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

• Published in: Acta pharmaceutica Sinica. B 2024-01, Vol.14 (1), p.241-255
• Main Authors: Yang, Xuezhi, Zhao, Yingjie, Wei, Qi, Zhu, Xuemin, Wang, Luping, Zhang, Wankang, Liu, Xiaoyi, Kuai, Jiajie, Wang, Fengling, Wei, Wei
• Format: Article
• Language: English
• Subjects: Flt-1; GRK2; Monocyte-derived macrophages; Original; PPARγ; Rheumatoid arthritis
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2023.09.013

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. The recruitment of GRK2 to the membrane inhibits PPARγ-Tyr473 activation, consequently leading to synovial Flt-1+ macrophages infiltration, ultimately aggravating synovial inflammation and angiogenesis in rheumatoid arthritis. [Display omitted]