瘦素通过NLRP3炎性体对SLE中Th17的调节作用及其机制

The pathogenesis of systemic lupus erythematosus（SLE）is extremely complicated，related to immune disorder rooted in hyper-respond of pathological effector T cells and/or hypo-respond of regulatory T cells.As one major of pathological effector T cells，Th17 plays an important role in the pathogenesis of SLE. It is indicated that activation of NLRP3 inflammasome upregulates Th17/IL-17.Leptin is a kind of proinflammatory cytokine，our previous study showed that leptin promoted Th17 response in SLE. Does leptin promote Th17 response and aggravate disease activity in SLE throug regulating NLRP3 inflammasome？In this study we will mainly focuse on the following questions，and try to explore:1.Whether leptin intervenes the secretion of IL-1β and IL-18 in wild type mice through regulating NLRP3 inflammasome. 2.Whether leptin promotes Th17 response through activating NLRP3 inflammsome in SLE.3.Whether leptin exacerbates disease activity,through activating NLRP3 inflammosme to promote Th17 response in pristane induced lupus mice model--respectively in wild type or leptin deficient mice. This study may provide insight on the prevention and treatment of SLE.

系统性红斑狼疮（SLE）的发病与病理性效应T细胞高应答和/或调节性T细胞低应答导致的免疫紊乱有关，Th17作为一种病理性效应T细胞是SLE发病的重要致炎因素。目前一些研究表明NLRP3炎性体活化能上调Th17/IL-17的表达。瘦素是一种促炎因子，本课题组前期研究发现瘦素促进SLE中Th17应答，那么瘦素是否通过调节NLRP3炎性体促进Th17/IL-17应答而加重SLE的疾病活动度？本课题将围绕该疑问展开研究，首先观察瘦素是否通过激活NLRP3炎性体干预小鼠IL-1β、IL-18生成；其次观察瘦素是否通过激活NLRP3炎性体/IL-1β/IL-18促进SLE中Th17应答；最后以pristane诱导野生型小鼠及瘦素缺陷小鼠狼疮动物模型观察瘦素是否通过激活NLRP3炎性体促进Th17应答而加速狼疮小鼠的病程及加重疾病活动度，从而为SLE的临床治疗研究奠定基础。

瘦素是一种促炎因子，目前发现其在多种自身免疫性疾病中发挥作用，我们前期研究中发现瘦素促进SLE中Th17应答，一些研究表明NLRP3炎性体活化能上调Th17应答。本研究主要探讨瘦素是否通过活化NLRP3炎性体促进Th17应答而加重SLE的疾病活动度。另外，痛风患者大多存在肥胖，肥胖患者瘦素水平升高，而瘦素具有促炎作用，故推测瘦素在痛风发病中发挥重要作用。本研究发现瘦素在免疫性疾病（系统性红斑狼疮及急性痛风性关节炎）的发病中起重要作用。瘦素通过激活NLRP3炎性体促进小鼠RAW 264.7细胞分泌IL-18，通过激活NLRP3炎性体促进小鼠DC细胞分泌IL-1β和IL-18，促进狼疮小鼠Th17 中NLRP3和IL-1β的表达。同时推测并验证了急性痛风患者外周血瘦素水平升高，MSU诱导的小鼠足掌急性痛风炎症部位免疫组化可见瘦素聚集，提示瘦素参与急性痛风发作。瘦素促进MSU刺激的人滑膜细胞caspase-1及促炎因子IL-1β、IL-6上调，抑炎因子IL-37下调。瘦素缺陷的ob小鼠足掌急性痛风模型足掌肿胀度明显减轻，病理HE染色示炎症细胞浸润减少，补充瘦素后ob小鼠足掌肿胀及炎症细胞浸润加重到野生型小鼠水平，表明瘦素加重急性痛风炎症。并进一步通过PCR array检测瘦素相关的信号分子，证明瘦素通过mTOR、MAPK信号通路发挥促炎作用。Wt小鼠提前2小时注射mTOR抑制剂雷帕霉素后再用MSU诱导小鼠急性痛风炎症，注射雷帕霉素组小鼠足掌肿胀度明显减轻，PCR检测炎症因子IL-1β下降。表明瘦素相关靶点在免疫性疾病中存在治疗价值。