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Neutrophil Phospholipase Cγ2 Drives Autoantibody‐Induced Arthritis Through the Generation of the Inflammatory Microenvironment
Author(s) -
Futosi Krisztina,
Kása Orsolya,
Szilveszter Kata P.,
Mócsai Attila
Publication year - 2021
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41704
Subject(s) - arthritis , immunology , inflammation , chemotaxis , autoantibody , inflammatory arthritis , neutrophil extracellular traps , haematopoiesis , myeloid , biology , chemistry , microbiology and biotechnology , antibody , stem cell , receptor , biochemistry
Objective Gain‐of‐function mutations and genome‐wide association studies have linked phospholipase Cγ2 (PLCγ2) to various inflammatory diseases, including arthritis in humans and mice. PLCγ2‐deficient ( Plcg2 –/– ) mice are also protected against experimental arthritis. This study was undertaken to test how PLCγ2 triggers autoantibody‐induced arthritis in mice. Methods PLCγ2 was deleted from various mouse cellular lineages. Deletion efficacy and specificity were tested by immunoblotting and intracellular flow cytometry. Autoantibody‐induced arthritis was triggered by K/BxN serum transfer. The role of neutrophil PLCγ2 was further investigated by analysis of 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 deletion of PLCγ2 from myeloid cells or neutrophils but not from mast cells or platelets. Neutrophil infiltration was reduced in neutrophil‐specific PLCγ2‐deficient ( Plcg2 Δ PMN ) mice. However, this was not due to an intrinsic migration defect since Plcg2 Δ PMN neutrophils accumulated normally when wild‐type cells were also present in mixed bone marrow chimeras. Instead, the Plcg2 Δ PMN mutation blocked the accumulation of interleukin‐1β, macrophage inflammatory protein 2 (MIP‐2), and leukotriene B 4 (LTB 4 ) in synovial tissues and reduced the secondary infiltration of macrophages. These findings were supported by in vitro studies showing normal chemotactic migration but defective immune complex–induced respiratory burst and MIP‐2 or LTB 4 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.