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<p>Acute kidney injury (AKI) can progress to chronic kidney disease (CKD) in the setting of maladaptive repair characterized by tubular atrophy, inflammation, and fibrosis. Programmed cell death is a key driver of proximal tubule (PT) loss, yet how immune infiltration promotes tubular injury and death remains incompletely understood. Using a mouse model of maladaptive repair, we integrated bulk and single-cell RNA sequencing with immunohistochemistry and protein analyses to define immune-epithelial interactions during AKI-to-CKD transition. Injured kidneys exhibited loss of healthy PTs, expansion of injured PT subsets, and late-stage T cell accumulation. Apoptotic and necroptotic signaling pathways were markedly upregulated, particularly in VCAM1+ PT cells. Cell-cell interaction analysis identified macrophage-derived <i>Cxcl16</i> as the dominant chemokine mediating recruitment of <i>Cxcr6</i>+ T cells. Genetic deletion of <i>Cxcr6</i> reduced renal T cell accumulation, cytotoxic effector expression, and activation of apoptotic (cleaved caspase-3, Bax) and necroptotic signaling (MLKL, phospho-MLKL) in PT cells. Accordingly, <i>Cxcr6</i><sup>−/−</sup> mice displayed preserved PT differentiation, reduced fibrosis, and improved renal function. Together, these findings identify <i>Cxcr6</i>+ T cells as key mediators of immune-driven tubular cell death during maladaptive repair and suggest that targeting the CXCL16-CXCR6 axis may mitigate tubular injury and slow AKI-to-CKD progression.</p>

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CXCR6+ T cells promote apoptosis and necroptosis in proximal tubules during AKI-to-CKD transition

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月24日

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  • Xiaoxu Li,
  • Isabel Melchinger,
  • Yuchu Chen,
  • Jiankan Guo,
  • Lloyd G. Cantley,
  • Leyuan Xu

摘要

Acute kidney injury (AKI) can progress to chronic kidney disease (CKD) in the setting of maladaptive repair characterized by tubular atrophy, inflammation, and fibrosis. Programmed cell death is a key driver of proximal tubule (PT) loss, yet how immune infiltration promotes tubular injury and death remains incompletely understood. Using a mouse model of maladaptive repair, we integrated bulk and single-cell RNA sequencing with immunohistochemistry and protein analyses to define immune-epithelial interactions during AKI-to-CKD transition. Injured kidneys exhibited loss of healthy PTs, expansion of injured PT subsets, and late-stage T cell accumulation. Apoptotic and necroptotic signaling pathways were markedly upregulated, particularly in VCAM1+ PT cells. Cell-cell interaction analysis identified macrophage-derived Cxcl16 as the dominant chemokine mediating recruitment of Cxcr6+ T cells. Genetic deletion of Cxcr6 reduced renal T cell accumulation, cytotoxic effector expression, and activation of apoptotic (cleaved caspase-3, Bax) and necroptotic signaling (MLKL, phospho-MLKL) in PT cells. Accordingly, Cxcr6−/− mice displayed preserved PT differentiation, reduced fibrosis, and improved renal function. Together, these findings identify Cxcr6+ T cells as key mediators of immune-driven tubular cell death during maladaptive repair and suggest that targeting the CXCL16-CXCR6 axis may mitigate tubular injury and slow AKI-to-CKD progression.