TRIM家族分子TRIM40调控小胶质细胞活化和炎症因子表达及其在POCD进展中的作用和机制研究

Post-operative Cognitive Dysfunction (POCD) is a common complication of surgery in elder patients. However, the mechanisms have not been well identified. Neuro-inflammation plays an important role in POCD. Microglial activation and inflammatory cytokines production are the primary factors in neuro-inflammation, and their regulatory mechanisms have attracted much attention. Tripartite motif(TRIM) family members play important roles in immune regulation, such as TRIM27 in infection immunity and TRIM38 in the regulation of inflammation. However, whether TRIM family member participates in POCD progress and neuro-inflammation is still unknown up to now. We examined the expression of TRIM family members in microglial cells of POCD mice model, and found that TRIM40 expression is significantly reduced. Hence, we constructed conditional TRIM40 knockout mice, and TRIM40 knockout in macrophages significantly enhances the neuro-inflammation and POCD progression. However, TRIM40 knockout in neurons or astrocytes did not significantly influence POCD progression. Therefore, we focused on the function of TRIM40 in microglia activation and inflammatory cytokines production, and its effects on POCD progression, so as to present new molecular mechanisms for POCD development.

术后认知功能障碍（POCD）是术后常见的并发症，其发生发展的调控机制是重要科学问题。中枢炎症是POCD进展的关键因素，小胶质细胞活化和炎症因子表达是中枢炎症的始动环节，其活化的分子调控机制目前受广泛关注。TRIM家族分子在免疫调节中发挥重要作用，如TRIM27在感染免疫、TRIM38在炎症中发挥重要调控作用。但是，在POCD进展和中枢炎症调控中，目前尚无TRIM家族分子的系统研究。我们前期利用POCD小鼠模型系统研究了TRIM家族分子的表达，发现，POCD小鼠小胶质细胞TRIM40表达显著降低，进一步构建了TRIM40条件型基因敲除小鼠，发现巨噬细胞TRIM40敲除显著增强了中枢炎症和POCD进展，而神经细胞或星形胶质细胞TRIM40敲除无明显影响。由此，本研究拟探求TRIM40在小胶质细胞活化和炎症因子表达中的调控作用，对中枢炎症和POCD进展的影响，为POCD提出新机制和干预新靶点。

术后认知功能障碍（POCD）是老年患者术后常见的并发症之一，显著增加老年患者术后死亡率。中枢神经炎症发挥着重要的作用。我们发现TRIM40在小胶质细胞活化和炎症因子表达中的调控作用在POCD发挥重要的作用，因培育繁殖LyzM-Cre敲除小鼠和NSE-Cre敲除小鼠培育较困难，繁殖LyzM-Cre敲除小鼠和NSE-Cre敲除小鼠构建动物模型构建死亡率较高，欠稳定。为了课题顺利进展，在体外细胞模型构建成熟基础上，后续我们发现甲烷饱和盐水（MS）可改善小鼠POCD，降低血清与海马中TNF-α和IL-6的产生。MS显著抑制LPS诱导的ERK、JNK和p38以及p65的磷酸。在体外验证MS对IL-10水平的影响，发现 MS组IL-10的产生明显增多，且存在量效关系。利用IL-10功能性抗体阻断IL-10通路后，逆转了MS抑制炎性因子分泌的能力，对小鼠POCD有保护作用，同时阻断IL-10通路可逆转MS对LPS刺激BV2细胞中NF-κB、MAPKs的抑制作用。我们进一步利用大量的临床样本研究了蛋白（代谢组学）在POCD早期诊断中的作用。从而为POCD的早期诊断和治疗打下坚实基础。