Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Center for Cardiovascular Research, Charité-Medical Faculty Berlin, Berlin, Germany.
Front Immunol. 2022 Jul 8;13:921488. doi: 10.3389/fimmu.2022.921488. eCollection 2022.
The angiotensin AT receptor (ATR) is a main receptor of the protective arm of the renin-angiotensin system and exerts for instance anti-inflammatory effects. The impact of ATR stimulation on autoimmune diseases such as rheumatoid arthritis (RA) is not yet known. We investigated the therapeutic potential of ATR-stimulation with the selective non-peptide ATR 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 CD4CD25FoxP3 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 CD4FoxP3 cells in Treg polarizing cultures compared to medium-treated controls, whereas the percentage of CD4IL-17A and CD4IFN-gamma T cells was suppressed. To conclude, C21 exerts beneficial effects on T cell-mediated experimental arthritis. We found that C21-induced ATR-stimulation promotes the expansion of CD4 regulatory T cells and suppresses IL-17A production. Thus, ATR-stimulation may represent an attractive treatment strategy for arthritis.
血管紧张素 AT 受体（ATR）是肾素-血管紧张素系统保护臂的主要受体，例如具有抗炎作用。ATR 刺激对类风湿关节炎（RA）等自身免疫性疾病的影响尚不清楚。我们研究了用选择性非肽 ATR 激动剂化合物 21（C21）刺激 ATR 在胶原诱导关节炎（CIA）中的治疗潜力，CIA 是一种炎症性关节炎的动物模型。通过用 II 型胶原（CII）免疫 DBA/1J 小鼠诱导关节炎。预防性和治疗性 C21 治疗可减轻 CIA 中关节炎的严重程度和发生率。关节组织学显示，C21 治疗的小鼠中 IL-1β和 IL-17A 表达细胞的浸润明显减少，关节软骨得到很好的保存。在 CIA 中，与载体相比，C21 治疗后 CD4CD25FoxP3 调节性 T（Treg）细胞的数量显著增加。T 细胞分化实验表明 FoxP3 mRNA 的表达增加，而 C21 处理后 IL-17A、STAT3 和 IFN-γ mRNA 的表达减少。与 mRNA 数据一致，与中处理对照相比，C21 在 Treg 极化培养物中上调 CD4FoxP3 细胞的百分比，而 CD4IL-17A 和 CD4IFN-γ T 细胞的百分比受到抑制。总之，C21 对 T 细胞介导的实验性关节炎具有有益作用。我们发现 C21 诱导的 ATR 刺激促进了 CD4 调节性 T 细胞的扩增，并抑制了 IL-17A 的产生。因此，ATR 刺激可能是关节炎的一种有吸引力的治疗策略。
