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(ΔIEC)) and macrophages (Slco2a1(ΔMP)) 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(ΔMP), but not Slco2a1(ΔIEC) mice, were more susceptible to DSS-induced colitis than WT mice, partly phenocopying Slco2a(−/−) mice. Concentrations of PGE(2) 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(2) concentration, resulting in NLRP3 inflammasome activation in macrophages, thus exacerbating intestinal inflammation.