Neutrophils orchestrate their own recruitment in murine arthritis through C5aR and FcγR signaling

Neutrophil recruitment into the joint is a hallmark of inflammatory arthritides, including rheumatoid arthritis (RA). In a mouse model of autoantibody-induced inflammatory arthritis, neutrophils infiltrate the joint via multiple chemoattractant receptors, including the leukotriene B-4 (LTB4) receptor BLT1 and the chemokine receptors CCR1 and CXCR2. Once in the joint, neutrophils perpetuate their own recruitment by releasing LTB4 and IL-1 beta, presumably after activation by immune complexes deposited on joint structures. Two pathways by which immune complexes may activate neutrophils include complement fixation, resulting in the generation of C5a, and direct engagement of Fc gamma receptors (Fc gamma Rs). Previous investigations showed that this model of autoantibody-induced arthritis requires the C5a receptor C5aR and Fc gamma Rs, but the simultaneous necessity for both pathways was not understood. Here we show that C5aR and Fc gamma Rs work in sequence to initiate and sustain neutrophil recruitment in vivo. Specifically, C5aR activation of neutrophils is required for LTB4 release and early neutrophil recruitment into the joint, whereas Fc gamma R engagement upon neutrophils induces IL-1 beta release and subsequent neutrophil-active chemokine production, ensuring continued inflammation. These findings support the concept that immune complex-mediated leukocyte activation is not composed of overlapping and redundant pathways, but that each element serves a distinct and critical function in vivo, culminating in tissue inflammation.