Suppression of Glucagon-Like Peptide-1 Release by Inhibition of Intestinal NLRP3 Inflammasome Activation in Asc -/- and Nlrp3 -/- Mice

• Published in: Frontiers in physiology 2019-10, Vol.10, p.1213
• Main Authors: Chen, Yu, Kidd, Jason, Bhat, Owais M, Yuan, Xinxu, Hong, Jinni, He, Xingxiang, Li, Pin-Lan
• Format: Article
• Language: English
• Subjects: GLP-1; HMGB1; IL-1β; inflammasome; NLRP3; Physiology
• ISSN: 1664-042X; 1664-042X
• DOI: 10.3389/fphys.2019.01213

The glucagon-like peptide-1 (GLP-1) is an insulinotropic hormone secreted by intestinal enteroendocrine L-cells, which plays a crucial role in glucose control, regulation, and protection from different pathological conditions such as diabetes mellitus. The present study sought to test whether GLP-1 release increases gut injury with a high-fat diet (HFD) and whether this GLP-1 release is associated with NLRP3 inflammasome activation. Our results showed that the NLRP3 inflammasome is activated in the intestinal tissue of wild-type mice on a HFD, accompanied by GLP-1 overexpression. The number of intestinal L-cells and the GLP-1 level in serum are increased in WT mice with HFD. However, in the Asc and Nlrp3 mice, these HFD-induced intestinal and serum GLP-1 changes were suppressed. Using confocal microscopy, the colocalization of GLP-1 and FLICA that labels activated caspase-1 in intestine was decreased in the Asc and Nlrp3 mice compared to WT mice. Mechanistically, the inhibitor of caspase-1 or HMGB1 blocker is used to demonstrate the regulatory action of NRLP3 inflammasome in GLP-1 release. It was found that the level of GLP-1 and its colocalization with IL-1β were reduced by inhibition of the caspase-1 activity, but not altered by blockade of HMGB1 action. Our results suggest that NLRP3 inflammasome activation triggers GLP-1 production from the intestine, which is associated with IL-1β, but not with HMGB1. These findings for the first time provide evidence that the activation of NLRP3 inflammasome in the intestine increases GLP-1 release in mice, which may serve as an adaptive response to intestinal inflammation.