| First Author | Pellegrini C | Year | 2021 |
| Journal | Br J Pharmacol | Volume | 178 |
| Issue | 19 | Pages | 3924-3942 |
| PubMed ID | 34000757 | Mgi Jnum | J:348014 |
| Mgi Id | MGI:7627211 | Doi | 10.1111/bph.15532 |
| Citation | Pellegrini C, et al. (2021) NLRP3 at the crossroads between immune/inflammatory responses and enteric neuroplastic remodelling in a mouse model of diet-induced obesity. Br J Pharmacol 178(19):3924-3942 |
| abstractText | BACKGROUND AND PURPOSE: Enteric neurogenic/inflammation contributes to bowel dysmotility in obesity. We examined the role of NLRP3 in colonic neuromuscular dysfunctions in mice with high-fat diet (HFD)-induced obesity. EXPERIMENTAL APPROACH: Wild-type C57BL/6J and NLRP3-KO (Nlrp3(-/-) ) mice were fed with HFD or standard diet for 8 weeks. The activation of inflammasome pathways in colonic tissues from obese mice was assessed. The role of NLRP3 in in vivo colonic transit and in vitro tachykininergic contractions and substance P distribution was evaluated. The effect of substance P on NLRP3 signalling was tested in cultured cells. KEY RESULTS: HFD mice displayed increased body and epididymal fat weight, cholesterol levels, plasma resistin levels and plasma and colonic IL-1beta levels, colonic inflammasome adaptor protein apoptosis-associated speck-like protein containing caspase-recruitment domain (ASC) and caspase-1 mRNA expression and ASC immunopositivity in macrophages. Colonic tachykininergic contractions were enhanced in HFD mice. HFD NLRP3(-/-) mice developed lower increase in body and epididymal fat weight, cholesterol levels, systemic and bowel inflammation. In HFD Nlrp3(-/-) mice, the functional alterations of tachykinergic pathways and faecal output were normalized. In THP-1 cells, substance P promoted IL-1beta release. This effect was inhibited upon incubation with caspase-1 inhibitor or NK(1) antagonist and not observed in ASC(-/-) cells. CONCLUSION AND IMPLICATIONS: In obesity, NLRP3 regulates an interplay between the shaping of enteric immune/inflammatory responses and the activation of substance P/NK(1) pathways underlying the onset of colonic dysmotility. Identifying NLRP3 as a therapeutic target for the treatment of bowel symptoms related to obesity. |
