Points of control exerted along the macrophage-endothelial cell-polymorphonuclear neutrophil axis by PECAM-1 in the innate immune response of acute colonic inflammation
Points of control exerted along the macrophage-endothelial cell-polymorphonuclear neutrophil axis by PECAM-1 in the innate immune response of acute colonic inflammation
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DOI：
10.4049/jimmunol.181.3.2145
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发表时间：
2008-08-01
影响因子：
4.4
通讯作者：
Kvietys, Peter R.
中科院分区：
文献类型：
--
作者：
Sugimoto, Naohito;Rui, Tao;Kvietys, Peter R.
PECAM-1 在内皮细胞和白细胞上表达。其胞外结构域与白细胞渗出有关。在这项研究中，我们使用 PECAM-1(-/-) 小鼠和源自它们的相关细胞来评估 PECAM-1 在以先天免疫反应为主的急性结肠炎症实验模型中的作用，即 2,4,6-三硝基苯磺酸 (TNBS)。使用嵌合方法，我们解决了 PECAM-1 沿巨噬细胞-内皮细胞-多形核中性粒细胞 (PMN) 轴施加的控制点。在体内，TNBS诱导的结肠炎在PECAM-1(-/-)小鼠中得到改善，这一事件归因于造血细胞上的PECAM-1而不是内皮细胞上的PECAM-1。通过使用血管-间质界面的构建体在体外模拟体内先天免疫反应，即，通过来自 TNBS 小鼠的结肠灌洗液 (CLF) 或用 CLF 攻击的巨噬细胞 (M[4)) 诱导 PMN 跨内皮迁移。使用该构建体，我们证实内皮细胞 PECAM-1 在 PMN 跨内皮迁移中不起作用。尽管CLF诱导的M(D激活(NF-κB核结合)和功能(角质形成细胞衍生的趋化因子产生)在PECAM-1(-/-)M Phi中减弱)，但这并不影响它们促进PMN跨内皮迁移的能力。相比之下，PECAM-1(-/-) PMN 不会响应 CLF 粘附或迁移穿过内皮细胞单层。此外，与PECAM-1(+/+)PMN相比，PECAM-1(-/-)PMN在使CXCR2受体(极化)沿趋化梯度方向定向方面效果较差。总的来说，我们的研究结果表明，PECAM-1 对 PMN 功能的调节（在血细胞渗出之前的步骤）最有可能导致具有强大先天免疫成分的结肠炎模型中的炎症。
PECAM-1 is expressed on endothelial cells and leukocytes. Its extracellular domain has been implicated in leukocyte diapedesis. In this study, we used PECAM-1(-/-) mice and relevant cells derived from them to assess the role of PECAM-1 in an experimental model of acute colonic inflammation with a predominant innate immune response, i.e., 2,4,6-trinitrobenzine sulfonic acid (TNBS). Using chimeric approaches, we addressed the points of control exerted by PECAM-1 along the macrophage-endothelial cell-polymorphonuclear neutrophil (PMN) axis. In vivo, TNBS-induced colitis was ameliorated in PECAM-1(-/-) mice, an event attributed to PECAM-1 on hematopoietic cells rather than to PECAM-1 on endothelial cells. The in vivo innate immune response was mimicked in vitro by using a construct of the vascular-interstitial interface, i.e., PMN transendothelial migration was induced by colonic lavage fluid (CLF) from TNBS mice or macrophages (M[4)) challenged with CLF. Using the construct, we confirmed that endothelial cell PECAM-1 does not play a role in PMN transendothelial migration. Although M(D activation (NF-kappa B nuclear binding) and function (keratinocyte-derived chemokine production) induced by CLF was diminished in PECAM-1(-/-) M Phi), this did not affect their ability to promote PMN transendothelial migration. By contrast, PECAM-1(-/-) PMN did not adhere to or migrate across endothelial cell monolayers in response to CLF. Further, as compared with PECAM-1(+/+) PMN, PECAM-1(-/-)PMN were less effective in orientating their CXCR2 receptors (polarization) in the direction of a chemotactic gradient. Collectively, our findings indicate that PECAM-1 modulation of PMN function (at a step before diapedesis) most likely contributes to the inflammation in a colitis model with a strong innate immune component.