Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
NHC Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, China.
Cell Death Dis. 2024 Jun 6;15(6):397. doi: 10.1038/s41419-024-06785-5.
Integrin αvβ6 holds promise as a therapeutic target for organ fibrosis, yet targeted therapies are hampered by concerns over inflammatory-related side effects. The role of αvβ6 in renal inflammation remains unknown, and clarifying this issue is crucial for αvβ6-targeted treatment of chronic kidney disease (CKD). Here, we revealed a remarkable positive correlation between overexpressed αvβ6 in proximal tubule cells (PTCs) and renal inflammation in CKD patients and mouse models. Notably, knockout of αvβ6 not only significantly alleviated renal fibrosis but also reduced inflammatory responses in mice, especially the infiltration of pro-inflammatory macrophages. Furthermore, conditional knockout of αvβ6 in PTCs in vivo and co-culture of PTCs with macrophages in vitro showed that depleting αvβ6 in PTCs suppressed the migration and pro-inflammatory differentiation of macrophages. Screening of macrophage activators showed that αvβ6 in PTCs activates macrophages via secreting IL-34. IL-34 produced by PTCs was significantly diminished by αvβ6 silencing, and reintroduction of IL-34 restored macrophage activities, while anti-IL-34 antibody restrained macrophage activities enhanced by αvβ6 overexpression. Moreover, RNA-sequencing of PTCs and verification experiments demonstrated that silencing αvβ6 in PTCs blocked hypoxia-stimulated IL-34 upregulation and secretion by inhibiting YAP expression, dephosphorylation, and nuclear translocation, which resulted in the activation of Hippo signaling. While application of a YAP agonist effectively recurred IL-34 production by PTCs, enhancing the subsequent macrophage migration and activation. Besides, reduced IL-34 expression and YAP activation were also observed in global or PTCs-specific αvβ6-deficient injured kidneys. Collectively, our research elucidates the pro-inflammatory function and YAP/IL-34/macrophage axis-mediated mechanism of αvβ6 in renal inflammation, providing a solid rationale for the use of αvβ6 inhibition to treat kidney inflammation and fibrosis.
整合素 αvβ6 有望成为治疗器官纤维化的靶点，但靶向治疗受到炎症相关副作用的担忧的阻碍。αvβ6 在肾脏炎症中的作用尚不清楚，澄清这一问题对于 αvβ6 靶向治疗慢性肾脏病 (CKD) 至关重要。在这里，我们揭示了 CKD 患者和小鼠模型中近端肾小管细胞 (PTC) 中过表达的 αvβ6 与肾脏炎症之间存在显著的正相关。值得注意的是，αvβ6 的敲除不仅显著减轻了肾脏纤维化，而且还减轻了小鼠的炎症反应，尤其是促炎巨噬细胞的浸润。此外，体内 PTC 中 αvβ6 的条件性敲除和 PTC 与巨噬细胞的体外共培养表明，PTC 中 αvβ6 的耗竭抑制了巨噬细胞的迁移和促炎分化。巨噬细胞激活剂的筛选表明，PTC 中的 αvβ6 通过分泌 IL-34 激活巨噬细胞。PTC 中 αvβ6 的沉默显著减少了 IL-34 的产生，而 IL-34 的重新引入恢复了巨噬细胞的活性，而抗 IL-34 抗体则抑制了由 αvβ6 过表达增强的巨噬细胞活性。此外，PTC 的 RNA 测序和验证实验表明，通过抑制 YAP 表达、去磷酸化和核易位，沉默 PTC 中的 αvβ6 阻断了缺氧刺激的 IL-34 上调和分泌，从而激活了 Hippo 信号通路。而 YAP 激动剂的应用有效地恢复了 PTC 中 IL-34 的产生，增强了随后的巨噬细胞迁移和激活。此外，在全局或 PTC 特异性 αvβ6 缺陷性损伤肾脏中也观察到 IL-34 表达和 YAP 激活减少。总之，我们的研究阐明了 αvβ6 在肾脏炎症中的促炎功能和 YAP/IL-34/巨噬细胞轴介导的机制，为使用 αvβ6 抑制治疗肾脏炎症和纤维化提供了坚实的理论依据。
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