Department of Cardiology and Angiology, Hannover Medical School, 30165, Hannover, Germany.
Blood. 2010 Mar 25;115(12):2543-52. doi: 10.1182/blood-2009-05-224402. Epub 2010 Jan 7.
Toll-like receptors (TLRs) are known primarily as pathogen recognition receptors of the innate immunity, initiating inflammatory pathways to organize the immune defense. More recently, an involvement of TLRs in various physiologic and pathologic processes has been reported. Because many of these processes implicate angiogenesis, we here elucidated the role of a TLR2/6-dependent pathway on angiogenesis using the TLR2/6 agonist macrophage-activating lipopeptide of 2 kDa (MALP-2), a common bacterial lipopeptide. In vivo and in vitro Matrigel assays demonstrated that MALP-2 promoted angiogenesis in a TLR2/6-dependent manner. Moreover, MALP-2 induced endothelial cell proliferation and migration and a strong secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF release in response to MALP-2 from isolated vascular segments was completely prevented when the endothelium was removed. MALP-2 containing Matrigel implants exhibited vascular structures as well as CD45(+) cells. MALP-2 induced migration of leukocytes and likewise GM-CSF release, particularly from the monocyte population. Inhibition of GM-CSF by siRNA or antibodies suppressed MALP-2-induced angiogenesis in vitro and in vivo. These results clearly identified a TLR2/6-dependent induction of angiogenesis by the bacterial lipopeptide MALP-2, which is mediated by GM-CSF. This might represent a general mechanism to enhance or restore blood flow and recruit immune cells for pathogen defense and tissue regeneration.
Toll 样受体 (TLRs) 主要作为先天免疫的病原体识别受体，启动炎症途径以组织免疫防御。最近，已经报道 TLRs 参与各种生理和病理过程。由于这些过程中的许多都涉及血管生成，因此我们使用 TLR2/6 激动剂 2 kDa 巨噬细胞激活脂质肽（MALP-2），一种常见的细菌脂肽，阐明了 TLR2/6 依赖性途径对血管生成的作用。体内和体外 Matrigel 测定表明，MALP-2 以 TLR2/6 依赖的方式促进血管生成。此外，MALP-2 诱导内皮细胞增殖和迁移，并强烈分泌粒细胞-巨噬细胞集落刺激因子 (GM-CSF)。当从分离的血管段中去除内皮细胞时，MALP-2 引起的 GM-CSF 释放被完全阻止。含有 MALP-2 的 Matrigel 植入物表现出血管结构和 CD45(+)细胞。MALP-2 诱导白细胞迁移，同样 GM-CSF 释放，特别是来自单核细胞群体。siRNA 或抗体抑制 GM-CSF 可抑制 MALP-2 诱导的体外和体内血管生成。这些结果清楚地表明细菌脂肽 MALP-2 通过 GM-CSF 诱导 TLR2/6 依赖性血管生成，这可能代表一种增强或恢复血流并招募免疫细胞进行病原体防御和组织再生的一般机制。
