Suzuki Hidenori, Fujimoto Masashi, Kawakita Fumihiro, Liu Lei, Nakano Fumi, Nishikawa Hirofumi, Okada Takeshi, Imanaka-Yoshida Kyoko, Yoshida Toshimichi, Shiba Masato
Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
Acta Neurochir Suppl. 2020;127:91-96. doi: 10.1007/978-3-030-04615-6_15.
Toll-like receptor 4 (TLR4) is expressed in various cell types in the central nervous system and exerts maximal inflammatory responses among the TLR family members. TLR4 can be activated by many endogenous ligands having damage-associated molecular patterns including heme and fibrinogen at the rupture of a cerebral aneurysm, and therefore its activation is reasonable as an initial step of cascades to brain injuries after aneurysmal subarachnoid hemorrhage (SAH). TLR4 activation induces tenascin-C (TNC), a representative of matricellular proteins that are a class of inducible, nonstructural, secreted, and multifunctional extracellular matrix glycoproteins. TNC is also an endogenous activator and inducer of TLR4, forming positive feedback mechanisms leading to more activation of the signaling transduction. Our studies have demonstrated that TLR4 as well as TNC are involved in inflammatory reactions, blood-brain barrier disruption, neuronal apoptosis, and cerebral vasospasm after experimental SAH. This article reviews recent understanding of TLR4 and TNC in SAH to suggest that the TLR4-TNC signaling may be an important therapeutic target for post-SAH brain injuries.
Toll样受体4（TLR4）在中枢神经系统的多种细胞类型中表达，在TLR家族成员中引发最大的炎症反应。TLR4可被许多具有损伤相关分子模式的内源性配体激活，包括脑动脉瘤破裂时的血红素和纤维蛋白原，因此其激活作为动脉瘤性蛛网膜下腔出血（SAH）后脑损伤级联反应的初始步骤是合理的。TLR4激活诱导腱生蛋白-C（TNC），它是基质细胞蛋白的代表，基质细胞蛋白是一类可诱导、非结构性、分泌性和多功能的细胞外基质糖蛋白。TNC也是TLR4的内源性激活剂和诱导剂，形成导致信号转导更多激活的正反馈机制。我们的研究表明，TLR4以及TNC参与实验性SAH后的炎症反应、血脑屏障破坏、神经元凋亡和脑血管痉挛。本文综述了近期对SAH中TLR4和TNC的认识，提示TLR4-TNC信号可能是SAH后脑损伤的重要治疗靶点。
