AUTHOR=Sehnert Bettina , Valero-Esquitino Veronica , Schett Georg , Unger Thomas , Steckelings Ulrike Muscha , Voll Reinhard Edmund 

TITLE=Angiotensin AT2 Receptor Stimulation Alleviates Collagen-Induced Arthritis by Upregulation of Regulatory T Cell Numbers

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.921488

DOI=10.3389/fimmu.2022.921488

ISSN=1664-3224

ABSTRACT=<p>The angiotensin AT<sub>2</sub> receptor (AT<sub>2</sub>R) is a main receptor of the protective arm of the renin-angiotensin system and exerts for instance anti-inflammatory effects. The impact of AT<sub>2</sub>R stimulation on autoimmune diseases such as rheumatoid arthritis (RA) is not yet known. We investigated the therapeutic potential of AT<sub>2</sub>R-stimulation with the selective non-peptide AT<sub>2</sub>R agonist Compound 21 (C21) in collagen-induced arthritis (CIA), an animal model for inflammatory arthritis. Arthritis was induced by immunization of DBA/1J mice with collagen type II (CII). Prophylactic and therapeutic C21 treatment alleviates arthritis severity and incidence in CIA. Joint histology revealed significantly less infiltrates of IL-1 beta and IL-17A expressing cells and a well-preserved articular cartilage in C21- treated mice. In CIA, the number of CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup> regulatory T (Treg) cells significantly increased upon C21 treatment compared to vehicle. T cell differentiation experiments demonstrated increased expression of FoxP3 mRNA, whereas IL-17A, STAT3 and IFN-gamma mRNA expression were reduced upon C21 treatment. In accordance with the mRNA data, C21 upregulated the percentage of CD4<sup>+</sup>FoxP3<sup>+</sup> cells in Treg polarizing cultures compared to medium-treated controls, whereas the percentage of CD4<sup>+</sup>IL-17A<sup>+</sup> and CD4<sup>+</sup>IFN-gamma<sup>+</sup> T cells was suppressed. To conclude, C21 exerts beneficial effects on T cell-mediated experimental arthritis. We found that C21-induced AT<sub>2</sub>R-stimulation promotes the expansion of CD4<sup>+</sup> regulatory T cells and suppresses IL-17A production. Thus, AT<sub>2</sub>R-stimulation may represent an attractive treatment strategy for arthritis.</p>