Rheumatoid arthritis (RA) is a debilitating autoimmune disease of unknown cause, characterized by infiltration and accumulation of activated immune cells in the synovial joints where cartilage and bone destructions occur. Myeloid-derived suppressor cells (MDSCs) are of myeloid origin and are able to suppress T cell responses. Src homology 2 domain containing inositol polyphosphate 5-phosphatase 1 (SHIP1) was shown to be involved in the regulation of MDSC differentiation. The purpose of the present study was to investigate the effect of inhibition of SHIP1 on expansion of MDSCs in RA using a collagen-induced inflammatory arthritis (CIA) mouse model. In DBA/1 mice treatment with a small molecule specific SHIP1 inhibitor 3α-aminocholestane (3AC) induced a marked expansion of MDSCs in vivo. Both pre-treatment with 3AC of DBA/1 mice prior to CIA induction and intervention with 3AC during CIA progression significantly reduced disease incidence and severity. Adoptive transfer of MDSCs isolated from 3AC-treated mice, but not naïve MDSCs from normal mice, into CIA mice significantly reduced disease incidence and severity, indicating that the 3AC-induced MDSCs were the cellular mediators of the observed amelioration of the disease. In conclusion, inhibition of SHIP1 expands MDSCs in vivo and attenuates development of CIA in mice. Small molecule specific inhibition of SHIP1 may therefore offer therapeutic benefit to patients with RA and other autoimmune diseases.

中文翻译：

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抑制脂质磷酸酶 SHIP1 可扩大骨髓来源的抑制细胞并减轻小鼠的类风湿性关节炎

类风湿性关节炎 (RA) 是一种原因不明的使人衰弱的自身免疫性疾病，其特征是活化的免疫细胞在发生软骨和骨破坏的滑膜关节中浸润和积累。骨髓来源的抑制细胞 (MDSC) 是骨髓来源的，能够抑制 T 细胞反应。含有肌醇多磷酸 5-磷酸酶 1 (SHIP1) 的 Src 同源 2 域显示参与 MDSC 分化的调节。本研究的目的是使用胶原诱导的炎症性关节炎 (CIA) 小鼠模型研究抑制 SHIP1 对 RA 中 MDSCs 扩增的影响。在 DBA/1 小鼠中，用小分子特异性 SHIP1 抑制剂 3α-氨基胆甾烷 (3AC) 治疗诱导了体内 MDSC 的显着扩增。在 CIA 诱导之前用 3AC 对 DBA/1 小鼠进行预处理和在 CIA 进展期间用 3AC 干预都显着降低了疾病的发病率和严重程度。将分离自 3AC 处理的小鼠的 MDSC（而非来自正常小鼠的幼稚 MDSC）过继转移到 CIA 小鼠中显着降低了疾病的发病率和严重程度，表明 3AC 诱导的 MDSC 是观察到的疾病改善的细胞介质。总之，抑制 SHIP1 可在体内扩展 MDSC，并减弱小鼠 CIA 的发展。因此，SHIP1 的小分子特异性抑制可能为患有 RA 和其他自身免疫性疾病的患者提供治疗益处。但不是来自正常小鼠的幼稚 MDSC，进入 CIA 小鼠显着降低了疾病的发病率和严重程度，表明 3AC 诱导的 MDSC 是观察到的疾病改善的细胞介质。总之，抑制 SHIP1 可在体内扩展 MDSC，并减弱小鼠 CIA 的发展。因此，SHIP1 的小分子特异性抑制可能为患有 RA 和其他自身免疫性疾病的患者提供治疗益处。但不是来自正常小鼠的幼稚 MDSC，进入 CIA 小鼠显着降低了疾病的发病率和严重程度，表明 3AC 诱导的 MDSC 是观察到的疾病改善的细胞介质。总之，抑制 SHIP1 可在体内扩展 MDSC，并减弱小鼠 CIA 的发展。因此，SHIP1 的小分子特异性抑制可能为患有 RA 和其他自身免疫性疾病的患者提供治疗益处。