Neutrophil extracellular trap-derived double-stranded RNA aggravates PANoptosis in renal ischemia reperfusion injury
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<sup>-/-</sup> 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.
Authors
- Xianyun Zhang (ORCID: https://orcid.org/0000-0002-0453-6879)
- Xiaodong Yuan
- Ruoyang Chen (ORCID: https://orcid.org/0000-0002-1424-7528)
- Shaoyong Zhuang
- Zhongping Lai (ORCID: https://orcid.org/0000-0002-0139-9346)
- Liya Wang (ORCID: https://orcid.org/0000-0003-3496-6084)
- Jiajin Wu (ORCID: https://orcid.org/0000-0003-0462-442X)
- Junwen Qu (ORCID: https://orcid.org/0000-0001-6146-4720)
- Haoyu Wu (ORCID: https://orcid.org/0000-0002-8995-3486)
- Dawei Li (ORCID: https://orcid.org/0000-0001-9150-5159)
- Ming Zhang (ORCID: https://orcid.org/0000-0002-6293-0700)
- Fangzhou Li (ORCID: https://orcid.org/0000-0002-7623-719X)
Institutions
- Xuzhou Medical College (CN)
- Shanghai Jiao Tong University (CN)
- Sichuan University (CN)
- Renji Hospital (CN)
- Jiading District Central Hospital (CN)
- West China Hospital of Sichuan University (CN)
Publication Details
- Journal
- Cell Communication and Signaling
- Published
- 2025-03-17
- DOI
- https://doi.org/10.1186/s12964-025-02145-8
- Citations
- 12
- Primary Topic
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 9.57
Funders
- National Natural Science Foundation of China