Xiao Jianqiu, Sun Kai, Wang Chun, Abu-Amer Yousef, Mbalaviele Gabriel
Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
J Transl Autoimmun. 2022 Aug 30;5:100162. doi: 10.1016/j.jtauto.2022.100162. eCollection 2022.
Gasdermin D (GSDMD) and gasdermin E (GSDME) perpetuate inflammation by mediating the release of cytokines such as interleukin-1β (IL-1β) and IL-18. However, not only are the actions of GSDMD in colitis still controversial, but its interplay with GSDME in the pathogenesis of this disease has not been investigated. We sought to fill these knowledge gaps using the dextran sodium sulfate (DSS) experimental mouse colitis model. DSS ingestion by wild-type mice caused body weight loss as the result of severe gut inflammation, outcomes that were significantly attenuated in or mice and nearly fully prevented in ; animals. To assess the translational implications of these findings, we tested the efficacy of the active metabolite of US Food and Drug Administration (FDA)-approved disulfiram, which inhibits GSDMD and GSDME function. The severe DSS-induced gut toxicity was significantly decreased in mice treated with the inhibitor. Collectively, our findings indicate that disruption of the function of both GSDMD and GSDME is necessary to achieve maximal therapeutic effect in colitis.
Gasdermin D（GSDMD）和Gasdermin E（GSDME）通过介导白细胞介素-1β（IL-1β）和IL-18等细胞因子的释放来维持炎症。然而，GSDMD在结肠炎中的作用不仅仍存在争议，而且其在该疾病发病机制中与GSDME的相互作用尚未得到研究。我们试图利用葡聚糖硫酸钠（DSS）实验性小鼠结肠炎模型来填补这些知识空白。野生型小鼠摄入DSS会因严重的肠道炎症而导致体重减轻，在 或 小鼠中这些结果显著减轻，而在 动物中几乎完全得到预防。为了评估这些发现的转化意义，我们测试了美国食品药品监督管理局（FDA）批准的双硫仑的活性代谢产物的疗效，该产物可抑制GSDMD和GSDME的功能。在用该抑制剂治疗的小鼠中，严重的DSS诱导的肠道毒性显著降低。总体而言，我们的研究结果表明，破坏GSDMD和GSDME的功能对于在结肠炎中实现最大治疗效果是必要的。
