Exploiting a novel conformational switch to control innate immunity mediated by complement protein C3a

• Published in: Nature communications Vol. 8; no. 1; pp. 351 - 15
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 24.08.2017; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adaptive immunity; Animals; Anti-Asthmatic Agents - pharmacology; Antibodies; Cell activation; Cell Degranulation - drug effects; Cells, Cultured; Complement; Complement C3a - genetics; Complement C3a - metabolism; Complement C3a - physiology; Complement component C3; Complement component C3a; Complement receptors; Cromolyn Sodium - pharmacology; Degranulation; Edema; Humans; Immunity; Immunity, Innate - genetics; Inflammation; Innate immunity; Leukocytes (neutrophilic); Ligands; Macrophages; Macrophages - immunology; Male; Mast cells; Mast Cells - immunology; Modulators; Neutrophils; Neutrophils - immunology; Oral administration; Protein Conformation; Proteins; Rats; Rats, Wistar; Receptors, Complement - agonists; Receptors, Complement - antagonists & inhibitors; Receptors, Complement - chemistry
• ISSN: 2041-1723; 2041-1723
• 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.