RIPK1 抑制通过抑制破骨细胞生成来减轻实验性自身免疫性关节炎。

RIPK1 inhibition attenuates experimental autoimmune arthritis via suppression of osteoclastogenesis.

机构信息

The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.

Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.

出版信息

J Transl Med. 2019 Mar 15;17(1):84. doi: 10.1186/s12967-019-1809-3.

BACKGROUND

Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disease characterized by upregulation of inflammatory cell death and osteoclastogenesis. Necrostatin (NST)-1s is a chemical inhibitor of receptor-interacting serine/threonine-protein kinase (RIPK)1, which plays a role in necroptosis.

METHODS

We investigated whether NST-1s decreases inflammatory cell death and inflammatory responses in a mouse model of collagen-induced arthritis (CIA).

RESULTS

NST-1s decreased the progression of CIA and the synovial expression of proinflammatory cytokines. Moreover, NST-1s treatment decreased the expression of necroptosis mediators such as RIPK1, RIPK3, and mixed lineage kinase domain-like (MLKL). In addition, NST-1s decreased osteoclastogenesis in vitro and in vivo. NST-1s downregulated T helper (Th)1 and Th17 cell expression, but promoted Th2 and regulatory T (Treg) cell expression in CIA mice.

CONCLUSIONS

These results suggest that NST-1s attenuates CIA progression via the inhibition of osteoclastogenesis and might be a potential therapeutic agent for RA therapy.

背景

类风湿性关节炎（RA）是一种慢性全身性炎症性疾病，其特征是炎症细胞死亡和破骨细胞生成的上调。Necrostatin-1s（NST-1s）是受体相互作用丝氨酸/苏氨酸蛋白激酶（RIPK）1 的化学抑制剂，在细胞程序性坏死中发挥作用。

方法

我们研究了 NST-1s 是否可以减少胶原诱导性关节炎（CIA）小鼠模型中的炎症细胞死亡和炎症反应。

结果

NST-1s 可降低 CIA 的进展和滑膜中促炎细胞因子的表达。此外，NST-1s 治疗可降低程序性坏死介质如 RIPK1、RIPK3 和混合谱系激酶结构域样（MLKL）的表达。此外，NST-1s 可减少体外和体内的破骨细胞生成。NST-1s 下调 CIA 小鼠中的辅助性 T（Th）1 和 Th17 细胞表达，但促进 Th2 和调节性 T（Treg）细胞表达。