ORIGINAL RESEARCH article
Front. Immunol.
Sec. Molecular Innate Immunity
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1654295
This article is part of the Research TopicRole of Endogenous Regulators of Innate Immunity in SepsisView all 10 articles
Tubular epithelial cell-derived extracellular vesicles carrying serum amyloid A1 exacerbate sepsis-associated acute kidney injury by promoting NETs formation
Provisionally accepted
Yang Jiao1
Mei Liu1Xin Xie1Mengying Pi1Luyang Zhou1Wei Zhu1Jia Song1
Ti Zhang2
Zhengliang Ma1
Xiaoping Gu1*- 1Nanjing Drum Tower Hospital, Nanjing, China
- 2Jinling Hospital, Nanjing, China
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Sepsis-associated acute kidney injury (SA-AKI) is a highly lethal condition with a rapid onset, and effective treatments are lacking because the molecular pathogenesis remains unclear.Tubular epithelial cells (TECs) have increasingly been recognized as driving forces in the progression of kidney diseases, partly through the release of extracellular vesicles (EVs) carrying proinflammatory cargos. However, the function of TECs-derived EVs in the development of SA-AKI remains uncertain. This study demonstrated that EVs secreted from lipopolysaccharide (LPS)-stimulated TECs exacerbated AKI by promoting neutrophil extracellular traps (NETs) formation, which is an established feature of sepsis. By combining proteomics and single-cell RNA sequencing (scRNA-seq) analysis, we found that LPS increased serum amyloid A1 (SAA1) expression in TECs, and then released extracellularly through EVs. Further mechanistic studies revealed that SAA1 packaged in TECs-derived EVs was responsible for NETs formation and AKI via activation of the TLR4/MAPK signaling pathway in neutrophils. Specifically blocking EVs secretion from TECs or inhibiting SAA1 upregulation in TECs via AAV9s reduced NETs formation and alleviated LPS-induced AKI. Interestingly, modulating EVs release from TECs or SAA1 expression in TECs also alleviated remote lung injury induced by LPS, indicated that TECs-derived EVs participate in kidneylung crosstalk during sepsis. More importantly, plasma TECs-derived EVs proportion and SAA1 expression in plasma EVs may be promising prognostic indexes for SA-AKI patients.Here, we explored a new mode of TECs-neutrophil crosstalk mediated by EVs during SA-AKI, and strategies to modify TECs-derived EVs and the cargo SAA1 could be a new avenue for developing therapeutics against SA-AKI.
Keywords: Sepsis-associated acute kidney injury, Tubular epithelial cells, extracellular vesicles, neutrophil extracellular traps, serum amyloid A1
Received: 26 Jun 2025; Accepted: 11 Aug 2025.
Copyright: © 2025 Jiao, Liu, Xie, Pi, Zhou, Zhu, Song, Zhang, Ma and Gu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Xiaoping Gu, Nanjing Drum Tower Hospital, Nanjing, China
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