Angiotensin II Type 2 Receptor Modulates Synovial Macrophage Polarization by Inhibiting GRK2 Membrane Translocation in a Rat Model of Collagen-Induced Arthritis

• Published in: The Journal of immunology (1950) 2020-12, Vol.205 (11), p.3141-3153
• Main Authors: Wang, Xinming, Tu, Jiajie, Jiang, Ji, Zhang, Qiaolin, Liu, Qi, Körner, Heinrich, Wu, Jingjing, Wu, Huaxun, Wei, Wei
• Format: Article
• Language: English
• Subjects: Animals; Arthritis, Experimental - chemically induced; Arthritis, Experimental - metabolism; Arthritis, Rheumatoid - chemically induced; Arthritis, Rheumatoid - metabolism; Collagen - pharmacology; Disease Models, Animal; Female; G-Protein-Coupled Receptor Kinase 2 - metabolism; Humans; Inflammation - chemically induced; Inflammation - metabolism; Macrophages - drug effects; Macrophages - metabolism; Mice; Protein Transport - physiology; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 2 - metabolism; Signal Transduction - physiology; Synovial Membrane - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2000561

The chronic inflammatory autoimmune disease rheumatoid arthritis (RA) is characterized by an infiltration of activated proinflammatory immune cells into the joint that is accompanied by an overproduction of various mediators, leading to destruction of cartilage and bone erosion. Angiotensin II type 2 receptor (AT2R) is involved in antioxidative, anti-inflammatory, and antifibrotic responses. Synovial macrophages (SMs) are a type of tissue macrophages that are derived from bone marrow cells. SMs plays a central role in synovial regional immunization, which is significantly increased in both collagen-induced mice with arthritis mice and RA patients. AT2R activation caused a reversal of the polarization of SMs in the joint from the proinflammatory M1 SM to the tolerogenic, benign M2 SM. In consequence, this switch resulted in an attenuated form of the joint pathology in a rat model of collagen-induced arthritis. These results were mechanistically linked to the observation that GRK2 was translocated into cytoplasm, and ERK1/2 and NF-κB activation were inhibited. These findings open the way to a new therapeutic approach using an activation of AT2R to subvert joint inflammation in RA.