GRK2 inhibits Flt-1+ macrophage infiltration and its proangiogenic properties in rheumatoid arthritis.
10.1016/j.apsb.2023.09.013
- Author:
Xuezhi YANG
1
;
Yingjie ZHAO
2
;
Qi WEI
1
;
Xuemin ZHU
1
;
Luping WANG
1
;
Wankang ZHANG
1
;
Xiaoyi LIU
1
;
Jiajie KUAI
1
;
Fengling WANG
1
;
Wei WEI
1
Author Information
1. Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
2. Department of Clinical Pharmacology, the Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
- Publication Type:Journal Article
- Keywords:
Flt-1;
GRK2;
Monocyte-derived macrophages;
PPARγ;
Rheumatoid arthritis
- From:
Acta Pharmaceutica Sinica B
2024;14(1):241-255
- CountryChina
- Language:English
-
Abstract:
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.
