Abstract
Rheumatoid arthritis (RA) is characterized by the massive infiltration of various chronic inflammatory cells in synovia. In synovial fluid of patients with RA, M1 macrophages are dominant among all subtypes of macrophages, the mechanisms of macrophages polarization imbalance in RA has not been fully illuminated. The prostaglandin E2 (PGE2) augments M2 polarization in part via the cyclic adenosine monophosphate (cAMP)-cyclic AMP responsive element binding (CREB) signaling. However, previous study found constant stimulus of PGE2 on fibroblast-like synovial cells of adjuvant arthritis rats induced the decrease of cAMP, which is primarily caused by G protein-coupled receptor kinase 2 (GRK2)-induced EP4 over- desensitization. Whether GRK2 mediated-EP4 over-desensitization reduces the level of cAMP and inhibits M2 polarization in RA is unclear. Here we observed M1 macrophages were dominant in peritoneal macrophages (PMs), bone-marrow-derived macrophages (BMMs) and synovial macrophages of collagen-induced arthritis (CIA) mice. PGE2 stimulated M2 polarization via the EP4-cAMP-CREB in normal mice, while failed to promote M2 polarization in the PMs of CIA mice. Further, we found the EP4 over-desensitization stimulated by PGE2 induced abnormal PGE2-cAMP-CREB signaling as well as the imbalance of macrophage polarization. Targeted disruption of GRK2 in Raw264.7 (RAW) through GRK2 siRNA or CRISPR/Cas9 downregulated the M1 macrophage markers, upregulated the M2 macrophage markers and the EP4 membrane localization. The reduced M1/M2 ratio and increased p-CREB expression were observed in BMMs and PMs of GRK2+/− mice. This study highlighted a novel role of GRK2 in regulating macrophages function in RA and provided new idea for precision treatment of RA.
Highlights
Rheumatoid arthritis (RA) is a systemic autoimmune disease, with major pathological features including synovitis and cartilage destruction [1,2,3,4]
We established collagen-induced arthritis (CIA) mice model and the polyarthritis index significantly increased after modeling, and reached peak at d41 (Figure 1A)
We have demonstrated that the increase of G protein-coupled receptor kinase 2 (GRK2) transferring to membrane induced the over-desensitization of EP4, as well as the abnormal transduction of prostaglandin E2 (PGE2)-EP4-cyclic adenosine monophosphate (cAMP) in fibroblast-like synovial cell (FLS) of adjuvant induced arthritis (AA) rats [15]
Summary
Rheumatoid arthritis (RA) is a systemic autoimmune disease, with major pathological features including synovitis and cartilage destruction [1,2,3,4]. According to the phenotype and function, macrophages are mainly divided into M1 macrophages (as proinflammatory) and M2 macrophages (as anti-inflammatory). The phenotypes of these macrophages keep dynamic balance and maintain homeostasis. In RA patients and animal models of arthritis, multiple factors bring the predominant position to M1 macrophages in peritoneal blood, peritoneal fluid and synovium [5]. M1 macrophages in turn aggravate inflammation by producing inflammatory factors which activate fibroblast-like synovial cell (FLS) proliferation and Th17 polarization [6]. The mechanisms of polarization imbalance of macrophages in RA have not been elucidated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
