan quantitative real-time polymerase chain reaction (qPCR). The expressions of NOD-like receptor protein (NLRP)1, NLRP2 and Absent In Melanoma (AIM)2 inflammasome sensors, as well as their effector Caspase-1 were not affected. However, NLRP3 was up-regulated, while NLRP6 was down-regulated. This effect was not dependent on the leukotoxin or the cytolethal distending toxin, as demonstrated by the use of specific gene knock-out mutant strains. IL-1 and IL-18 expressions were also up-regulated by the bacterial challenge. In conclusion, A. actinomycetemcomitans enhances NLRP3 and reduces NLRP6 inflammasome expression, irrespective of its major virulence factors, confirming the high pathogenic profile of this species, and providing further insights to the mechanisms of periodontal inflammation. actinomycetemcomitans enhances NLRP3 and reduces NLRP6 inflammasome expression, irrespective of its major virulence factors, confirming the high pathogenic profile of this species, and providing further insights to the mechanisms of periodontal inflammation.

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Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin

Cited by 781 publications

References 30 publications

Inflammatory caspases and inflammasomes: master switches of inflammation

Inflammatory caspases and inflammasomes: master switches of inflammation

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

Aggregatibacter actinomycetemcomitans targets NLRP3 and NLRP6 inflammasome expression in human mononuclear leukocytes

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