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<p>Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI). Although Th17 cells have been implicated in the pathogenesis of renal IRI, the mechanisms regulating Th17 responses in this context remain incompletely understood. Here, we detected abundant neutrophil extracellular traps (NETs) in kidneys following IRI. Notably, genetic ablation of <i>Padi4</i> attenuated kidney injury in mice. <i>Padi4</i> deficiency also reduced renal infiltration of neutrophils and macrophages. Furthermore, inhibition of NET formation by <i>Padi4</i> deletion or DNase-I treatment diminished IL-17A expression and Th17 cell accumulation within IRI kidneys. Conversely, adoptive transfer of NETs elevated renal IL-17A levels and Th17 cell infiltration. Mechanistically, histones derived from NETs directly promoted Th17 differentiation via TLR2-dependent activation of intracellular STAT3 signaling. Systemic administration of histones exacerbated renal injury, kidney inflammation, and IL-17A production. Additionally, NETs-mediated Th17 responses induced CXCL1 and CXCL2 expression, thereby driving neutrophil recruitment and amplifying inflammatory cascades. Thus, our study uncovers a pathogenic loop in which NETs orchestrate Th17-driven inflammation during renal IRI.</p>

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Neutrophil extracellular traps promote renal ischemia-reperfusion injury via a TLR2/STAT3-mediated Th17 inflammatory response

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月30日

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  • Yunjie Yang,
  • Yangyang Wu,
  • Xiaowei Zhang,
  • Yanpei Yang,
  • Yuandong Tao,
  • Huixia Zhou

摘要

Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI). Although Th17 cells have been implicated in the pathogenesis of renal IRI, the mechanisms regulating Th17 responses in this context remain incompletely understood. Here, we detected abundant neutrophil extracellular traps (NETs) in kidneys following IRI. Notably, genetic ablation of Padi4 attenuated kidney injury in mice. Padi4 deficiency also reduced renal infiltration of neutrophils and macrophages. Furthermore, inhibition of NET formation by Padi4 deletion or DNase-I treatment diminished IL-17A expression and Th17 cell accumulation within IRI kidneys. Conversely, adoptive transfer of NETs elevated renal IL-17A levels and Th17 cell infiltration. Mechanistically, histones derived from NETs directly promoted Th17 differentiation via TLR2-dependent activation of intracellular STAT3 signaling. Systemic administration of histones exacerbated renal injury, kidney inflammation, and IL-17A production. Additionally, NETs-mediated Th17 responses induced CXCL1 and CXCL2 expression, thereby driving neutrophil recruitment and amplifying inflammatory cascades. Thus, our study uncovers a pathogenic loop in which NETs orchestrate Th17-driven inflammation during renal IRI.