PDF(Pubmed)
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.
摘要：
类风湿性关节炎(RA)是一种病因复杂的自身免疫性疾病。单核细胞衍生的巨噬细胞(MDMs)浸润与RA严重程度相关。我们已经报道了G蛋白偶联受体激酶2（GRK2）的缺失通过恢复G蛋白偶联受体信号传导将巨噬细胞重新编程为抗炎表型。然而,随着越来越多的GRK2相互作用蛋白被发现，RA中GRK2相互作用的机制尚未得到充分研究.因此，在胶原诱导的关节炎小鼠模型中，我们使用GRK2f/fLyz2-Cre+/-小鼠进行遗传GRK2缺失。GRK2f/fLyz2-Cre+/-小鼠滑膜炎症和M1极化得到改善。支持RNA-seq和双荧光素酶报告基因测定的实验将过氧化物酶体增殖物激活受体γ（PPARγ）鉴定为新的GRK2相互作用蛋白。我们进一步证实了fms相关酪氨酸激酶1（Flt-1），促进巨噬细胞迁移以诱导血管生成，被GRK2-PPARγ信号抑制。机械上,CIAMDM中过量的GRK2膜募集减少了PPARγ配体结合域的激活并增强了Flt-1转录。此外，用GRK2活性抑制剂治疗小鼠导致CIA病理显著减少，Flt-1+巨噬细胞诱导的滑膜炎症，和血管生成。总之,我们预计将有助于阐明之前未被理解的GRK2特异性细胞内信号传导的细节。靶向GRK2活性是抑制MDMs浸润的可行策略，提供了一种独特的方法来控制RA的关节炎症和血管生成。
