FGFR3 deficiency enhances CXCL12-dependent chemotaxis of macrophages via upregulating CXCR7 and aggravates joint destruction in mice
FGFR3 deficiency enhances CXCL12-dependent chemotaxis of macrophages via upregulating CXCR7 and aggravates joint destruction in mice
复制标题
FGFR3 缺陷通过上调 CXCR7 增强巨噬细胞的 CXCL12 依赖性趋化性，并加剧小鼠关节破坏
DOI：
10.1136/annrheumdis-2019-215696
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发表时间：
2020-01-01
影响因子：
27.4
通讯作者：
Chen, Lin
中科院分区：
文献类型：
--
作者：
Kuang, Liang;Wu, Jiangyi;Chen, Lin
本研究旨在探讨FGFR3在巨噬细胞中的作用、机制及其在关节炎病理中的生物学效应。方法制备条件敲除骨髓细胞中FGFR3的小鼠（R3cKO）。监测不同年龄小鼠的步态行为。采用数字x线摄影和μCT分析评价自发性滑膜关节破坏；通过组织学分析确定关节软骨和滑膜炎的变化。采用免疫染色法和单核细胞运输法观察滑膜巨噬细胞的募集情况。对对照组和fgfr3缺陷巨噬细胞进行RNA-seq分析、Western blotting和趋化实验。分析了非骨关节炎（OA）供者和OA患者的外周血。用抗CXCR7的中和抗体治疗小鼠，研究CXCR7在关节炎中的作用。结果R3cKO小鼠在13月龄时出现自发性多滑膜关节软骨破坏，对照组未出现。此外，在9月龄R3cKO小鼠关节软骨未严重破坏时，观察到关节滑膜炎和巨噬细胞积聚。骨髓细胞中FGFR3缺乏也加重了DMM小鼠模型的关节破坏。机械上，FGFR3缺失部分通过激活NF-κB/CXCR7途径促进巨噬细胞趋化。抑制CXCR7可显著逆转fgfr3缺陷增强的巨噬细胞趋化性和R3cKO小鼠的关节炎表型。我们的研究确定了FGFR3在滑膜巨噬细胞募集和滑膜炎中的作用，这为炎症相关性关节炎的病理机制提供了新的见解。
Objectives This study aims to investigate the role and mechanism of FGFR3 in macrophages and their biological effects on the pathology of arthritis. Methods Mice with conditional knockout of FGFR3 in myeloid cells (R3cKO) were generated. Gait behaviours of the mice were monitored at different ages. Spontaneous synovial joint destruction was evaluated by digital radiographic imaging and μCT analysis; changes of articular cartilage and synovitis were determined by histological analysis. The recruitment of macrophages in the synovium was examined by immunostaining and monocyte trafficking assay. RNA-seq analysis, Western blotting and chemotaxis experiment were performed on control and FGFR3-deficient macrophages. The peripheral blood from non-osteoarthritis (OA) donors and patients with OA were analysed. Mice were treated with neutralising antibody against CXCR7 to investigate the role of CXCR7 in arthritis. Results R3cKO mice but not control mice developed spontaneous cartilage destruction in multiple synovial joints at the age of 13 months. Moreover, the synovitis and macrophage accumulation were observed in the joints of 9-month-old R3cKO mice when the articular cartilage was not grossly destructed. FGFR3 deficiency in myeloid cells also aggravated joint destruction in DMM mouse model. Mechanically, FGFR3 deficiency promoted macrophage chemotaxis partly through activation of NF-κB/CXCR7 pathway. Inhibition of CXCR7 could significantly reverse FGFR3-deficiency-enhanced macrophage chemotaxis and the arthritic phenotype in R3cKO mice. Conclusions Our study identifies the role of FGFR3 in synovial macrophage recruitment and synovitis, which provides a new insight into the pathological mechanisms of inflammation-related arthritis.