Splenic SUMO1 controls systemic inflammation in experimental sepsis.
Splenic SUMO1 controls systemic inflammation in experimental sepsis.
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DOI：
10.3389/fimmu.2023.1200939
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
最近发现的 TAK981（Subasumstat）是一流的 SUMOylation 选择性抑制剂，使新的免疫治疗成为可能。 TAK981 已进入临床试验，以增强转移性肿瘤和血液恶性肿瘤的免疫治疗。癌症患者的感染风险高出十倍以上，但 TAK981 在脓毒症中的作用尚不清楚，而且之前关于 SUMO 在感染中的研究是相互矛盾的。我们在两个脓毒症模型中使用了 TAK981；多种微生物腹膜炎（CLP）和LPS内毒素血症。在两种模型中均进行了脾切除术以研究脾脏的作用。对脾裂解物中的 SUMO 结合蛋白进行蛋白质印迹分析。采用全局 SUMO1 和 SUMO3 敲除小鼠来研究 SUMO 对 LPS 内毒素血症炎症的特异性调节。将 SUMO 敲除小鼠的脾细胞过继转移至野生型小鼠，以研究脾脏 SUMO 化在实验性脓毒症中的作用。在这里，我们报告用 TAK981 抑制 SUMOylation 通过增强先天免疫反应和腹膜细菌清除来改善轻度多种微生物腹膜炎的存活率。因此，我们重点研究了 TAK981 对细菌内毒素免疫反应的影响，结果表明 TAK981 增强了早期 TNFα 的产生，但不影响炎症的消退。脾切除术使血清 TNFα 水平降低近 60%，并降低 TAK981 诱导的 TNFα 反应。在脾脏中，内毒素血症诱导 SUMO1 和 SUMO2/3 具有明显的时间和底物特异性，并且两者均被 TAK981 抑制。 SUMO1（而非 SUMO3）的整体基因缺失增强了 TNFα 的产生和代谢性酸中毒。将 SUMO1 缺失（而非野生型）的脾细胞转移到脾脏切除的野生型小鼠中，会加剧内毒素血症中 TNFα 的产生和代谢性酸中毒。这些结果表明脾 SUMO1 的特异性调节可以调节对细菌感染的免疫和代谢反应。
The recent discovery of TAK981(Subasumstat), the first-in-class selective inhibitor of SUMOylation, enables new immune treatments. TAK981 is already in clinical trials to potentiate immunotherapy in metastatic tumors and hematologic malignancies. Cancer patients have more than ten times higher risk of infections, but the effects of TAK981 in sepsis are unknown and previous studies on SUMO in infections are conflicting. We used TAK981 in two sepsis models; polymicrobial peritonitis (CLP) and LPS endotoxemia. Splenectomy was done in both models to study the role of spleen. Western blotting of SUMO-conjugated proteins in spleen lysates was done. Global SUMO1 and SUMO3 knockout mice were used to study the specific SUMO regulation of inflammation in LPS endotoxemia. Splenocytes adoptive transfer was done from SUMO knockouts to wild type mice to study the role of spleen SUMOylation in experimental sepsis. Here, we report that inhibition of SUMOylation with TAK981 improved survival in mild polymicrobial peritonitis by enhancing innate immune responses and peritoneal bacterial clearance. Thus, we focused on the effects of TAK981 on the immune responses to bacterial endotoxin, showing that TAK981 enhanced early TNFα production but did not affect the resolution of inflammation. Splenectomy decreased serum TNFα levels by nearly 60% and TAK981-induced TNFα responses. In the spleen, endotoxemia induced a distinct temporal and substrate specificity for SUMO1 and SUMO2/3, and both were inhibited by TAK981. Global genetic depletion of SUMO1, but not SUMO3, enhanced TNFα production and metabolic acidosis. The transfer of SUMO1-null, but not wild-type, splenocytes into splenectomized wild-type mice exacerbated TNFα production and metabolic acidosis in endotoxemia. These results suggest that specific regulation of splenic SUMO1 can modulate immune and metabolic responses to bacterial infection.
影响因子：
3.7
作者：
Aillet F;Lopitz-Otsoa F;Egaña I;Hjerpe R;Fraser P;Hay RT;Rodriguez MS;Lang V
通讯作者：
Lang V
影响因子：
5
作者：
Heaton, Phillip R.;Deyrieux, Adeline F.;Bian, Xue-Lin;Wilson, Van G.
通讯作者：
Wilson, Van G.