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中性粒细胞胞外诱捕网衍生的双链RNA加重肾缺血再灌注损伤中的PAN细胞焦亡

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

作者信息

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

机构信息

Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China.

Department of Urology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, 201800, China.

出版信息

Cell Commun Signal. 2025 Mar 17;23(1):140. doi: 10.1186/s12964-025-02145-8.

DOI:10.1186/s12964-025-02145-8
PMID:40098148
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11912734/
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.

摘要

炎症反应失调和炎症相关的细胞死亡是肾缺血再灌注损伤（IRI）的核心特征。PANoptosis是一种最近被认识的炎症程序性细胞死亡形式，其特征为焦亡、凋亡和坏死性凋亡的关键特征；然而，PANoptosis在肾IRI中的具体作用仍不清楚。通过使用缺乏中性粒细胞胞外陷阱（NETs）的Pad4小鼠，我们发现NETs对于加重肾IRI中的组织损伤至关重要。单细胞RNA测序（scRNA-seq）显示，IRI促进近端肾小管上皮细胞（PTs）中的PANoptosis信号传导，而PAD4基因敲除则抑制PANoptosis信号传导。PTs主要表达RIPK1-PANoptosomes，其在肾IRI模型小鼠的PTs中执行NET诱导的PANoptosis。机制上，NET衍生的双链RNA（dsRNA）促进PTs中的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，本研究结果揭示了一种机制，即NET-dsRNA-TLR3轴加重肾IRI中PT细胞的PANoptosis。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f211/11912734/2e30f2ce0707/12964_2025_2145_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f211/11912734/2e30f2ce0707/12964_2025_2145_Fig7_HTML.jpg
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本文引用的文献

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Therapeutic potential of PANoptosis: innate sensors, inflammasomes, and RIPKs in PANoptosomes.PANoptosis 的治疗潜力：先天传感器、炎性体和 RIPKs 在 PANoptosomes 中的作用。
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Extracellular RNAs-TLR3 signaling contributes to cognitive impairment after chronic neuropathic pain in mice.
细胞外 RNA-TLR3 信号通路参与慢性神经病理性疼痛小鼠的认知功能障碍
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Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA.应激颗粒是一种减震器，可以防止 dsRNA 引起过度的先天免疫反应。
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Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis.多核苷酸磷酸化酶通过阻断 mt-dsRNA-PKR-eIF2α 轴保护肾小管免受损伤。
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