Abstract：
Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease in preterm infants and the most common cause of neonatal death, whereas the molecular mechanism of intestinal injury remains unclear accompanied by deficiency of effective therapeutic approaches. GIT2 (G-protein-coupled receptor kinase interacting proteins 2) can affect innate and adaptive immunity and has been involved in multiple inflammatory disorders. In this study, we investigated whether GIT2 participates in the pathogenesis of NEC. Here we found that intestinal Git2 gene expression was significantly increased in NEC patients and NEC mice, which positively correlated with the tissue damage severity, and Git2 deficiency could potently protect against NEC development in mice. Mechanistically, Git2 gene knockout dramatically increased the recruitment of MDSCs in the intestine, and in vivo depletion of MDSCs almost completely abrogated the protective effect of Git2 deficiency on NEC. Moreover, Git2 deficiency induced MDSCs intestinal accumulation mainly relied on CXCL1/CXCL12 signaling, as evidenced by the significant increment of CXCL1 and CXCL12 levels in intestinal epithelium of Git2-/- mice and dramatically decrease of MDSCs accumulation in intestine as well as increase of NEC severity upon treatment of CXCL1/CXCL12 pathway inhibitors. In addition, Git2 deficiency induced up-regulation of CXCL1 and CXCL12 is at least partially mediated through activating NF-κB signaling. Thus, our findings suggest that GIT2 is involved in the pathogenesis of NEC, and targeting GIT2 may be a potential preventive and therapeutic approach for NEC.
摘要：
坏死性小肠结肠炎（NEC）是早产儿的严重胃肠道疾病，是新生儿死亡的最常见原因，而肠道损伤的分子机制尚不清楚，同时缺乏有效的治疗方法。GIT2（G蛋白偶联受体激酶相互作用蛋白2）可影响先天和适应性免疫，并已参与多种炎症性疾病。在这项研究中,我们研究了GIT2是否参与了NEC的发病机制。在这里，我们发现NEC患者和NEC小鼠的肠道Git2基因表达显著增加，与组织损伤严重程度呈正相关，和Git2缺乏可以有效地防止小鼠的NEC发育。机械上,Git2基因敲除大大增加了肠道中MDSCs的募集，体内MDSC的消耗几乎完全消除了Git2缺乏对NEC的保护作用。此外，Git2缺陷诱导的MDSCs肠道蓄积主要依靠CXCL1/CXCL12信号,如Git2-/-小鼠肠上皮中CXCL1和CXCL12水平显着升高，并且在CXCL1/CXCL12途径抑制剂治疗后，MDSC在肠道中的积累显着减少以及NEC严重程度增加所证明。此外,Git2缺陷诱导的CXCL1和CXCL12的上调至少部分是通过激活NF-κB信号介导的。因此，我们的研究结果表明，GIT2参与了NEC的发病机制，靶向GIT2可能是NEC的潜在预防和治疗方法。
