NOD-Like Receptor Family Pyrin Domain-Containing 3 Inflammasome Activation Exacerbates 5-Fluorouracil-Induced Small Intestinal Mucositis via Interleukin-1β Activation

Background and Aim: 5-Fluorouracil (5-FU) is an anticancer agent that induces intestinal mucositis, which causes diarrhea and dehydration. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is responsible for inflammatory response activation via caspase-1 cleavage and subsequent interleukin-1 beta (IL-1 beta) and IL-18 activation and secretion. The objective of this study was to determine the role of the NLRP3 inflammasome in 5-FU-induced small intestinal mucositis. Methods: Small intestinal mucositis was induced in wild-type, NLRP3(-/-), and caspase-1(-/-) mice by intraperitoneal injection of 5-FU. Some mice received intraperitoneal injection of a caspase-1 inhibitor, recombinant IL-1 beta or IL-18, or neutralizing antibody against IL-1 beta. Results: Mice treated with 5-FU developed small intestinal mucositis with diarrhea and body weight loss, characterized by a decrease in villus height and the villus height-to-crypt depth ratio. These histological changes peaked on day 3 and were accompanied by an increase in mRNA expression of NLRP3 and IL-1 beta and protein expression of cleaved caspase-1 and mature IL-1 beta. Mature IL-18 protein expression was not affected by 5-FU administration. NLRP3(-/-) mice exhibited less severe 5-FU-induced mucositis, and this phenotype was mimicked by genetic depletion or pharmacological inhibition of caspase-1. Small intestinal mucositis was aggravated by exogenous IL-1 beta and neutralized by IL-1 beta antibody treatment. Administration of exogenous IL-18 or anti-IL-18 antibody did not affect any parameters associated with mucositis. NLRP3, cleaved caspase-1, and IL-1 beta were expressed by inflammatory cells (mainly macrophages) in the lamina propria and damaged epithelial cells. Conclusions: NLRP3 inflammasome activation may exacerbate 5-FU-induced small intestinal mucositis via IL-1 beta maturation.

Automated summary

The study revealed that NLRP3 inflammasome plays a crucial role in 5-FU-induced small intestinal mucositis, possibly exacerbating the disease through IL-1 beta maturation.