The function of Sphingosine-1-phosphate receptor 2 (S1PR2) in maintaining intestinal barrier and inducing ulcerative colitis

Sphingosine-1-phosphate receptor 2 (S1PR2) was highly expressed in intestinal epithelial cells (IECs) and facilitated the proliferation of IECs. However, the specific function of S1PR2 in intestinal diseases, such as ulcerative colitis (UC), remains unclear. Accordingly, the current study set out to investigate the function of S1PR2 in maintaining intestinal barrier and inducing UC. S1PR2-overexpressed and knockdown Caco-2 cells were established to explore the function of S1PR2 on the permeability of IECs barrier. The UC-like mouse model in which UC is induced by dextran sulfate sodium (DSS) was established and utilized to investigate the role for S1PR2. The results showed that S1PR2 functioned as a maintainer of IECs permeability and a pathogenic factor for UC. A series of in vitro and in vivo experiments were conducted, and it was found that S1PR2 played an important role in intestinal epithelial cell proliferation and maintenance of intestinal epithelial cell barrier, possibly by the regulation on the expression level of SphK2, HDAC1, HDAC2, and ERK1/2 signaling pathway. The expression of S1PR2 was upregulated in UC mice and the colonic pathological damage in UC mice could be alleviated by the inhibition of S1PR2. Collectively, these results suggest that S1PR2 functions as a maintainer of IECs permeability and a pathogenic factor for UC. The research suggests S1PR2 may be an effective target for developing therapeutic strategies against UC. <b>Abbreviations:</b> S1PR2, Sphingosine-1-phosphate receptor 2; UC, ulcerative colitis; IECs, intestinal epithelial cells; DSS, dextran sulfate sodium; IBD, inflammation bowel disease; CD, Crohn’s disease; S1P, sphingosin-1-phosphate; SphK, sphingosine kinase; HIECs, human IECs; siRNA, small interfering RNA; CCK-8, cell counting kit-8; TEER, transepithelial electrical resistance; TEM, transmission electron microscope; RT-PCR, real-time reverse transcriptase polymerase-chain reaction; ELISA, enzyme-linked immunosorbent assay; HE, hematoxylin and eosin.

1-磷酸鞘氨醇受体2（Sphingosine-1-phosphate receptor 2, S1PR2）在肠上皮细胞（intestinal epithelial cells, IECs）中呈高表达，且可促进肠上皮细胞增殖。然而，S1PR2在溃疡性结肠炎（ulcerative colitis, UC）等肠道疾病中的具体功能仍未明确。
为此，本研究旨在探究S1PR2在维持肠屏障功能及参与溃疡性结肠炎发生发展中的作用。研究人员构建了过表达及敲低S1PR2的Caco-2细胞模型，以探讨S1PR2对肠上皮细胞屏障通透性的影响；同时利用葡聚糖硫酸钠（dextran sulfate sodium, DSS）诱导建立溃疡性结肠炎样小鼠模型，用于验证S1PR2的体内生物学功能。
实验结果显示，S1PR2可维持肠上皮细胞屏障通透性，同时作为溃疡性结肠炎的致病因子。通过一系列体外与体内实验，本研究发现S1PR2可通过调控鞘氨醇激酶2（Sphingosine Kinase 2, SphK2）、组蛋白去乙酰化酶1（Histone Deacetylase 1, HDAC1）、组蛋白去乙酰化酶2（Histone Deacetylase 2, HDAC2）及细胞外调节蛋白激酶1/2（Extracellular Regulated Protein Kinases 1/2, ERK1/2）信号通路的表达水平，在肠上皮细胞增殖及肠上皮屏障维持中发挥关键作用。此外，溃疡性结肠炎模型小鼠体内S1PR2的表达水平显著上调，而抑制S1PR2可减轻该模型小鼠的结肠病理损伤。
综上，上述结果表明S1PR2可维持肠上皮细胞屏障通透性，并作为溃疡性结肠炎的致病因子。本研究提示，S1PR2有望成为开发溃疡性结肠炎治疗策略的有效靶点。
<b>缩写：</b> S1PR2：1-磷酸鞘氨醇受体2（Sphingosine-1-phosphate receptor 2）；UC：溃疡性结肠炎（ulcerative colitis）；IECs：肠上皮细胞（intestinal epithelial cells）；DSS：葡聚糖硫酸钠（dextran sulfate sodium）；IBD：炎症性肠病（inflammation bowel disease）；CD：克罗恩病（Crohn’s disease）；S1P：1-磷酸鞘氨醇（sphingosin-1-phosphate）；SphK：鞘氨醇激酶（sphingosine kinase）；HIECs：人肠上皮细胞（human IECs）；siRNA：小干扰RNA（small interfering RNA）；CCK-8：细胞计数试剂盒-8（cell counting kit-8）；TEER：跨上皮电阻（transepithelial electrical resistance）；TEM：透射电子显微镜（transmission electron microscope）；RT-PCR：实时逆转录聚合酶链反应（real-time reverse transcriptase polymerase-chain reaction）；ELISA：酶联免疫吸附测定（enzyme-linked immunosorbent assay）；HE：苏木精-伊红染色（hematoxylin and eosin）