锌指蛋白CXXC5通过调节肠上皮细胞的增殖修复以控制肠炎的发生

Zinc-finger-containing protein CXXC5 is critical for the suppression of colitis by promoting the injury repair of intestinal epithelial cells

目的探讨CXXC5在炎症性肠病中的潜在功能。方法利用葡聚糖硫酸钠(DSS)诱导的小鼠急性溃疡性结肠炎模型检测野生型对照小鼠和CXXC5基因敲除小鼠对DSS的敏感性,利用免疫组织化学染色、实时荧光定量PCR和免疫印迹法分别检测了肠道上皮细胞增殖、炎症因子表达和细胞增殖相关通路的激活。结果发现CXXC5基因敲除小鼠比野生型对照小鼠更敏感,呈现严重的肠道组织损伤和高致死率。我们进一步发现CXXC5基因敲除小鼠的肠上皮细胞增殖在修复期非常低,而对照小鼠的肠上皮细胞则大量增殖。虽然炎症因子的表达在2组小鼠中相当,但是我们发现c-MYC蛋白在CXXC5基因敲除小鼠的肠上皮细胞中表达量明显偏低,这可能导致了细胞增殖的减少。结论证明CXXC5能够抑制炎症性肠病的发生,促进肠上皮细胞的损伤修复,因此是控制肠炎发生的一个重要调控子。

Zinc-finger CXXC protein 5 （CXXC5） has been reported to play important roles in viral infection and tissue remodeling, but its function in inflammatory bowel diseases remains unknown. The aim of this study is to investigate the role of CXXC5 in ulcerative colitis. Oral administration of dextran sulfate sodium （DSS） was used as an inducer of ulcerative colitis in wild-type and CXXCS-knockout mice. The results showed that compared with control mice, CXXC5 knockout mice were more sensitive to DSS-induced colitis, exhibiting higher mortality and stronger intestinal tissue injury. Immunohistochemistry, real-time PCR and Western blot were performed to examine cell proliferation, inflammatory genes expression and pathways associating with cell proliferation, respectively. While the intestinal epithelial cells （IECs） of wild-type mice proliferated rapidly in the repair phase after DSS treatment, while the proliferation of CXXCS-deficient IECs were blunted. Mechanistically, the expression of c-MYC was much lower in the IECs of CXXC5-knockout mice, which might contributed to the abrogated cell proliferation. Together, our study uncovers CXXC5 as an important regulator of cell proliferation and injury repair, thereby controlling colitis.