Journal Article

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

Kamata, Noriko, Nishida, Yu, Okuda, Hiroaki, Nadatani, Yuji, Tanaka, Fumio, Nakamura, Yoshinobu, Watanabe, Toshio, Sugita, Naoko, Nakata, Rieko, Hosomi, Shuhei, Nakanishi, Takeo, Nagami, Yasuaki, Yamagami, Hirokazu, Otani, Koji, Itani, Shigehiro, Tanigawa, Tetsuya, Fujiwara, Yasuhiro, Taira, Koichi

2020

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/256 / 631/250/347 / 631/80/304 / 692/4020/1503/1581 / 692/4020/1503/583 / Animals / Blotting, Western / Cell activation / Cells, Cultured / Colitis / Colitis - chemically induced / Colitis - genetics / Colitis - metabolism / Colitis - pathology / Colon / Dextran / Dextran Sulfate - toxicity / Enteritis / Enterocolitis - chemically induced / Enterocolitis - genetics / Enterocolitis - metabolism / Enterocolitis - pathology / Enzyme-Linked Immunosorbent Assay / Epithelial cells / Humanities and Social Sciences / Inflammasomes / Inflammasomes - immunology / Inflammasomes - metabolism / Inflammatory bowel disease / Leucine / Macrophages / Macrophages - drug effects / Macrophages - metabolism / Mice / Models, Theoretical / multidisciplinary / NLR Family, Pyrin Domain-Containing 3 Protein - genetics / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / Organic Anion Transporters - deficiency / Organic Anion Transporters - genetics / Organic Anion Transporters - metabolism / Prostaglandin E2 / Pyrin protein / Reverse Transcriptase Polymerase Chain Reaction / Rodents / Science / Science (multidisciplinary) / Small intestine / Sodium sulfate / Ulcers