Neutrophil Phospholipase Cγ2 Drives Autoantibody-Induced Arthritis Through the Generation of the Inflammatory Microenvironment
Neutrophil Phospholipase Cγ2 Drives Autoantibody-Induced Arthritis Through the Generation of the Inflammatory Microenvironment
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DOI：
10.1002/art.41704
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发表时间：
2021-07-14
影响因子：
13.3
通讯作者：
Mocsai, Attila
中科院分区：
文献类型：
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作者：
Futosi, Krisztina;Kasa, Orsolya;Mocsai, Attila
Objective.功能获得性突变和全基因组关联研究将磷脂酶C γ 2（PLC γ 2）与各种炎症性疾病联系起来，包括人类和小鼠的关节炎。PLC γ 2-缺陷（Plcg 2（-/-））小鼠也被保护免于实验性关节炎。本研究旨在检测PLC γ 2如何触发小鼠自身抗体诱导的关节炎。从各种小鼠细胞谱系中删除PLC γ 2。通过免疫印迹和细胞内流式细胞术检测缺失效率和特异性。自身抗体诱导的关节炎由K/BxN血清转移触发。中性粒细胞PLC γ 2的作用通过分析炎性渗出物、竞争性体内迁移试验和体外功能研究进一步研究。PLC γ 2在整个造血隔室的缺陷完全阻断自身抗体诱导的关节炎。关节炎的发展被废除删除PLC γ 2从骨髓细胞或中性粒细胞，但不是从肥大细胞或血小板。中性粒细胞特异性PLC γ 2缺陷（Plcg 2（Delta PMN））小鼠的中性粒细胞浸润减少。然而，这不是由于固有的迁移缺陷，因为Plcg 2（Δ PMN）中性粒细胞正常积累时，野生型细胞也存在于混合骨髓嵌合体。相反，Plcg 2（Δ PMN）突变阻断了滑膜组织中白细胞介素-1 β、巨噬细胞炎性蛋白2（MIP-2）和白三烯B-4（LTB 4）的积累，并减少了巨噬细胞的继发性浸润。这些发现得到了体外研究的支持，该研究显示PLC γ 2缺陷中性粒细胞中正常的趋化迁移，但免疫复合物缺陷诱导的呼吸爆发和MIP-2或LTB 4释放。结论。神经元PLC γ 2对关节炎的发展至关重要，据说是通过炎症微环境的产生。表达PLC γ 2的中性粒细胞对其他炎症细胞产生复杂的间接作用。PLC γ 2靶向治疗可能对主要中性粒细胞成分的炎性疾病有特别的益处。
Objective. Gain-of-function mutations and genome-wide association studies have linked phospholipase C gamma 2 (PLC gamma 2) to various inflammatory diseases, including arthritis in humans and mice. PLC gamma 2-deficient (Plcg2(-/-)) mice are also protected against experimental arthritis. This study was undertaken to test how PLC gamma 2 triggers autoantibody-induced arthritis in mice.Methods. PLC gamma 2 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 PLC gamma 2 was further investigated by analysis of the inflammatory exudate, competitive in vivo migration assays, and in vitro functional studies.Results. PLC gamma 2 deficiency in the entire hematopoietic compartment completely blocked autoantibody-induced arthritis. Arthritis development was abrogated by deletion of PLC gamma 2 from myeloid cells or neutrophils but not from mast cells or platelets. Neutrophil infiltration was reduced in neutrophil-specific PLC gamma 2-deficient (Plcg2(Delta PMN)) mice. However, this was not due to an intrinsic migration defect since Plcg2(Delta PMN) neutrophils accumulated normally when wild-type cells were also present in mixed bone marrow chimeras. Instead, the Plcg2(Delta PMN) mutation blocked the accumulation of interleukin-1 beta, macrophage inflammatory protein 2 (MIP-2), and leukotriene B-4 (LTB4) 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 LTB4 release in PLC gamma 2-deficient neutrophils.Conclusion. Neutrophil PLC gamma 2 is critical for arthritis development, supposedly through the generation of the inflammatory microenvironment. PLC gamma 2-expressing neutrophils exert complex indirect effects on other inflammatory cells. PLC gamma 2-targeted therapies may provide particular benefit in inflammatory diseases with a major neutrophil component.