Bauer, C. et al. Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome. Gut 59, 1192-1199
ABSTRACT The proinflammatory cytokines interleukin 1beta (IL-1beta) and IL-18 are central players in the pathogenesis of inflammatory bowel disease (IBD). In response to a variety of microbial components and crystalline substances, both cytokines are processed via the caspase-1-activating multiprotein complex, the NLRP3 inflammasome. Here, the role of the NLRP3 inflammasome in experimental colitis induced by dextran sodium sulfate (DSS) was examined.
IL-1beta production in response to DSS was studied in macrophages of wild-type, caspase-1(-/-), NLRP3(-/-), ASC(-/-), cathepsin B(-/-) or cathepsin L(-/-) mice. Colitis was induced in C57BL/6 and NLRP3(-/-) mice by oral DSS administration. A clinical disease activity score was evaluated daily. Histological colitis severity and expression of cytokines were determined in colonic tissue.
Macrophages incubated with DSS in vitro secreted high levels of IL-1beta in a caspase-1-dependent manner. IL-1beta secretion was abrogated in macrophages lacking NLRP3, ASC or caspase-1, indicating that DSS activates caspase-1 via the NLRP3 inflammasome. Moreover, IL-1beta secretion was dependent on phagocytosis, lysosomal maturation, cathepsin B and L, and reactive oxygen species (ROS). After oral administration of DSS, NLRP3(-/-) mice developed a less severe colitis than wild-type mice and produced lower levels of proinflammatory cytokines in colonic tissue. Pharmacological inhibition of caspase-1 with pralnacasan achieved a level of mucosal protection comparable with NLRP3 deficiency.
The NLRP3 inflammasome was identified as a critical mechanism of intestinal inflammation in the DSS colitis model. The NLRP3 inflammasome may serve as a potential target for the development of novel therapeutics for patients with IBD.
- SourceAvailable from: Juan Pablo De Rivero Vaccari
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- "Palmitate, a saturated free fatty acid, activates the NLRC4 inflammasome in primary rat astrocytes (Liu and Chan, 2012). Reactive oxygen species (ROS) are also capable of activating the inflammasome (Bauer et al., 2010), although the mechanism of activation is controversial. It is possible that mitochondrial dysfunction following injury results in ROS production that leads to activation of inflammasomes. "
ABSTRACT: Pattern recognition receptors (PRRs) are part of the innate immune response and were originally discovered for their role in recognizing pathogens by ligating specific pathogen associated molecular patterns (PAMPs) expressed by microbes. Now the role of PRRs in sterile inflammation is also appreciated, responding to endogenous stimuli referred to as “damage associated molecular patterns” (DAMPs) instead of PAMPs. The main families of PRRs include Toll-like receptors (TLRs), Nod-like receptors (NLRs), RIG-like receptors (RLRs), AIM2-like receptors (ALRs), and C-type lectin receptors. Broad expression of these PRRs in the CNS and the release of DAMPs in and around sites of injury suggest an important role for these receptor families in mediating post-injury inflammation. Considerable data now show that PRRs are among the first responders to CNS injury and activation of these receptors on microglia, neurons, and astrocytes triggers an innate immune response in the brain and spinal cord. Here we discuss how the various PRR families are activated and can influence injury and repair processes following CNS injury.Experimental Neurology 08/2014; 258:5–16. DOI:10.1016/j.expneurol.2014.01.001 · 4.62 Impact Factor
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- "Additionally, colonic epithelial cells deficient in caspase-1 bear greater resistance to apoptosis and increased proliferation relative to colon epithelial cells from wild-type mice (Hu et al., 2010). The tumor-suppressing function of inflammasomes does not always correlate with their role in promoting or suppressing DSS-induced inflammation; rather some studies have reported that Casp1 −/− and Nlrp3 −/− mice have decreased DSSinduced inflammation and colitis (Siegmund et al., 2001; Bauer et al., 2010). NLRP6, another NLR family member, can also suppress tumorigenesis in the AOM/DSS CAC model, likely through secretion of IL-18 from hematopoietic cells (Chen et al., 2011), or regulation of wound healing by myofibroblasts (Normand et al., 2011). "
ABSTRACT: Chronic inflammatory responses have long been observed to be associated with various types of cancer and play decisive roles at different stages of cancer development. Inflammasomes, which are potent inducers of interleukin (IL)-1β and IL-18 during inflammation, are large protein complexes typically consisting of a Nod-like receptor (NLR), the adapter protein ASC, and Caspase-1. During malignant transformation or cancer therapy, the inflammasomes are postulated to become activated in response to danger signals arising from the tumors or from therapy-induced damage to the tumor or healthy tissue. The activation of inflammasomes plays diverse and sometimes contrasting roles in cancer promotion and therapy depending on the specific context. Here we summarize the role of different inflammasome complexes in cancer progression and therapy. Inflammasome components and pathways may provide novel targets to treat certain types of cancer; however, using such agents should be cautiously evaluated due to the complex roles that inflammasomes and pro-inflammatory cytokines play in immunity.Protein & Cell 08/2013; 5(1). DOI:10.1007/s13238-013-3051-8 · 2.85 Impact Factor
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- "NACHT domain (domain present in NAIP，CIITA，HET-E and TP1), also known as NBS (nucleotide-binding site domain) coded by exon 3 of the rabbit NLRP3 gene, plays a pivotal role in molecular recognition of host innate immunity (Royet and Reichhart, 2003). The variations and functions of NLRP3 gene, especially the exon 3 of the NLRP3 gene of mouse and human, have been widely investigated (Bauer et al., 2010; Roberts et al., 2010). However, the association between genetic polymorphisms and expression of NLRP3 and in domestic rabbit digestive disorders has not been reported. "
ABSTRACT: NLR family pyrin domain containing 3 (NLRP3) is a key component of the inflammasome, whose assembly is a crucial part of the innate immune response. The aim of the present study was to evaluate the association between exon 3 polymorphisms of NLRP3 and the susceptibility to digestive disorders in rabbits. In total, five coding single-nucleotide polymorphisms (cSNPs) were identified; all of which are synonymous. Among them, c.456 C> and c.594 G> were further genotyped for association analysis based on case-control design (n =162 vs n =102). Meanwhile, growing rabbits were experimentally induced to digestive disorders by feeding a fiber-deficient diet, subsequently they were subjected to mRNA expression analysis. Association analysis revealed that haplotype H1 (the two cSNPs: GT) played a potential protective role against digestive disorders (p<0.001). The expression of NLRP3 in the group H1HX1 (H1HX1 is composed of H1H1, H1H3 and H1H4) was the lowest among four groups which were classified by different types of diplotypes. Those results suggested that the NLRP3 gene was significantly associated with susceptibility to digestive disorders in rabbit.Asian Australasian Journal of Animal Sciences 04/2013; 26(4):455-62. DOI:10.5713/ajas.2012.12522 · 0.56 Impact Factor