Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China.
Intensive Care Unit, Shandong Provincial Qianfoshan Hospital, the First Affiliated Hospital of Shandong First Medical University, Jinan, China.
JCI Insight. 2022 Jun 16;7(14):e158571. doi: 10.1172/jci.insight.158571.
Although macrophages are undoubtedly attractive therapeutic targets for acute kidney injury (AKI) because of their critical roles in renal inflammation and repair, the underlying mechanisms of macrophage phenotype switching and efferocytosis in the regulation of inflammatory responses during AKI are still largely unclear. The present study elucidated the role of junctional adhesion molecule-like protein (JAML) in the pathogenesis of AKI. We found that JAML was significantly upregulated in kidneys from 2 different murine AKI models including renal ischemia/reperfusion injury (IRI) and cisplatin-induced AKI. By generation of bone marrow chimeric mice, macrophage-specific and tubular cell-specific Jaml conditional knockout mice, we demonstrated JAML promoted AKI mainly via a macrophage-dependent mechanism and found that JAML-mediated macrophage phenotype polarization and efferocytosis is one of the critical signal transduction pathways linking inflammatory responses to AKI. Mechanistically, the effects of JAML on the regulation of macrophages were, at least in part, associated with a macrophage-inducible C-type lectin-dependent mechanism. Collectively, our studies explore for the first time to our knowledge new biological functions of JAML in macrophages and conclude that JAML is an important mediator and biomarker of AKI. Pharmacological targeting of JAML-mediated signaling pathways at multiple levels may provide a novel therapeutic strategy for patients with AKI.
虽然巨噬细胞在急性肾损伤 (AKI) 中的作用至关重要，因为它们在肾脏炎症和修复中起着关键作用，但巨噬细胞表型转换和吞噬作用在 AKI 炎症反应调节中的潜在机制在很大程度上仍不清楚。本研究阐明了连接黏附分子样蛋白 (JAML) 在 AKI 发病机制中的作用。我们发现，2 种不同的 AKI 小鼠模型（包括肾缺血/再灌注损伤 (IRI) 和顺铂诱导的 AKI）的肾脏中 JAML 表达显著上调。通过生成骨髓嵌合小鼠、巨噬细胞特异性和肾小管细胞特异性 Jaml 条件性敲除小鼠，我们证明 JAML 主要通过巨噬细胞依赖性机制促进 AKI，并发现 JAML 介导的巨噬细胞表型极化和吞噬作用是将炎症反应与 AKI 联系起来的关键信号转导途径之一。从机制上讲，JAML 对巨噬细胞的调节作用至少部分与巨噬细胞诱导的 C 型凝集素依赖性机制有关。总之，我们的研究首次探索了 JAML 在巨噬细胞中的新生物学功能，并得出结论，JAML 是 AKI 的重要介质和生物标志物。针对 JAML 介导的信号通路在多个水平上的药理学靶向可能为 AKI 患者提供一种新的治疗策略。
