Donor kidney injury molecule-1 promotes graft recovery by regulating systemic necroinflammation
Donor kidney injury molecule-1 promotes graft recovery by regulating systemic necroinflammation
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DOI：
10.1111/ajt.14745
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发表时间：
2018-08-01
影响因子：
8.8
通讯作者：
Gunaratnam, Lakshman
中科院分区：
文献类型：
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作者：
Lee, Ji Yun;Ismail, Ola Z.;Gunaratnam, Lakshman
肾移植过程中的缺血再灌注损伤易导致移植物功能延迟、排斥反应和移植物过早衰竭。坏死炎症可以解释组织损伤和同种免疫反应的加剧：坏死细胞释放损伤相关分子模式（例如，高迁移率组盒1；HMGB1），激活先天和适应性免疫途径，介导细胞死亡和炎症的自身扩增循环。肾损伤分子-1 （KIM-1）是一种磷脂酰丝氨酸受体，在损伤的近端小管上皮细胞上表达上调，使其能够清除凋亡和坏死细胞。在这里，我们展示了在同基因小鼠肾移植模型中，死亡细胞的清除在调节坏死性炎症中的关键作用。我们发现在移植后的KIM-1（+/+）肾移植中持续表达KIM-1。与KIM-1（+/+）肾受体相比，KIM-1（-/-）肾受体表现出明显更多的肾功能障碍、细胞凋亡和坏死、肾小管阻塞和移植物衰竭。与KIM-1（+/+）移植物相比，KIM-1（-/-）移植物也有更多的炎症细胞因子、浸润性中性粒细胞和巨噬细胞。最重要的是，凋亡和坏死细胞中HMGB1的被动释放导致KIM-1（-/-）移植受体血清HMGB1水平显著升高，促炎巨噬细胞增加。我们的数据确定了一种内源性的抗肾移植坏死性炎症的保护机制，这可能与移植治疗相关。在小鼠肾移植模型中，供体肾脏中的KIM-1通过吞噬清除死亡细胞，促进移植相关缺血再灌注损伤的组织修复，限制危险信号的释放，减少局部和全身炎症。
Ischemia-reperfusion injury during kidney transplantation predisposes to delayed graft function, rejection, and premature graft failure. Exacerbation of tissue damage and alloimmune responses may be explained by necroinflammation: an autoamplification loop of cell death and inflammation, which is mediated by the release of damage-associated molecular patterns (eg, high-mobility group box-1; HMGB1) from necrotic cells that activate both innate and adaptive immune pathways. Kidney injury molecule-1 (KIM-1) is a phosphatidylserine receptor that is upregulated on injured proximal tubular epithelial cells and enables them to clear apoptotic and necrotic cells. Here we show a pivotal role for clearance of dying cells in regulating necroinflammation in a syngeneic murine kidney transplant model. We found persistent KIM-1 expression in KIM-1(+/+) kidney grafts posttransplantation. Compared to recipients of KIM-1(+/+) kidneys, recipients of KIM-1(-/-) kidneys exhibited significantly more renal dysfunction, apoptosis and necrosis, tubular obstruction, and graft failure. KIM-1(-/-) grafts also had more inflammatory cytokines, infiltrating neutrophils, and macrophages compared to KIM-1(+/+) grafts. Most significantly, passive release of HMGB1 from apoptotic and necrotic cells led to dramatically higher serum HMGB1 levels and increased proinflammatory macrophages in recipients of KIM-1(-/-) grafts. Our data identify an endogenous protective mechanism against necroinflammation in kidney grafts that may be of therapeutic relevance in transplantation.In a murine model of kidney transplantation, KIM-1 in the donor kidney promotes tissue repair from transplant-related ischemia-reperfusion injury through the phagocytic clearance of dying cells, limiting the release of danger signals and reducing local and systemic inflammation.