Slco2a1 deficiency exacerbates experimental colitis via inflammasome activation in macrophages: a possible mechanism of chronic enteropathy associated with SLCO2A1 gene
Slco2a1 deficiency exacerbates experimental colitis via inflammasome activation in macrophages: a possible mechanism of chronic enteropathy associated with SLCO2A1 gene
复制标题
DOI：
10.1038/s41598-020-61775-9
复制
发表时间：
2020-03-17
影响因子：
4.6
通讯作者：
Fujiwara, Yasuhiro
中科院分区：
文献类型：
--
作者：
Nakata, Rieko;Nakamura, Yoshinobu;Fujiwara, Yasuhiro
编码前列腺素转运蛋白(PG)转运蛋白的溶质载体有机阴离子转运蛋白家族成员2A1基因(SLCO2A1)功能缺失突变已被认为是引起小肠慢性非特异性多发性溃疡的原因，但其潜在机制尚未被揭示。因此，我们评估了系统基因敲除Slco2a1(Slco2a1(-/-))和肠道上皮细胞条件性基因敲除(Slco2a1(Delta IEC))和巨噬细胞(Slco2a1(Delta MP))对葡聚糖硫酸钠(DSS)诱导的急性结肠炎小鼠的影响。SLCO2a(-/-)小鼠比野生型(WT)小鼠更容易患上DSS诱导的结肠炎，但不会自发发生肠炎或结肠炎。在给予DSS的Slco2a(-/-)小鼠的结肠组织和从Slco2a1(-/-)小鼠分离的巨噬细胞中，含有富含亮氨酸重复序列的家族，吡咯结构域-3(NLRP3)炎症小体的核苷酸结合域和亮氨酸重复序列比WT对应的小鼠更强上调。SLco2a1(Delta MP)小鼠，而不是Slco2a1(Delta IEC)小鼠，比WT小鼠更易患DSS诱导的结肠炎，部分表型与Slco2a(-/-)小鼠相似。SLco2a1(-/-)小鼠结肠组织和巨噬细胞中PGE(2)浓度显著高于WT小鼠。阻断炎性小体激活可抑制结肠炎的加重。这些结果表明，SLCO2a1缺乏导致PGE(2)浓度升高，导致巨噬细胞NLRP3炎性小体激活，从而加重肠道炎症。
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(Delta IEC)) and macrophages (Slco2a1(Delta MP)) 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(Delta MP), but not Slco2a1(Delta IEC) 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.