C-反应蛋白调控巨噬细胞Toll样受体炎性应答的机制研究

C-reactive protein (CRP) is a typical human acute phase reactant whose serum level increases several hundred fold in response to tissue injury or pathogen invasion. Since CRP has been reported to possess various pro-inflammatory activities, it is considered as a promising target for treating multiple human inflammatory diseases. However, our previous work indicate that the pro-inflammatory activities of CRP is most likely due to the conformational rearranged, monomeric form. Moreover, our preliminary experiments demonstrate that the native pentameric CRP can inhibit the pro-inflammatory responses of macrophages induced by Toll-like receptor (TLR) agonists and can reverse the endotoxin tolerance induced by persistent TLR stimulation. These findings would implicate anti-inflammation and anti-immunosuppression functions of CRP in acute inflammation. The aim of the current proposal is to elucidate the mechanisms by which the two pattern recognition receptors cross-talk, which may help to clarify some current controversies and guide the design of CRP-targeted therapy.

C-反应蛋白（CRP）是一种典型的人类急性期蛋白，其血浆浓度在机体受到组织损伤或病菌侵染时会迅速上升数百乃至上千倍。大量研究指出CRP具有多种促炎活性，因此可能成为治疗包括心血管疾病等在内的若干人类重大（慢性）炎症疾病的新标靶。但项目组的长期研究显示，先前报道的CRP促炎效应可能主要源于其变构形式；而我们的近期预实验则进一步发现CRP不但能有效压制细菌脂蛋白、脂多糖等Toll样受体（TLR）配体所激发的巨噬细胞炎性应答，还可逆转因持续应激导致的TLR失敏，暗示CRP在败血症等急性炎症中同时具备抗炎及缓解免疫压制的功能。对此进行深入研究，一方面有助于回答领域内存在的一些重要争议，阐明CRP与TLR这两种先天免疫中的关键模式识别受体间的交互机制，另一方面也指出在以CRP为标靶的炎症治疗策略中全局性压制CRP活性的潜在风险。

C-反应蛋白（C-reactive protein，CRP）是一种推定的可溶模式识别受体，表达水平在炎症应激条件下成千倍升高。虽然推测CRP在宿主防御和炎症调节中发挥重要作用，但长期以来缺乏在体证据和对具体过程及机制的理解。本项目首次发现了CRP在炎症中核心作用的人类病理表型证据，揭示了CRP与Toll样受体（Toll-like receptor，TLR）在调节固有免疫细胞（巨噬细胞）应答中的密切交互以及对适应性免疫细胞（CD4 T细胞）分化的直接调节。这些结果回答了领域内的长期未决问题，并为以CRP为标靶的疾病干预策略提供了理论依据和应用途径。