School of Biological Sciences, Department of Internal Medicine, University of Ulsan, Ulsan 680-749, Korea.
Proc Natl Acad Sci U S A. 2012 Jan 3;109(1):E13-22. doi: 10.1073/pnas.1112256109. Epub 2011 Dec 12.
Renal ischemia-reperfusion injury (IRI) after kidney transplantation is a major cause of delayed graft function. Even though IRI is recognized as a highly coordinated and specific process, the pathways and mechanisms through which the innate response is activated are poorly understood. In this study, we used a mouse model of acute kidney IRI to examine whether the interactions of costimulatory receptor CD137 and its ligand (CD137L) are involved in the early phase of acute kidney inflammation caused by IRI. We report here that the specific expressions of CD137 on natural killer cells and of CD137L on tubular epithelial cells (TECs) are required for acute kidney IRI. Reverse signaling through CD137L in TECs results in their production of the chemokine (C-X-C motif) receptor 2 ligands CXCL1 and CXCL2 and the subsequent induction of neutrophil recruitment, resulting in a cascade of proinflammatory events during kidney IRI. Our findings identify an innate pathogenic pathway for renal IRI involving the natural killer cell-TEC-neutrophil axis, whereby CD137-CD137L interactions provide the causal contribution of epithelial cell dysregulation to renal IRI. The CD137L reverse signaling pathway in epithelial cells therefore may represent a good target for blocking the initial stage of inflammatory diseases, including renal IRI.
肾移植后肾缺血再灌注损伤（IRI）是导致移植物功能延迟的主要原因。尽管 IRI 被认为是一个高度协调和特异的过程，但固有免疫反应被激活的途径和机制仍知之甚少。在本研究中，我们使用急性肾 IRI 的小鼠模型来研究共刺激受体 CD137 及其配体（CD137L）的相互作用是否参与 IRI 引起的急性肾炎症的早期阶段。我们在这里报告，自然杀伤细胞上的 CD137 和肾小管上皮细胞（TECs）上的 CD137L 的特异性表达是急性肾 IRI 所必需的。TECs 中 CD137L 的反向信号导致其产生趋化因子（C-X-C 基序）受体 2 配体 CXCL1 和 CXCL2，随后诱导中性粒细胞募集，导致肾 IRI 期间发生一连串促炎事件。我们的研究结果确定了涉及自然杀伤细胞-TEC-中性粒细胞轴的肾 IRI 的固有致病途径，其中 CD137-CD137L 相互作用为上皮细胞失调对肾 IRI 的因果贡献提供了依据。因此，上皮细胞中的 CD137L 反向信号通路可能代表阻断包括肾 IRI 在内的炎症性疾病初始阶段的一个良好靶点。
