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

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

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  • Medientyp: E-Artikel
  • Titel: Slco2a1 deficiency exacerbates experimental colitis via inflammasome activation in macrophages: a possible mechanism of chronic enteropathy associated with SLCO2A1 gene
  • Beteiligte: Nakata, Rieko; Nakamura, Yoshinobu; Hosomi, Shuhei; Okuda, Hiroaki; Nishida, Yu; Sugita, Naoko; Itani, Shigehiro; Nadatani, Yuji; Otani, Koji; Tanaka, Fumio; Kamata, Noriko; Taira, Koichi; Nagami, Yasuaki; Tanigawa, Tetsuya; Watanabe, Toshio; Yamagami, Hirokazu; Nakanishi, Takeo; Fujiwara, Yasuhiro
  • Erschienen: Springer Science and Business Media LLC, 2020
  • Erschienen in: Scientific Reports, 10 (2020) 1
  • Sprache: Englisch
  • DOI: 10.1038/s41598-020-61775-9
  • ISSN: 2045-2322
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: AbstractLoss-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 (Slco2a1ΔIEC) and macrophages (Slco2a1ΔMP) 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. Slco2a1ΔMP, but not Slco2a1ΔIEC mice, were more susceptible to DSS-induced colitis than WT mice, partly phenocopying Slco2a−/− mice. Concentrations of PGE2 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 PGE2 concentration, resulting in NLRP3 inflammasome activation in macrophages, thus exacerbating intestinal inflammation.
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