Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
Department of Radiation Cancer Science, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
J Korean Med Sci. 2017 Oct;32(10):1616-1625. doi: 10.3346/jkms.2017.32.10.1616.
Effective clearance of inflammatory cells is required for resolution of inflammation. Here, we show in vivo evidence that apoptosis and reverse transendothelial migration (rTEM) are important mechanisms in eliminating neutrophils and facilitating recovery following ischemia/reperfusion injury (IRI) of the kidney. The clearance of neutrophils was delayed in the Bax knockout (KO)(BM) → wild-type (WT) chimera in which bone marrow derived cells are partially resistant to apoptosis, compared to WT(BM) → WT mice. These mice also showed delayed functional, histological recovery, increased tissue cytokines, and accelerated fibrosis. The circulating intercellular adhesion molecule-1 (ICAM-1)⁺ Gr-1⁺ neutrophils displaying rTEM phenotype increased during the recovery phase and blockade of junctional adhesion molecule-C (JAM-C), a negative regulator of rTEM, resulted in an increase in circulating ICAM-1⁺ neutrophils, faster resolution of inflammation and recovery. The presence of Tamm-Horsfall protein (THP) in circulating ICAM-1⁺ neutrophils could suggest that they are derived from injured kidneys. In conclusion, we suggest that apoptosis and rTEM are critically involved in the clearance mechanisms of neutrophils during the recovery phase of IRI.
有效的炎症细胞清除是炎症消退所必需的。在这里，我们在体内证明了细胞凋亡和反向跨内皮迁移（rTEM）是消除中性粒细胞并促进肾缺血/再灌注损伤（IRI）后恢复的重要机制。与 WT(BM) → WT 小鼠相比，在骨髓来源细胞对细胞凋亡部分有抗性的 Bax 敲除（KO）（BM）→野生型（WT）嵌合体中，中性粒细胞的清除被延迟。这些小鼠还表现出功能和组织学恢复延迟、组织细胞因子增加和纤维化加速。在恢复阶段，循环中显示 rTEM 表型的细胞间黏附分子-1（ICAM-1）⁺Gr-1⁺中性粒细胞增加，阻断 rTEM 的负调节剂连接黏附分子-C（JAM-C）会导致循环中 ICAM-1⁺中性粒细胞增加，炎症更快消退和恢复。循环中 ICAM-1⁺中性粒细胞中 Tamm-Horsfall 蛋白（THP）的存在表明它们来自受损的肾脏。总之，我们认为细胞凋亡和 rTEM 是 IRI 恢复阶段中性粒细胞清除机制中至关重要的作用。
