SENP2介导NALP3去SUMO化修饰调控脓毒症巨噬细胞焦亡的分子机制研究

Macrophage pyroptosis is the core event of sepsis progression. The acute inflammation waterfall and tolerance immune suppression induced by macrophage pyroptosis are one of the key causes of MODS. However, its regulatory mechanism is still unclear. We previously found that the expression of SENP2, a deSUMOylation enzyme, was significantly increased during macrophage pyroptosis. Silencing SENP2 could inhibit the activation of NALP3 and the expression of pyroptosis proteins. Therefore, we speculate that SENP2 participates in the regulation of macrophage pyroptosis and sepsis by regulating deSUMOylation of NALP3, but the specific mechanism remains to be studied. In this study, bone marrow derived macrohages were selected as target cells, SUMOylation was used as entry point, and SENP2 gene was over-expressed and silenced to establish sepsis mice model, explore the role of SENP2 in macrophage pyroptosis and its exact mechanism, and do some exploratory work for clinical treatment of sepsis.

巨噬细胞（MΦ）焦亡是脓毒症进展的核心事件，其诱发的急性期炎症瀑布和耐受期免疫抑制是造成MODS关键原因之一，然而其调控机制尚不清楚。我们前期发现MΦ焦亡时去SUMO化修饰酶SENP2的表达明显提高，沉默SENP2能抑制NALP3炎症体活化和焦亡蛋白的表达。因此，我们猜测SENP2通过调控NALP3去SUMO化修饰参与MΦ焦亡和脓毒症的调控，但具体机制有待研究。本研究选择骨髓来源MΦ为靶细胞，以SUMO化修饰为切入点，采用过表达和沉默SENP2基因的手段，建立脓毒症小鼠模型，探索SENP2在MΦ焦亡中的作用及确切机制，为临床治疗脓毒症做些探索性工作。

免疫调节紊乱是脓毒症患者死亡的主要原因之一。巨噬细胞焦亡可能在其中扮演着重要角色，其在脓毒症过度免疫阶段会介导大量炎症介质的释放，而在免疫麻痹时又因炎症细胞过度耗竭而不能发挥足够的免疫能力。因此探索巨噬细胞焦亡的分子机制和关键靶点，对脓毒症的治疗具有重要的意义。我们按计划开展了实验研究，结果发现：（1）脓毒症患者外周血巨噬细胞SENP2基因的表达量和焦亡信号通路活化程度明显高于健康对照组；（2）脓毒症小鼠与正常小鼠相比，肝、肺、肾和肠组织中SENP2表达明显增高，尾静脉注射SENP2沉默质粒后，LPS腹腔注射诱导的小鼠死亡率明显降低；（3）NLRP3与SENP2蛋白在体内外均能发生结合；当巨噬细胞发生焦亡时，NLRP3的SUMO化修饰明显减弱，去SUMO化修饰明显增强；沉默巨噬细胞SENP2基因，能促进SENP2的SUMO化，同时抑制焦亡信号的传导和炎症因子的释放。本研究表明SENP2通过调控NALP3的SUMO化修饰参与MΦ焦亡和脓毒症的调控，为脓毒症的治疗提供了新的研究方案。