Walter-Brendel-Centre of Experimental Medicine, Department of Cardiovascular Physiology and Pathophysiology, and.
Blood. 2014 Mar 20;123(12):1887-96. doi: 10.1182/blood-2013-06-510875. Epub 2014 Jan 23.
Emerging evidence suggests a role of the cytokine midkine (MK) in inflammation. In this study, its functional relevance for recruitment of polymorphonuclear neutrophils (PMNs) during acute inflammation was investigated. Intravital microscopy and histologic analysis of tumor necrosis factor-α-stimulated cremaster muscle venules revealed severely compromised leukocyte adhesion and extravasation in MK(-/-) mice compared with MK(+/+) animals. Systemic administration of recombinant MK completely rescued the adhesion defect in MK(-/-) mice. In a hind limb ischemia model, leukocyte accumulation in MK(-/-) mice was significantly diminished compared with MK(+/+) animals. However, MK did not lead to an inflammatory activation of PMNs or endothelial cells suggesting that it does not serve as classical proinflammatory cytokine. Unexpectedly, immobilized MK mediated PMN adhesion under static and flow conditions, whereas PMN-derived MK was dispensable for the induction of adhesion. Furthermore, adhesion strengthening remained unaffected by MK. Flow cytometry revealed that immobilized, but not soluble MK, significantly promoted the high affinity conformation of β2 integrins of PMNs. Blocking studies of low-density lipoprotein receptor-related protein 1 (LRP1) suggested that LRP1 may act as a receptor for MK on PMNs. Thus, MK seems to support PMN adhesion by promoting the high affinity conformation of β2 integrins, thereby facilitating PMN trafficking during acute inflammation.
新出现的证据表明细胞因子中期因子（MK）在炎症中起作用。在这项研究中，研究了其在急性炎症期间募集多形核粒细胞（PMN）的功能相关性。肿瘤坏死因子-α刺激的隐静脉中皮显微镜和组织学分析显示，与 MK(+/+)动物相比，MK(-/-)小鼠的白细胞黏附和渗出严重受损。重组 MK 的系统给药完全挽救了 MK(-/-)小鼠的黏附缺陷。在下肢缺血模型中，与 MK(+/+)动物相比，MK(-/-)小鼠的白细胞积聚明显减少。然而，MK 并没有导致 PMN 或内皮细胞的炎症激活，这表明它不作为经典的促炎细胞因子。出乎意料的是，固定化的 MK 在静态和流动条件下介导 PMN 的黏附，而PMN 衍生的 MK 对于诱导黏附是可有可无的。此外，黏附强化不受 MK 的影响。流式细胞术显示，固定化但不是可溶性的 MK 显著促进了 PMN 的β2 整合素的高亲和力构象。对低密度脂蛋白受体相关蛋白 1（LRP1）的阻断研究表明，LRP1 可能作为 PMN 上的 MK 受体发挥作用。因此，MK 似乎通过促进β2 整合素的高亲和力构象来支持 PMN 黏附，从而促进急性炎症期间 PMN 的迁移。
