GRK2 inhibits Flt-1+ macrophage infiltration and its proangiogenic properties in rheumatoid arthritis

炎症 癌症研究 细胞生物学 类风湿性关节炎 MAPK/ERK通路 血管生成 激酶 盘状结构域 巨噬细胞极化 β肾上腺素能受体激酶 关节炎 化学 信号转导 生物 免疫学 受体酪氨酸激酶 巨噬细胞 G蛋白偶联受体 生物化学 体外
作者
Xuezhi Yang,Yingjie Zhao,Wei Qi,Xuemin Zhu,Luping Wang,Wankang Zhang,Xiaoyi Liu,Jiajie Kuai,Fengling Wang,Wei Wei
出处
期刊:Acta Pharmaceutica Sinica B [Elsevier]
卷期号:14 (1): 241-255 被引量:4
标识
DOI:10.1016/j.apsb.2023.09.013
摘要

Rheumatoid arthritis (RA) is an autoimmune disease with a complex etiology. Monocyte-derived macrophages (MDMs) infiltration are associated with RA severity. We have reported the deletion of G-protein-coupled receptor kinase 2 (GRK2) reprograms macrophages toward an anti-inflammatory phenotype by recovering G-protein-coupled receptor signaling. However, as more GRK2-interacting proteins were discovered, the GRK2 interactome mechanisms in RA have been understudied. Thus, in the collagen-induced arthritis mouse model, we performed genetic GRK2 deletion using GRK2f/fLyz2-Cre+/‒ mice. Synovial inflammation and M1 polarization were improved in GRK2f/fLyz2-Cre+/‒ mice. Supporting experiments with RNA-seq and dual-luciferase reporter assays identified peroxisome proliferator-activated receptor γ (PPARγ) as a new GRK2-interacting protein. We further confirmed that fms-related tyrosine kinase 1 (Flt-1), which promoted macrophage migration to induce angiogenesis, was inhibited by GRK2-PPARγ signaling. Mechanistically, excess GRK2 membrane recruitment in CIA MDMs reduced the activation of PPARγ ligand-binding domain and enhanced Flt-1 transcription. Furthermore, the treatment of mice with GRK2 activity inhibitor resulted in significantly diminished CIA pathology, Flt-1+ macrophages induced-synovial inflammation, and angiogenesis. Altogether, we anticipate to facilitate the elucidation of previously unappreciated details of GRK2-specific intracellular signaling. Targeting GRK2 activity is a viable strategy to inhibit MDMs infiltration, affording a distinct way to control joint inflammation and angiogenesis of RA.
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