Neutrophil phospholipase Cγ2 drives autoantibody-induced arthritis through the generation of the inflammatory microenvironment.

OBJECTIVE Gain-of function mutations and genome-wide association studies linked phospholipase Cγ2 (PLCγ2) to various human inflammatory diseases including arthritis in humans and mice. PLCγ2-deficient (Plcg2-/- ) mice are also protected from experimental arthritis. Here we tested how PLCγ2 triggers autoantibody-induced arthritis in mice. METHODS PLCγ2 was deleted from various cellular lineages. Deletion efficacy and specificity was tested by immunoblotting and intracellular flow cytometry. Autoantibody-induced arthritis was triggered by K/B×N serum transfer. The role of neutrophil PLCγ2 was further tested by analyzing the inflammatory exudate, competitive in vivo migration assays and in vitro functional studies. RESULTS PLCγ2 deficiency in the entire hematopoietic compartment completely blocked autoantibody-induced arthritis. Arthritis development was abrogated by PLCγ2 deletion from myeloid cells or neutrophils but not from mast cells or platelets. Neutrophil infiltration was reduced in neutrophil-specific PLCγ2-deficient (Plcg2ΔPMN ) mice. However, this was not due to an intrinsic migration defect since Plcg2ΔPMN neutrophils accumulated normally when wild type cells were also present in mixed bone-marrow chimeras. Instead, the Plcg2ΔPMN mutation blocked the accumulation of IL-1β, MIP-2 and LTB4 in synovial tissues and reduced the secondary infiltration of macrophages. Those findings were supported by in vitro studies showing normal chemotactic migration but defective immune complex-induced respiratory burst and MIP-2 or LTB4 release in PLCγ2-deficient neutrophils. CONCLUSION Neutrophil PLCγ2 is critical for arthritis development, supposedly through the generation of the inflammatory microenvironment. PLCγ2-expressing neutrophils exert complex indirect effects on other inflammatory cells. PLCγ2-targeted therapies may provide particular benefit in inflammatory diseases with a major neutrophil component.