Abstract
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.
Highlights
The NLRP3 inflammasome is composed of nod-like receptor (NLR) innate immune cell sensors and responds to toxic signals
Previous studies have shown that the formation and activation of NLRP3 inflammasome led to the secretion of IL-1β and increase in high mobility group box-1 protein (HMGB1) (Chen et al, 2018)
We further confirmed the expression of NLRP3 inflammasome in intestine cells induced by a high-fat diet (HFD)
Summary
The NLRP3 inflammasome is composed of nod-like receptor (NLR) innate immune cell sensors and responds to toxic signals. It recruits the adapter protein ASC and pro-caspase leading to caspase-1 activation and subsequent secretion of interleukin-1β (IL-1β), IL-18, or high mobility group box-1 protein (HMGB1) (Kamo et al, 2013). Inflammasome components were upregulated in liver, but downregulated in gut, which was shown to be associated with microbiota modifications and bacterial translocation (De Minicis et al, 2014). NLRP3 deficiency in the gut is associated with the Western lifestyle diet and can lead to dysbiosis and alteration of the intestinal barrier and bacterial translocation (Pierantonelli et al, 2017). There is a complex balance among HFD, gut microbiota, intestinal homeostasis, and NLRP3 function
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