NLRP6 in host defense and intestinal inflammation

Abstract

NLRP6 is a member of the NLR (nucleotide-oligomerization domain-like receptor) family of proteins that recognize pathogen-derived factors and damage-associated molecular patterns in the cytosol. The function of NLRP6 has been attributed to the maintenance of epithelial integrity and host defense against microbial infections. Under some physiological conditions, NLRP6 forms a complex with ASC and caspase-1 or caspase-11 to form an inflammasome complex cleaving pro-interleukin-1b (IL-1b) and IL-18 into their biologically active forms. Here, we summarize recent advances in the understanding of the mechanisms of activation of the NLRP6 inflammasome and discuss its relevance to human disease.NLRP6 inflammasome NLRP6 was originally called PYPAF5 and was expressed predominantly in mucosal tissues that are constantly exposed to microbial components. NLRP6 is expressed by epithelial cells, fibroblasts, granulocytes, dendritic cells, CD4 and CD8 T cells,

Nod-like Receptors: Critical Intracellular Sensors for Host Protection and Cell Death in Microbial and Parasitic Infections

“…NLRP6: It is originally called PYRIN-containing Apaf-1-like proteins 5 (PYPAF5), a cell-specific function receptor that coordinates a synergistic activation of NF-κB and the activated caspase 1-dependent cytokine processing when co-expressed with ASC [ 160 ]. It is chiefly expressed in epithelial cells, fibroblasts, granulocytes, dendritic cells, macrophages and CD4+ and CD8+ T cells [ 161 ]. Human and mouse epithelial cells treated with TNF and rosiglitazone, an agonist of PPARγ (transcriptional factors peroxisome proliferator-activated receptor-γ), exhibited enhanced NLRP6 expression.…”

“…NLRP6 is transcriptionally regulated by a series of stimuli, including synthetic polyinosinic:polycytidylic acid (poly(I:C)), encephalomyocarditis virus, LPS, MDP and iE-DAP, as well as IFN-α in many types of cells [ 162 , 163 ]. As an NLR inflammasome, NLRP6 has been shown to form multi-protein complexes with ASC for the maturation and production of IL-1β and IL-18 [ 161 , 164 ], as evident in a dextran sulfate sodium (DSS)-induced colitis model [ 164 , 165 ]. Excessive inflammation by NLRP6-dependent IL-18 production could be regulated by CYLD, which mechanistically deconjugates the K63-linked ubiquitin chains on NLRP6 to prevent an NLRP6–ASC inflammasome complex [ 166 ].…”

Molecular and Cellular Mechanisms Influenced by Postbiotics

“…This is caused by the suppression of NF-κB signaling, which in turn attenuates the inflammatory response, i.e., dampens cytokine, chemokine, and cell surface protein expression. Interestingly, the NLRP6-LTA interaction leads to an excessive inflammatory response, but mild stimulation may be protective [294].…”

Host–Viral Interactions in the Pathogenesis of Ulcerative Colitis

“…The inflammasome NOD-like receptor family pyrin domain containing 6 (NLRP6) is expressed in mucosal tissues [ 71 ] and predominately in the small and large intestine, especially by absorptive enterocytes, colonic goblet cells, and myofibroblasts [ 72 ], and participates in the progression of intestinal inflammation and enteric pathogen infections, which is in addition to being pivotal for homeostatic mucin secretion from goblet cells. NLRP6 is shown to respond to the internal ligands leading to the release of anti-microbial peptides (AMPs) and mucus, further demonstrating a protective role [ 73 , 74 , 75 ]. Inflammatory signals such as tumor necrosis factor-α (TNF-α) or viral stimuli induce the transcription of NLRP6 [ 76 ].…”

“…In the colonic mucosa of UC patients, the expression of CYLD is downregulated and is negatively correlated with IL-18 expression [ 79 ]. This suggests that the regulatory mechanisms inhibiting the excessive activation of NLRP6-mediated inflammation are defective in UC patients [ 73 ].…”