Mechanism of lactic acidemia-promoted pulmonary endothelial cells death in sepsis: role for CIRP-ZBP1-PANoptosis pathway

细胞生物学 医学 败血症 泛素连接酶 程序性细胞死亡 内化 信号转导 受体 癌症研究 免疫学 生物 泛素 内科学 生物化学 细胞凋亡 基因
作者
Ting Gong,Qingde Wang,Patricia Loughran,Yuehua Li,Melanie J. Scott,Timothy R. Billiar,You-Tan Liu,Jie Fan
出处
期刊:Military Medical Research [BioMed Central]
卷期号:11 (1) 被引量:8
标识
DOI:10.1186/s40779-024-00574-z
摘要

Abstract 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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
独特乘云发布了新的文献求助10
1秒前
悦耳冷松发布了新的文献求助10
1秒前
1秒前
dian完成签到 ,获得积分10
2秒前
吃饱饱完成签到 ,获得积分10
2秒前
彭于晏应助大力绿柏采纳,获得10
3秒前
3秒前
ri_290完成签到 ,获得积分10
4秒前
贾克斯发布了新的文献求助10
4秒前
何处芳歇发布了新的文献求助10
4秒前
小当家完成签到,获得积分10
4秒前
nightmare发布了新的文献求助10
5秒前
Ava应助独特乘云采纳,获得10
7秒前
义气黄焖排骨完成签到,获得积分10
7秒前
古藤完成签到 ,获得积分10
8秒前
shinian完成签到 ,获得积分10
8秒前
JamesPei应助nightmare采纳,获得10
9秒前
10秒前
11秒前
十年完成签到 ,获得积分10
12秒前
wwl发布了新的文献求助10
14秒前
15秒前
默默千亦完成签到 ,获得积分10
15秒前
贾克斯发布了新的文献求助10
16秒前
撸撸大仙完成签到,获得积分20
17秒前
打我呀发布了新的文献求助10
17秒前
18秒前
Jasper应助体贴的之卉采纳,获得10
19秒前
20秒前
20秒前
21秒前
ScholarZmm完成签到,获得积分10
22秒前
23秒前
24秒前
hzx发布了新的文献求助10
24秒前
24秒前
26秒前
saisyo发布了新的文献求助10
26秒前
26秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3989406
求助须知:如何正确求助?哪些是违规求助? 3531522
关于积分的说明 11254187
捐赠科研通 3270174
什么是DOI,文献DOI怎么找? 1804901
邀请新用户注册赠送积分活动 882105
科研通“疑难数据库(出版商)”最低求助积分说明 809174