Neutrophil extracellular trap-derived double-stranded RNA aggravates PANoptosis in renal ischemia reperfusion injury.

IF 11.6 2区生物学 Q1 CELL BIOLOGY Cell Communication and Signaling Pub Date : 2025-03-17 DOI:10.1186/s12964-025-02145-8

Shaoyong Zhuang, Fangzhou Li, Liya Wang, Zilong Lai, Dawei Li, Haoyu Wu, Jiajin Wu, Junwen Qu, Xianyun Zhang, Ming Zhang, Ruoyang Chen, Xiaodong Yuan

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Abstract

A dysregulated inflammatory response and inflammation-associated cell death are central features of renal ischemia-reperfusion injury (IRI). PANoptosis, is a recently recognized form of inflammatory programmed cell death characterized by key features of pyroptosis, apoptosis and necroptosis; however, the specific involvement of PANoptosis in renal IRI remains unknown. By using neutrophil extracellular trap (NETs)-depleted Pad4^-/- mice, we found that NETs are essential for exacerbating tissue injury in renal IRI. Single-cell RNA sequencing (scRNA-seq) revealed that IRI promoted PANoptosis signalling in proximal tubular epithelial cells (PTs), whereas PAD4 knockout inhibited PANoptosis signalling. PTs expressed mainly RIPK1-PANoptosomes, which executed NET-induced PANoptosis in PTs in renal IRI model mice. Mechanistically, NET-derived double-stranded RNA (dsRNA) promoted PANoptosis in PTs, and PT-expressed TLR3 was responsible for the sensing the extracellular dsRNA. Treating mice with chemical inhibitors of the dsRNA/TLR3 complex suppressed PANoptosis and alleviated tissue injury in renal IRI. Together, the results of this study reveal a mechanism by which the NET-dsRNA-TLR3 axis aggravates PT cell PANoptosis in renal IRI.

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中性粒细胞胞外陷阱衍生的双链RNA加重肾缺血再灌注损伤的PANoptosis。

炎症反应失调和炎症相关细胞死亡是肾缺血再灌注损伤（IRI）的中心特征。PANoptosis是最近发现的一种炎症性程序性细胞死亡形式，其主要特征是焦亡、凋亡和坏死亡；然而，PANoptosis在肾IRI中的具体作用尚不清楚。通过使用中性粒细胞胞外陷阱(NETs)-缺失的Pad4-/-小鼠，我们发现NETs在肾IRI中加重组织损伤是必不可少的。单细胞RNA测序（scRNA-seq）显示，IRI促进近端小管上皮细胞（PTs）的PANoptosis信号传导，而PAD4敲除抑制PANoptosis信号传导。肾IRI模型小鼠PTs主要表达RIPK1-PANoptosomes， RIPK1-PANoptosomes在肾IRI模型小鼠中导致net诱导的PANoptosis。在机制上，net衍生的双链RNA （dsRNA）促进了PTs的PANoptosis，而pt表达的TLR3负责感知细胞外dsRNA。用dsRNA/TLR3复合物的化学抑制剂治疗小鼠可抑制PANoptosis并减轻肾IRI中的组织损伤。总之，本研究的结果揭示了NET-dsRNA-TLR3轴加重肾IRI中PT细胞PANoptosis的机制。

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来源期刊

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

期刊介绍： Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.