首页|GRK2 inhibits Flt-1+macrophage infiltration and its proangiogenic properties in rheumatoid arthritis
GRK2 inhibits Flt-1+macrophage infiltration and its proangiogenic properties in rheumatoid arthritis
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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 dele-tion 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 un-derstudied.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 migra-tion 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 re-sulted 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.
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
Department of Clinical Pharmacology,the Second Affiliated Hospital of Anhui Medical University,Hefei 230601,China
国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金Research Fund of Anhui Institute of translational medicine2022 Basic and Clinical Collaborative Research of Anhui Medical University(2022)Natural Science Foundation of Anhui Provincial
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