Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury

Abstract

The colonic epithelium self-renews every 3 to 5 d, but our understanding of the underlying processes preserving wound healing from carcinogenesis remains incomplete. Here, we demonstrate that Nod-like receptor pyrin domain-containing protein 6 (NLRP6) suppresses inflammation and carcinogenesis by regulating tissue repair. NLRP6 was primarily produced by myofibroblasts within the stem-cell niche in the colon. Although NLRP6 expression was lowered in diseased colon, NLRP6-deficient mice were highly susceptible to experimental colitis. Upon injury, NLRP6 deficiency deregulated regeneration of the colonic mucosa and processes of epithelial proliferation and migration. Consistently, absence of NLRP6 accelerated colitis-associated tumor growth in mice. A gene-ontology analysis on a whole-genome expression profiling revealed a link between NLRP6 and self-renewal of the epithelium. Collectively, the integrity of the epithelial barrier is preserved by NLRP6 that may be manipulated to develop drugs capable of preventing adenoma formation in inflammatory bowel diseases.colonic myofibroblasts | colorectal cancer

Intestinal myofibroblast-specific Tpl2-Cox-2-PGE 2 pathway links innate sensing to epithelial homeostasis

“…A homeostatic function in the stroma has been shown for MyD88 (44) and NLRP3 (45). In addition, NLRP6, which also plays a homeostatic role in the gut, is highly expressed in IMFs (46). This key role of IMFs in epithelial homeostasis can be explained by their subepithelial localization and their physiological implication in mechanisms of epithelial proliferation and differentiation during development (23,26).…”

Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome

“…Currently, the inflammasome pathway and production of the cytokine IL-18 are the best-characterized molecular mechanisms for maintenance of epithelial integrity, repair and intestinal homeostasis [15][16][17][18] . Since dietary fibre as well as SCFAs are known contributors to epithelial integrity 14,21,24 , we examined the influence of diet and the SCFA receptors GPR43 on inflammasome activation and IL-18 production.…”

“…Currently, the inflammasome pathway and production of the cytokine interleukin (IL)-18 are the best-characterized molecular mechanisms for maintenance of epithelial integrity, repair and intestinal homeostasis [15][16][17][18][19] . Factors that trigger activation of the inflammasome in gut epithelium are poorly understood.…”

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

“…NLRP6 is as a critical regulator of proinflammatory signal transduction, particularly by activating NF-κB and Caspase-1 [41]. Recent studies demonstrated that it is and important PRR for developmental control of intestinal colonization by bacteria [42], epithelial self-renewal [43] and prevention of inflammation-induced tumorgenesis in the gut [44] or colitis [45].…”