Wang Yuxuan, Yuan Min, Qin Jingxue, Chen Xue, Lei Zihan, Kong Qian, Wang Qian, Song Xuemin, Wu Xiaojing
Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
Inflammation. 2025 Apr 29. doi: 10.1007/s10753-025-02288-3.
Sepsis-induced acute lung injury (ALI) is a life-threatening condition with high mortality rates, and its underlying mechanisms remain poorly understood. This study investigates the role of TNF-α-induced protein 8-like 2 (TIPE2) in modulating PANoptosis, an integrated form of programmed cell death that includes apoptosis, necroptosis, and pyroptosis, in the context of sepsis-induced lung injury. We utilized a cecal ligation and puncture (CLP) mouse model to examine the effects of TIPE2 knockout and overexpression on lung injury, inflammation, and cell death pathways. Our findings demonstrate that TIPE2 knockout exacerbates lung injury by promoting the abnormal activation of PANoptosis-related proteins, leading to increased inflammation and tissue damage. In contrast, overexpression of TIPE2 in macrophages significantly reduces these effects by inhibiting the ZBP1-dependent PANoptosis pathway via TRIF signaling. These results highlight the crucial role of TIPE2 in maintaining the balance between cell survival and death during sepsis and suggest that targeting TIPE2 could be a novel therapeutic strategy for treating sepsis-related lung injury.
脓毒症诱导的急性肺损伤（ALI）是一种危及生命的疾病，死亡率很高，其潜在机制仍知之甚少。本研究探讨了肿瘤坏死因子-α诱导蛋白8样2（TIPE2）在脓毒症诱导的肺损伤中调节PANoptosis（一种程序性细胞死亡的整合形式，包括凋亡、坏死性凋亡和焦亡）的作用。我们利用盲肠结扎和穿刺（CLP）小鼠模型来研究TIPE2基因敲除和过表达对肺损伤、炎症和细胞死亡途径的影响。我们的研究结果表明，TIPE2基因敲除通过促进PANoptosis相关蛋白的异常激活加重肺损伤，导致炎症和组织损伤增加。相反，巨噬细胞中TIPE2的过表达通过TRIF信号抑制ZBP1依赖性PANoptosis途径，显著降低了这些影响。这些结果突出了TIPE2在脓毒症期间维持细胞存活和死亡平衡中的关键作用，并表明靶向TIPE2可能是治疗脓毒症相关肺损伤的一种新的治疗策略。
