Li Na, Steiger Stefanie, Guo Yao, Li Muzheng, Wen Zheqi, Huang Mingcheng, Xie Chuyu, Jiang Shan, Zhang Dengyang, Zhao Yuming, Yu Liuting, Wang Xiaohua, Zheng Zhihua, Zhao Zhizhuang Joe, Chen Yun
Department of Nephrology, Center of Kidney and Urology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, China.
Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig Maximilian University of Munich, Munich 80336, Germany.
J Adv Res. 2025 Feb 27. doi: 10.1016/j.jare.2025.02.036.
Dendritic cells (DCs) play a crucial role in the recovery following acute kidney injury (AKI). Fms-related tyrosine kinase 3 ligand (Flt3L) is essential for the generation and maintenance of DCs. However, the cellular source of Flt3L in the kidney and its contribution on renal DC function during AKI remain unclear.
An online available dataset and specimens collected from AKI patients were used to analyze FLT3L expression. Wild type (WT) mice, T cell-deficient (Tcra), and type 1 conventional DC (cDC1)-deficient (Irf8) mice underwent ischemia-reperfusion (IR) injury to induce AKI. These mice were treated with either mouse recombinant Flt3L (rFlt3L) or the Flt3 inhibitor gilteritinib. In vitro experiments with human and murine bone marrow (BM) cells, HK-2 cell line, Jurkat T cells, the monocyte cell line THP1, CD4 T cells and cDC1s were conducted to validate the link between Flt3L and DCs.
Circulating FLT3L levels were significantly elevated in patients with AKI. This correlated with the degree of kidney dysfunction observed in these patients. Flt3L was expressed in and released by tubular epithelial cells, with minimal expression in immune cells. Flt3L primarily promoted the activation and expansion of cDC1s and polarization of CD4T cells in vitro, an effect that was blocked by dephosphorylation of AKT and ERK signaling with gilteritinib. In vivo, gilteritinib worsened the outcomes after AKI by decreasing kidney cDC1s expansion. Conversely, therapeutic administration of rFlt3L promoted renal cDC1 accumulation and improved kidney function in mice with AKI. However, in Irf8 mice, rFlt3L failed to improve outcomes.
Flt3L is upregulated in both humans and mice during IRI-induced AKI and is likely produced by tubular epithelial cells. It mainly promotes the expansion and activation of kidney cDC1 cells, thereby reducing the severity of AKI in mice. These findings suggest that Flt3L-dependent, cDC1-targeted immunotherapy could be a promising strategy for treating AKI.
树突状细胞（DCs）在急性肾损伤（AKI）后的恢复过程中起关键作用。Fms相关酪氨酸激酶3配体（Flt3L）对DCs的产生和维持至关重要。然而，肾脏中Flt3L的细胞来源及其在AKI期间对肾脏DC功能的贡献仍不清楚。
使用一个在线可用数据集和从AKI患者收集的标本分析FLT3L表达。野生型（WT）小鼠、T细胞缺陷型（Tcra）和1型传统DC（cDC1）缺陷型（Irf8）小鼠接受缺血再灌注（IR）损伤以诱导AKI。这些小鼠用小鼠重组Flt3L（rFlt3L）或Flt3抑制剂吉列替尼治疗。用人和小鼠骨髓（BM）细胞、HK-2细胞系、Jurkat T细胞、单核细胞系THP1、CD4 T细胞和cDC1进行体外实验，以验证Flt3L与DCs之间的联系。
AKI患者的循环FLT3L水平显著升高。这与这些患者中观察到的肾功能障碍程度相关。Flt3L由肾小管上皮细胞表达并释放，在免疫细胞中的表达极少。Flt3L主要在体外促进cDC1的激活和扩增以及CD4T细胞的极化，吉列替尼对AKT和ERK信号进行去磷酸化可阻断这种作用。在体内，吉列替尼通过减少肾脏cDC1的扩增而使AKI后的结局恶化。相反，rFlt3L的治疗性给药促进了肾cDC1的积聚并改善了AKI小鼠的肾功能。然而，在Irf8小鼠中，rFlt3L未能改善结局。
在缺血再灌注损伤诱导的AKI期间，人和小鼠体内的Flt3L均上调，并且可能由肾小管上皮细胞产生。它主要促进肾脏cDC1细胞的扩增和激活，从而减轻小鼠AKI的严重程度。这些发现表明，依赖Flt3L、以cDC1为靶点的免疫疗法可能是治疗AKI的一种有前景的策略。
