Slco2a1 deficiency exacerbates experimental colitis via inflammasome activation in macrophages: a possible mechanism of chronic enteropathy associated with SLCO2A1 gene.

Loss-of-function mutations in the solute carrier organic anion transporter family, member 2a1 gene (SLCO2A1), which encodes a prostaglandin (PG) transporter, have been identified as causes of chronic nonspecific multiple ulcers in the small intestine; however, the underlying mechanisms have not been revealed. We, therefore, evaluated the effects of systemic knockout of Slco2a1 (Slco2a1) and conditional knockout in intestinal epithelial cells (Slco2a1) and macrophages (Slco2a1) in mice with dextran sodium sulphate (DSS)-induced acute colitis. Slco2a mice were more susceptible to DSS-induced colitis than wild-type (WT) mice, but did not spontaneously develop enteritis or colitis. The nucleotide-binding domain, leucine-rich repeats containing family, pyrin domain-containing-3 (NLRP3) inflammasome was more strongly upregulated in colon tissues of Slco2a mice administered DSS and in macrophages isolated from Slco2a1 mice than in the WT counterparts. Slco2a1, but not Slco2a1 mice, were more susceptible to DSS-induced colitis than WT mice, partly phenocopying Slco2a mice. Concentrations of PGE in colon tissues and macrophages from Slco2a1 mice were significantly higher than those of WT mice. Blockade of inflammasome activation suppressed the exacerbation of colitis. These results indicated that Slco2a1-deficiency increases the PGE concentration, resulting in NLRP3 inflammasome activation in macrophages, thus exacerbating intestinal inflammation.