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

作　　者：Xuezhi Yang Yingjie Zhao Qi Wei Xuemin Zhu Luping Wang Wankang Zhang Xiaoyi Liu Jiajie Kuai Fengling Wang Wei Wei 

机构地区：[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

出　　处：《Acta Pharmaceutica Sinica B》2024年第1期241-255,共15页药学学报（英文版）

基　　金：We thank LetPub(www.letpub.com)for its linguistic assistance during the preparation of this manuscript.We thank all the patients who participated in providing us with synovial tissues and blood samples.Graphical abstract was created with BioRender.com(publication and licensing rights number JZ25ROGTF8);This study was supported by the National Natural Science Foundation of China(No.82003763,No.81973332,No.82173824,No.82204405,No.82204402);Research Fund of Anhui Institute of translational medicine(2022zhyx-B04,China);The 2022 Basic and Clinical Collaborative Research of Anhui Medical University(2022sfy015,China);Natural Science Foundation of Anhui Provincial(2108085QH383,China).

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 GRK2^(f/f)Lyz2-Cre^(+/−)mice.Synovial inflammation and M1 polarization were improved in GRK2^(f/f)Lyz2-Cre^(+/−)mice.Supporting experiments with RNA-seq and dual-luciferase reporter assays identified peroxisome proliferator-activated receptorγ(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-PPARγsignaling.Mechanistically,excess GRK2 membrane recruitment in CIA MDMs reduced the activation of PPARγligand-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.

关 键 词：GRK2 Monocyte-derived macrophages Rheumatoid arthritis PPARG FLT-1 

分 类 号：R965[医药卫生—药理学]