PTX3 抑制补体过度活化在抗动脉粥样硬化炎症中的作用及机制

PTX3 as an important part of the innate immunity in the inflammatory reaction plays an important role in anti-atherosclerosis, but the mechanism is still poorly understood. Complement mediating immune response and inflammatory reaction participated in the occurrence and development of atherosclerosis.The recently study showed that PTX3 combined with complement inhibitor inhibited the excessive complement activation and inflammatory processes in cancer. Our earlier research showed PTX3 expressed on cholesterol-induced apoptotic macrophage, promoting the clearance of apoptotic cells by activating classical complement pathway. That maybe important for inhibiting inflammation in plaque . Also we found plasma PTX3 is increased in patients with coronary heart disease. It's not clear that there is any true cause-and-effect relationship betweent the anti-inflammation effect in atherosclerosis and the inhibition of excessive complement activation by incresed PTX3. To verify the hypothesis we will discuss the effect and mechanism of PTX3 inhibits excessive complement activation implicated in inflammatory reaction in atherosclerosis. The specificity PTX3 knockout mice model and cell model of atherosclerosis is used. It is possible to find new molecular regulator of inflammatory reaction, and provid intervention targets and experiment basis for prevention and treatment of atherosclerosis.

PTX3作为先天免疫重要组成部分，在抗动脉粥样硬化炎症中具有重要作用，但机制至今不详。补体作为介导免疫应答和炎症反应的媒介，参与动脉粥样硬化的发生和发展。最新研究发现PTX3与补体抑制因子结合，抑制补体过度活化及抗肿瘤炎症。我们亦发现PTX3在胆固醇诱导的凋亡巨噬细胞上表达，通过经典补体途径促进凋亡细胞清除及抑制斑块炎症。我们还发现冠心病患者血浆PTX3水平升高。增多的PTX3是否通过抑制补体过度活化，发挥抗动脉粥样硬化作用，目前尚不清楚。我们将以特异性PTX3基因敲除小鼠动脉粥样硬化模型以及体外细胞模型为研究对象，探讨PTX3抑制补体过度活化在抗动脉粥样硬化炎症中的作用及机制。以期发现动脉粥样硬化炎症新的调控分子，为动脉粥样硬化防治提供干预靶点和实验依据。

PTX3作为先天免疫重要组成部分，在抗动脉粥样硬化炎症中具有重要作用，但机制至今不详。补体作为介导免疫应答和炎症反应的媒介，参与动脉粥样硬化的发生和发展。研究发现PTX3与补体抑制因子结合，抑制补体过度活化及抗肿瘤炎症。我们亦发现PTX3在胆固醇诱导的凋亡巨噬细胞上表达，通过经典补体途径促进凋亡细胞清除及抑制斑块炎症。我们还发现冠心病患者血浆PTX3水平升高。增多的PTX3是否通过抑制补体过度活化，发挥抗动脉粥样硬化作用，目前尚不清楚。我们以体外胆固醇刺激巨噬细胞模型及动脉粥样硬化小鼠模型为研究对象，探讨PTX3抑制补体过度活化在抗动脉粥样硬化炎症中的作用及机制。研究发现：胆固醇刺激巨噬细胞后， PTX3表达增多，补体H因子CFH及补体C3a，C5a表达增多，炎性小体NLRP3及其介导的炎性通路活化，Caspase1及IL1β的表达上调，加用外源性PTX3，可抑制补体活化，减少C3a、C5a的表达，并抑制NLRP3及其介导的炎性通路激活。加用C3a受体激动剂C3aRag，可上调炎性小体NLRP3及下游Caspase1及IL1β的表达。研究结果提示，补体活化成分C3a、C5a促进了炎性小体NLRP3及其下游炎性通路的活化，PTX3通过抑制补体活化，减少C3a、C5a的表达，从而减轻炎性小体NLRP3介导的炎性反应。上述研究结果揭示了，动脉粥样硬化炎症新的分子调控机制，为动脉粥样硬化防治提供了新的干预靶点和实验依据。