Semmelweis University School of Medicine, Budapest, Hungary.
Arthritis Rheumatol. 2021 Sep;73(9):1614-1625. doi: 10.1002/art.41704. Epub 2021 Jul 14.
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.
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.
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 ) mice. However, this was not due to an intrinsic migration defect since Plcg2 neutrophils accumulated normally when wild-type cells were also present in mixed bone marrow chimeras. Instead, the Plcg2 mutation blocked the accumulation of interleukin-1β, macrophage inflammatory protein 2 (MIP-2), and leukotriene B (LTB ) 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 release in PLCγ2-deficient neutrophils.
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.
功能获得性突变和全基因组关联研究将磷酯酶 Cγ2（PLCγ2）与各种炎症性疾病相关联，包括人类和小鼠的关节炎。PLCγ2 缺陷（Plcg2）小鼠也能预防实验性关节炎。本研究旨在检验 PLCγ2 如何引发小鼠自身抗体诱导性关节炎。
在各种小鼠细胞谱系中删除 PLCγ2。通过免疫印迹和细胞内流式细胞术测试删除效率和特异性。通过 K/BxN 血清转移引发自身抗体诱导性关节炎。通过分析炎症渗出物、竞争体内迁移测定和体外功能研究进一步研究中性粒细胞 PLCγ2 的作用。
整个造血细胞系中 PLCγ2 的缺失完全阻断了自身抗体诱导性关节炎。从髓样细胞或中性粒细胞中删除 PLCγ2 可消除关节炎的发生，但从肥大细胞或血小板中删除 PLCγ2 则不能。中性粒细胞特异性 PLCγ2 缺陷（Plcg2）小鼠中中性粒细胞浸润减少。然而，这不是由于内在的迁移缺陷引起的，因为在混合骨髓嵌合体中存在野生型细胞时，Plcg2 中性粒细胞正常积聚。相反，Plcg2 突变阻断了白介素-1β、巨噬细胞炎性蛋白 2（MIP-2）和白三烯 B（LTB）在滑膜组织中的积累，并减少了巨噬细胞的二次浸润。这些发现得到了体外研究的支持，表明 PLCγ2 缺陷中性粒细胞的趋化性迁移正常，但免疫复合物诱导的呼吸爆发以及 MIP-2 或 LTB 的释放缺陷。
中性粒细胞 PLCγ2 对关节炎的发展至关重要，可能是通过产生炎症微环境。表达 PLCγ2 的中性粒细胞对其他炎症细胞产生复杂的间接影响。针对 PLCγ2 的治疗方法可能在具有主要中性粒细胞成分的炎症性疾病中具有特殊益处。
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