Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Department of Urological Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, P.R. China.
Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Kidney Int. 2018 Nov;94(5):951-963. doi: 10.1016/j.kint.2018.06.010. Epub 2018 Sep 4.
Dendritic cells (DCs) are critical initiators of innate immunity in the kidney and orchestrate inflammation following ischemia-reperfusion injury. The role of the mammalian/mechanistic target of rapamycin (mTOR) in the pathophysiology of renal ischemia-reperfusion injury has been characterized. However, the influence of DC-based alterations in mTOR signaling is unknown. To address this, bone marrow-derived mTORC2-deficient (Rictor) DCs underwent hypoxia-reoxygenation and then analysis by flow cytometry. Adoptive transfer of wild-type or Rictor DC to C57BL/6 mice followed by unilateral or bilateral renal ischemia-reperfusion injury (20 min ischemia) was used to assess their in vivo migratory capacity and influence on tissue injury. Age-matched male DC-specific Rictor mice or littermate controls underwent bilateral renal ischemia-reperfusion, followed by assessment of renal function, histopathology, and biomolecular and cell infiltration analysis. Rictor DCs expressed more costimulatory CD80/CD86 but less coinhibitory programmed death ligand 1 (PDL1), a pattern that was enhanced by hypoxia-reoxygenation. They also demonstrated enhanced migration to the injured kidney and induced greater tissue damage. Following ischemia-reperfusion, Rictor DC mice developed higher serum creatinine levels, more severe histological damage, and greater proinflammatory cytokine production compared to littermate controls. Additionally, a greater influx of both neutrophils and T cells was seen in Rictor DC mice, along with CD11cMHCIICD11bF4/80 renal DC, that expressed more CD86 but less PDL1. Thus, DC-targeted elimination of Rictor enhances inflammation and migratory responses to the injured kidney, highlighting the regulatory roles of both DCs and Rictor in the pathophysiology of acute kidney injury.
树突状细胞 (DCs) 是肾脏固有免疫的关键启动者，并在缺血再灌注损伤后协调炎症反应。哺乳动物/雷帕霉素靶蛋白 (mTOR) 在肾缺血再灌注损伤的病理生理学中的作用已经得到了描述。然而，DC 中 mTOR 信号的改变的影响尚不清楚。为了解决这个问题，骨髓衍生的 mTORC2 缺陷 (Rictor) DC 经历了缺氧-复氧，然后通过流式细胞术进行分析。将野生型或 Rictor DC 过继转移到 C57BL/6 小鼠中，然后进行单侧或双侧肾缺血再灌注损伤（20 分钟缺血），以评估它们的体内迁移能力及其对组织损伤的影响。年龄匹配的雄性 DC 特异性 Rictor 小鼠或同窝对照小鼠进行双侧肾缺血再灌注，然后评估肾功能、组织病理学以及生物分子和细胞浸润分析。Rictor DC 表达更多的共刺激分子 CD80/CD86，但更少的共抑制分子程序性死亡配体 1 (PDL1)，这种模式在缺氧-复氧后增强。它们还表现出向受损肾脏的迁移增强，并诱导更大的组织损伤。与同窝对照相比，在发生缺血再灌注后，Rictor DC 小鼠的血清肌酐水平升高，组织学损伤更严重，促炎细胞因子产生增加。此外，在 Rictor DC 小鼠中还观察到更多的中性粒细胞和 T 细胞的涌入，以及 CD11cMHCIICD11bF4/80 肾 DC，它们表达更多的 CD86，但更少的 PDL1。因此，针对 DC 的 Rictor 消除增强了对受损肾脏的炎症和迁移反应，突出了 DC 和 Rictor 在急性肾损伤病理生理学中的调节作用。
