Abstract
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.
Highlights
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
C3a concentrations are reportedly elevated during inflammatory diseases[7], recombinant C3a reportedly induces hypertension and delayed neutrophilia in rats over 24 h8, while sustained activation of C3aR vs knockouts support a role in allergies[9], asthma[10], arthritis[11], sepsis[12], lupus[13], diabetes[14], ischemia-reperfusion injury[15], obesity and metabolic dysfunction[16]
Compounds 3 and 6 are the most potent small molecule agonists and antagonists reported for the human C3a receptor
Summary
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 used our more metabolically stable and C3aR-selective small molecule agonist BR103 (compound 3) to characterize for the first time a C3aR-induced innate immune response in vivo in rats.
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