自噬参与痛风炎症自发缓解机制的研究

Gout is a disease caused by monosodium urate (MSU) crystal deposition in articular joints and periarticular tissues to lead to acute inflammatory response, which have apparent characteristic of self-limition. however, the molecular mechanism of gouty inflammation is still unclear. It demonstrated that MSU could activated autophagy and NLRP3 inflammasome signaling pathways. Autophagy could inhibit MSU-induced pro-inflammatory mediators release. Our previous studies found that autophagy increased in gout patients, we hypothesis that autophagy would probably be involved in spontaneous remission of gouty inflammation. This program aims to detect characteristics of mRNA and protein level changes of autophagy and its related genes in PBMCs and stimulated by MSU, MSU with autophagy agonist or inhibitor of patients with gout and also investigate molecular mechanism of autophagy regulating gouty inflammation in vitro. Aim to clarify the mechanism of autophagy involved in spontaneous remission of gouty inflammation.

痛风是由尿酸盐（MSU）晶体沉积在关节及其周围组织引起的急性炎症反应性疾病，且具有显著的自限性特点，但其确切的发病机制不明确。研究表明MSU能激活自噬及NLRP3炎性体信号通路，自噬能抑制MSU晶体诱导的致炎因子释放。我们前期研究发现痛风患者自噬活性增强，我们推测自噬可能参与了痛风炎症自发缓解。本项目拟检测痛风患者PBMCs、MSU刺激、MSU联合自噬激活或抑制剂刺激后自噬及自噬及其相关基因的mRNA和蛋白水平变化特点及体外功能研究自噬调控痛风炎症的分子机制，旨在阐明自噬参与痛风炎症自发缓解的机制。

痛风是由尿酸盐（MSU）晶体沉积在关节及其周围组织引起的急性炎症反应性疾病。痛风的一个显著特征表现为急性炎症存在自限性，其具体发生机制并不明确。在该项目研究中，我们通过痛风性关节炎患者的外周血及体外功能干预实验证实NLRP3炎性体及自噬相关基因在痛风患者PBMC中的异常表达，说明NLRP3炎性体及自噬参与了痛风发病机制。自噬体标志蛋白LC3在急性痛风患者的表达水平显著增高，说明急性期痛风患者的自噬水平显著增强。通过不同自噬调控剂联合MSU刺激诱导痛风炎症反应，自噬抑制剂组的beclin-1和LC3-Ⅱ显著增高，特别是阻断自噬溶酶体组显著增高，说明自噬通量显著增加，痛风患者的自噬通路正常，beclin-1和LC3-Ⅱ均通过自噬溶酶体降解。自噬调控剂通过调控自噬功能能够改变NLRP3炎性体的功能状态，说明MSU通过自噬途径负调控NLRP3炎性体功能，抑制痛风炎症反应，这可能与痛风炎症自限性相关。因此，深入研究自噬参与痛风炎症调控，有助于阐明痛风的发病机制。