News Release

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

Peer-Reviewed Publication

Compuscript Ltd

https://doi.org/10.1016/j.apsb.2023.09.013

This new article publication from Acta Pharmaceutica Sinica B, discusses how GRK2 inhibits Flt-1+ macrophage infiltration and its proangiogenic properties in rheumatoid arthritis.

 

Rheumatoid arthritis (RA) is an autoimmune disease with a complex etiology. Monocyte-derived macrophages (MDMs) infiltration are associated with RA severity. The authors of this article report 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. It was 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, it is anticipated 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.

 

Keywords: GRK2, Monocyte-derived macrophages, Rheumatoid arthritis, PPARγ, Flt-1

Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383523003660-ga1_lrg.jpg  

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.

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The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association.

For more information please visit https://www.journals.elsevier.com/acta-pharmaceutica-sinica-b/

Editorial Board: https://www.journals.elsevier.com/acta-pharmaceutica-sinica-b/editorial-board

 

APSB is available on ScienceDirect (https://www.sciencedirect.com/journal/acta-pharmaceutica-sinica-b).

 

Submissions to APSB may be made using Editorial Manager® (https://www.editorialmanager.com/apsb/default.aspx).

 

CiteScore: 19.4

Impact Factor: 14.5

JIF without self-citation: 13.7

ISSN 2211-3835

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Xuezhi Yang, Yingjie Zhao, Qi Wei, Xuemin Zhu, Luping Wang, Wankang Zhang, Xiaoyi Liu, Jiajie Kuai, Fengling Wang, Wei Wei, GRK2 inhibits Flt-1+ macrophage infiltration and its proangiogenic properties in rheumatoid arthritis, Acta Pharmaceutica Sinica B, Volume 14, Issue 1, 2024, Pages 241-255, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2023.09.013.


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