Dataset Information

NLRP3 Inflammasome and Inflammatory Bowel Disease.

ABSTRACT: NLRP3 inflammasome can be widely found in epithelial cells and immune cells. The NOD-like receptors (NLRs) family member NLRP3 contains a central nucleotide-binding and oligomerization (NACHT) domain which facilitates self-oligomerization and has ATPase activity. The C-terminal conserves a leucine-rich repeats (LRRs) domain which can modulate NLRP3 activity and sense endogenous alarmins and microbial ligands. In contrast, the N-terminal pyrin domain (PYD) can account for homotypic interactions with the adaptor protein-ASC of NLRP3 inflammasome. These characters enable it function in innate immunity. Its downstream effector proteins include caspase-1 and IL-1? etc. which exhibit protective or detrimental roles in mucosal immunity in different studies. Here, we comprehensively review the current literature regarding the physiology of NLRP3 inflammasome and its potential roles in the pathogenesis of IBD. We also discuss about the complex interactions among the NLRP3 inflammasome, mucosal immune response, and gut homeostasis as found in experimental models and IBD patients.

SUBMITTER: Zhen Y

PROVIDER: S-EPMC6403142 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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NLRP3 Inflammasome and Inflammatory Bowel Disease.

Zhen Yu Y Zhang Hu H

Frontiers in immunology 20190228

NLRP3 inflammasome can be widely found in epithelial cells and immune cells. The NOD-like receptors (NLRs) family member NLRP3 contains a central nucleotide-binding and oligomerization (NACHT) domain which facilitates self-oligomerization and has ATPase activity. The C-terminal conserves a leucine-rich repeats (LRRs) domain which can modulate NLRP3 activity and sense endogenous alarmins and microbial ligands. In contrast, the N-terminal pyrin domain (PYD) can account for homotypic interactions w ...[more]

PMID: 30873162

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Project description:The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP. BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet. Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown. We report that BHB, but neither AcAc nor the structurally related short-chain fatty acids butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3 inflammasome by preventing K(+) efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or starvation-regulated mechanisms like AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the G protein-coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome-mediated interleukin (IL)-1β and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as Muckle-Wells syndrome, familial cold autoinflammatory syndrome and urate crystal-induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome.

Dataset Information

NLRP3 Inflammasome and Inflammatory Bowel Disease.

Publications

NLRP3 Inflammasome and Inflammatory Bowel Disease.

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