Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg, 79106 Freiburg, Germany.
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
Nat Commun. 2017 Jan 23;8:14188. doi: 10.1038/ncomms14188.
C-reactive protein (CRP) concentrations rise in response to tissue injury or infection. Circulating pentameric CRP (pCRP) localizes to damaged tissue where it leads to complement activation and further tissue damage. In-depth knowledge of the pCRP activation mechanism is essential to develop therapeutic strategies to minimize tissue injury. Here we demonstrate that pCRP by binding to cell-derived microvesicles undergoes a structural change without disrupting the pentameric symmetry (pCRP*). pCRP* constitutes the major CRP species in human-inflamed tissue and allows binding of complement factor 1q (C1q) and activation of the classical complement pathway. pCRP*-microvesicle complexes lead to enhanced recruitment of leukocytes to inflamed tissue. A small-molecule inhibitor of pCRP (1,6-bis(phosphocholine)-hexane), which blocks the pCRP-microvesicle interactions, abrogates these proinflammatory effects. Reducing inflammation-mediated tissue injury by therapeutic inhibition might improve the outcome of myocardial infarction, stroke and other inflammatory conditions.
C 反应蛋白（CRP）浓度会因组织损伤或感染而升高。循环五聚体 CRP（pCRP）定位于受损组织，在那里它会导致补体激活和进一步的组织损伤。深入了解 pCRP 激活机制对于开发治疗策略以最小化组织损伤至关重要。在这里，我们证明 pCRP 通过与细胞衍生的微泡结合发生结构变化，而不会破坏五聚体对称性（pCRP*）。pCRP* 构成人类炎症组织中 CRP 的主要形式，允许结合补体因子 1q（C1q）并激活经典补体途径。pCRP*-微泡复合物导致白细胞向炎症组织的募集增加。一种 pCRP 的小分子抑制剂（1,6-双（磷酸胆碱）-己烷），它可以阻断 pCRP-微泡相互作用，消除这些促炎作用。通过治疗性抑制减轻炎症介导的组织损伤可能会改善心肌梗死、中风和其他炎症性疾病的预后。
