脓毒症中乳酸血症促进肺内皮细胞死亡的机制:CIRP-ZBP1-PAN凋亡途径的作用

IF 16.7 2区 医学 Q1 MEDICINE, GENERAL & INTERNAL Military Medical Research Pub Date : 2024-10-28 DOI:10.1186/s40779-024-00574-z
Ting Gong, Qing-De Wang, Patricia A Loughran, Yue-Hua Li, Melanie J Scott, Timothy R Billiar, You-Tan Liu, Jie Fan
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引用次数: 0

摘要

背景:脓毒症通常伴有乳酸血症和急性肺损伤(ALI)。临床研究证实,高血清乳酸水平与脓毒症患者死亡率的增加有关。我们进一步观察到,血浆和支气管肺泡灌洗液(BALF)中冷诱导 RNA 结合蛋白(CIRP)的水平以及乳酸水平与败血症后 ALI 的严重程度之间存在明显的相关性。然而,其潜在机制仍难以捉摸:方法:对 C57BL/6 野生型(WT)、Casp8-/-、Ripk3-/- 和 Zbp1-/- 小鼠进行盲肠结扎和穿刺(CLP)败血症模型试验。在该模型中,我们测量了巨噬细胞内 CIRP 乳化及随后的 CIRP 释放。我们还追踪了肺血管内皮细胞(PVECs)细胞外 CIRP(eCIRP)的内化及其与 Z-DNA 结合蛋白 1(ZBP1)的相互作用。此外,我们还监测了肺血管内皮细胞中 ZBP1 水平的变化以及随之激活的细胞死亡途径:在当前的研究中,我们证明脓毒症期间积累的乳酸可促进巨噬细胞中 CIRP 的乳化,从而导致 CIRP 的释放。一旦 eCIRP 通过 Toll 样受体 4(TLR4)介导的内吞途径被 PVEC 内化,它就会竞争性地与 ZBP1 结合,并有效地阻断 ZBP1 与包含三方基序 32(TRIM32)的 E3 泛素连接酶之间的相互作用,TRIM32 是一种靶向 ZBP1 进行蛋白酶体降解的 E3 泛素连接酶。这种干扰机制稳定了 ZBP1,从而增强了 ZBP1-受体相互作用蛋白激酶 3(RIPK3)依赖的 PVEC PANoptosis(一种涉及同时激活多种细胞死亡途径的细胞死亡形式),从而加剧了 ALI:这些发现揭示了一种新的途径,即乳酸血症促进巨噬细胞衍生的 eCIRP 释放,进而在败血症诱导的 ALI 中介导 ZBP1 依赖性 PVEC PAN 细胞凋亡。这一发现为脓毒症相关肺部并发症的分子机制提供了新的见解,并提供了潜在的新治疗策略。
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Mechanism of lactic acidemia-promoted pulmonary endothelial cells death in sepsis: role for CIRP-ZBP1-PANoptosis pathway.

Background: Sepsis is often accompanied by lactic acidemia and acute lung injury (ALI). Clinical studies have established that high serum lactate levels are associated with increased mortality rates in septic patients. We further observed a significant correlation between the levels of cold-inducible RNA-binding protein (CIRP) in plasma and bronchoalveolar lavage fluid (BALF), as well as lactate levels, and the severity of post-sepsis ALI. The underlying mechanism, however, remains elusive.

Methods: C57BL/6 wild type (WT), Casp8-/-, Ripk3-/-, and Zbp1-/- mice were subjected to the cecal ligation and puncture (CLP) sepsis model. In this model, we measured intra-macrophage CIRP lactylation and the subsequent release of CIRP. We also tracked the internalization of extracellular CIRP (eCIRP) in pulmonary vascular endothelial cells (PVECs) and its interaction with Z-DNA binding protein 1 (ZBP1). Furthermore, we monitored changes in ZBP1 levels in PVECs and the consequent activation of cell death pathways.

Results: In the current study, we demonstrate that lactate, accumulating during sepsis, promotes the lactylation of CIRP in macrophages, leading to the release of CIRP. Once eCIRP is internalized by PVEC through a Toll-like receptor 4 (TLR4)-mediated endocytosis pathway, it competitively binds to ZBP1 and effectively blocks the interaction between ZBP1 and tripartite motif containing 32 (TRIM32), an E3 ubiquitin ligase targeting ZBP1 for proteasomal degradation. This interference mechanism stabilizes ZBP1, thereby enhancing ZBP1-receptor-interacting protein kinase 3 (RIPK3)-dependent PVEC PANoptosis, a form of cell death involving the simultaneous activation of multiple cell death pathways, thereby exacerbating ALI.

Conclusions: These findings unveil a novel pathway by which lactic acidemia promotes macrophage-derived eCIRP release, which, in turn, mediates ZBP1-dependent PVEC PANoptosis in sepsis-induced ALI. This finding offers new insights into the molecular mechanisms driving sepsis-related pulmonary complications and provides potential new therapeutic strategies.

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来源期刊
Military Medical Research
Military Medical Research Medicine-General Medicine
CiteScore
38.40
自引率
2.80%
发文量
485
审稿时长
8 weeks
期刊介绍: Military Medical Research is an open-access, peer-reviewed journal that aims to share the most up-to-date evidence and innovative discoveries in a wide range of fields, including basic and clinical sciences, translational research, precision medicine, emerging interdisciplinary subjects, and advanced technologies. Our primary focus is on modern military medicine; however, we also encourage submissions from other related areas. This includes, but is not limited to, basic medical research with the potential for translation into practice, as well as clinical research that could impact medical care both in times of warfare and during peacetime military operations.
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