Complement C5a receptor is the key initiator of neutrophil adhesion igniting immune complex-induced arthritis

The deposition of immune complexes (ICs) in tissues induces a type III hypersensitivity that results in tissue damage and underlies the pathogenesis of many autoimmune diseases. The neutrophil is the first immune cell recruited into sites of IC deposition and plays a critical role in shaping the overall tissue response. However, the mechanism by which ICs initiate and propagate neutrophil infiltration into tissue is not known. Using intravital multiphoton joint imaging of IC-induced arthritis in live mice, we found that the complement C5a receptor (C5aR) was the key initiator of neutrophil adhesion on joint endothelium. C5a presented on joint endothelium induced beta(2) integrin-dependent neutrophil arrest, facilitating neutrophil spreading and transition to crawling, and subsequent leukotriene B-4 receptor (BLT1)-mediated extravasation of the first neutrophils. The chemokine receptor CCR1 promoted neutrophil crawling on the joint endothelium, whereas CXCR2 amplified late neutrophil recruitment and survival once in the joint. Thus, imaging arthritis has defined a new paradigm for type III hypersensitivity, where C5a directly initiates neutrophil adhesion on the joint endothelium igniting inflammation.