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

Abstract

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 (LTB 4 ) receptor BLT1 and the chemokine receptors CCR1 and CXCR2. Once in the joint, neutrophils perpetuate their own recruitment by releasing LTB 4 and IL-1β, 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 Fcγ receptors (FcγRs). Previous investigations showed that this model of autoantibody-induced arthritis requires the C5a receptor C5aR and FcγRs, but the simultaneous necessity for both pathways was not understood. Here we show that C5aR and FcγRs work in sequence to initiate and sustain neutrophil recruitment in vivo. Specifically, C5aR activation of neutrophils is required for LTB 4 release and early neutrophil recruitment into the joint, whereas FcγR engagement upon neutrophils induces IL-1β 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.

RETRACTED: Dominant suppression of inflammation by glycan-hydrolyzed IgG

“…Conversely, antibodies as a constituent of ICs play an important role in triggering various inflammatory processes leading to the development of a number of autoimmune diseases. Neutrophils play a vital part during this process, and sequential complement fixation generating C5a and direct engagement of Fcγ receptors are needed to initiate and sustain such neutrophil recruitment in vivo and subsequent inflammation (26). Recent studies demonstrated bidirectional regulation of C5aR and FcγRs, which could significantly influence effector functions (27).…”

Interplay between CXCR2 and BLT1 Facilitates Neutrophil Infiltration and Resultant Keratinocyte Activation in a Murine Model of Imiquimod-Induced Psoriasis

“…To our knowledge, chemokine-driven LTB 4 production by neutrophils has never been documented. This mechanism is reminiscent of the case of formyl peptides in vitro (43) and C5aR in autoantibodyinduced arthritis model (44). In addition, a recent study revealed the central role of neutrophil-derived LTB 4 in swarming behavior of neutrophils in wound or infected area (45).…”

Evaluation of Serum Interleukin‐6 Level as a Surrogate Marker of Synovial Inflammation and as a Factor of Structural Progression in Early Rheumatoid Arthritis: Results From a French National Multicenter Cohort

“…CRP production is also dependent on IL-1b and anaphylatoxin C5a generated as a consequence of complement activation (27). Therefore, CRP levels reflect IL-6 as well as C5a (28)(29)(30) and IL-1b (31,32) levels, which are both involved in synovium inflammation and joint destruction. This might explain that the timeintegrated level of CRP was correlated with radiographic progression and IL-6 was not.…”