Recognition and functional activation of the human IgA receptor (FcαRI) by C-reactive protein

C-reactive protein (CRP) is an important biomarker for inflammatory diseases. However, its role in inflammation beyond complement-mediated pathogen clearance remains poorly defined. We identified the major IgA receptor, Fc alpha RI, as a ligand for pentraxins. CRP recognized Fc alpha RI both in solution and on cells, and the pentraxin binding site on the receptor appears distinct from that recognized by IgA. Further competitive binding and mutational analysis showed that Fc alpha RI bound to the effector face of CRP in a region overlapping with complement C1q and Fc gamma receptor (Fc gamma R) binding sites. CRP cross-linking of Fc alpha RI resulted in extracellular signal-regulated kinase (ERK) phosphorylation, cytokine production, and degranulation in Fc alpha RI-transfected RBL cells. In neutrophils, CRP induced Fc alpha RI surface expression, phagocytosis, and TNF-alpha secretion. The ability of CRP to activate Fc alpha RI defines a function for pentraxins in inflammatory responses involving neutrophils and macrophages. It also highlights the innate aspect of otherwise humoral immunity-associated antibody receptors.