Lohman Rink-Jan, Hamidon Johan K, Reid Robert C, Rowley Jessica A, Yau Mei-Kwan, Halili Maria A, Nielsen Daniel S, Lim Junxian, Wu Kai-Chen, Loh Zhixuan, Do Anh, Suen Jacky Y, Iyer Abishek, Fairlie David P
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.
Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD, 4072, Australia.
Nat Commun. 2017 Aug 24;8(1):351. doi: 10.1038/s41467-017-00414-w.
Complement C3a is an important protein in innate and adaptive immunity, but its specific roles in vivo remain uncertain because C3a degrades rapidly to form the C3a-desArg protein, which does not bind to the C3a receptor and is indistinguishable from C3a using antibodies. Here we develop the most potent, stable and highly selective small molecule modulators of C3a receptor, using a heterocyclic hinge to switch between agonist and antagonist ligand conformations. This enables characterization of C3 areceptor-selective pro- vs. anti-inflammatory actions in human mast cells and macrophages, and in rats. A C3a receptor-selective agonist induces acute rat paw inflammation by first degranulating mast cells before activating macrophages and neutrophils. An orally administered C3a receptor-selective antagonist inhibits mast cell degranulation, thereby blocking recruitment and activation of macrophages and neutrophils, expression of inflammatory mediators and inflammation in a rat paw edema model. These novel tools reveal the mechanism of C3a-induced inflammation and provide new insights to complement-based medicines.Complement C3a is an important protein in innate and adaptive immunity, but its roles in vivo are unclear. Here the authors develop novel chemical agonists and antagonists for the C3a receptor, and show that they modulate mast cell degranulation and inflammation in a rat paw edema model.
补体C3a是天然免疫和适应性免疫中的一种重要蛋白质，但其在体内的具体作用仍不明确，因为C3a会迅速降解形成C3a-去精氨酸蛋白，该蛋白不与C3a受体结合，且使用抗体无法将其与C3a区分开来。在此，我们利用杂环铰链在激动剂和拮抗剂配体构象之间切换，开发出了最有效、稳定且高度选择性的C3a受体小分子调节剂。这使得我们能够在人肥大细胞、巨噬细胞以及大鼠中，对C3a受体选择性的促炎和抗炎作用进行表征。一种C3a受体选择性激动剂通过首先使肥大细胞脱颗粒，然后激活巨噬细胞和中性粒细胞，从而诱导大鼠爪急性炎症。在大鼠爪水肿模型中，口服给药的C3a受体选择性拮抗剂可抑制肥大细胞脱颗粒，进而阻断巨噬细胞和中性粒细胞的募集与激活、炎症介质的表达以及炎症反应。这些新型工具揭示了C3a诱导炎症的机制，并为基于补体的药物提供了新的见解。补体C3a是天然免疫和适应性免疫中的一种重要蛋白质，但其在体内的作用尚不清楚。在此，作者开发了用于C3a受体的新型化学激动剂和拮抗剂，并表明它们在大鼠爪水肿模型中调节肥大细胞脱颗粒和炎症反应。
