金黄色葡萄球菌通过STAT3乳酸化抑制中性粒细胞铁死亡促进溃疡性结肠炎的机制研究

溃疡性结肠炎（UC）的疾病进展伴随着隐窝脓肿的形成，肠菌紊乱和免疫失衡是其重要特征，但作用机制尚未明确。近期研究发现组蛋白乳酸化作为一种新的蛋白质修饰，具有免疫调控作用，目前尚无胞浆蛋白乳酸化的报道。申请人发现UC肠道炎症部位金黄色葡萄球菌定植造成高乳酸微环境，且和中性粒细胞浸润呈显著相关性。进一步发现中性粒细胞胞浆信号转导及转录激活蛋白3（STAT3）的乳酸修饰并鉴定出乳酸修饰的调节酶，且乳酸修饰促进STAT3二聚体形成从而上调铁死亡抑制因子铁蛋白（FTH）表达。因此，本项目的假说是：金黄色葡萄球菌通过乳酸修饰STAT3使其二聚体化，从而上调FTH的表达，抑制铁死亡，造成中性粒细胞持续活化，加剧肠道炎症和隐窝脓肿形成。该机制的阐明对UC的治疗具有重要的指导意义。

Ulcerative colitis (UC) forms crypt abscess along with disease progression, which is characterized by gut microbial disorders and immune imbalance, but the underlying mechanism remains unclear. Recently, it has been discovered that histone lactylation is a new protein modification and could regulate immune, however, so far, no cytoplasmic protein lactylation has been reported. The applicant found that Staphylococcus aureus could cause high level of lactate in the damaged intestinal sites of UC and was significantly correlated with the infiltration of neutrophil. Further study showed that signal transducer and activator transcription 3(STAT3), one of cytoplasmic protein in neutrophil, could be modified by lactate, and identified the regulatory enzyme of lactylation modification. STAT3 lactylation promoted STAT3 dimerization and upregulated the expression of ferritin (FTH), one of ferroptosis inhibitors, to inhibit neutrophil ferroptosis. Hence, the hypothesis of the project is that Staphylococcus aureus facilitates STAT3 dimerization by lactate-derived lactylation. Dimerized STAT3 enters into the nucleus and increases the expression of FTH and inhibits neutrophil ferroptosis. The persistence of activated neutrophil exacerbates intestinal inflammation and promotes crypt abscess formation. It is important for UC therapy to elucidate the inter-relationship between Staphylococcus aureus and neutrophil.