Neurotrauma and Brain Barriers Research Laboratory, Alpert Medical School of Brown University, Providence, Rhode Island, USA.
Department of Neuroscience, Regis College, Weston, Massachusetts, USA.
J Neurotrauma. 2021 Feb 15;38(4):385-398. doi: 10.1089/neu.2020.7229. Epub 2020 Oct 19.
Neuroinflammation and dysfunction of the blood-brain barrier (BBB) are two prominent mechanisms of secondary injury in neurotrauma. It has been suggested that Toll-like receptors (TLRs) play important roles in initiating and propagating neuroinflammation resulting from traumatic brain injury (TBI), but potential beneficial effects of targeting these receptors in TBI have not been broadly studied. Here, we investigated the effect of targeting TLRs with proteoglycan 4 (PRG4) on post-traumatic neuroinflammation and BBB function. PRG4 is a mucinous glycoprotein with strong anti-inflammatory properties, exerting its biological effects by interfering with TLR2/4 signaling. In addition, PRG4 has the ability to inhibit activation of cluster of differentiation 44 (CD44), a cell-surface glycoprotein playing an important role in inflammation. Using the controlled cortical impact model of TBI in rats, we showed a rapid and prolonged upregulation of message for TLR2/4 and CD44 in the injured cortex. In the model of the BBB, recombinant human PRG4 (rhPRG4) crossed the endothelial monolayers through a high-capacity, saturable transport system. In rats sustaining TBI, PRG4 delivery to the brain was enhanced by post-traumatic increase in BBB permeability. rhPRG4 injected intravenously at 1 h post-TBI potently inhibited post-traumatic activation of nuclear factor kappa B and extracellular signal-regulated kinases 1/2, the two major signal transduction pathways associated with TLR2/4 and CD44, and curtailed the post-traumatic influx of monocytes. In addition, PRG4 restored normal BBB function after TBI by preventing the post-traumatic loss of tight junction protein claudin 5 and reduced neuronal death. Our observations provide support for therapeutic strategies targeting TLRs in TBI.
神经炎症和血脑屏障（BBB）功能障碍是神经创伤继发性损伤的两个突出机制。有研究表明，Toll 样受体（TLR）在创伤性脑损伤（TBI）引起的神经炎症的启动和传播中发挥重要作用，但针对这些受体的潜在有益影响尚未得到广泛研究。在这里，我们研究了用蛋白聚糖 4（PRG4）靶向 TLR 对创伤后神经炎症和 BBB 功能的影响。PRG4 是一种粘蛋白糖蛋白，具有很强的抗炎特性，通过干扰 TLR2/4 信号传导发挥其生物学作用。此外，PRG4 具有抑制细胞表面糖蛋白 CD44 激活的能力，CD44 在炎症中起着重要作用。我们在大鼠 TBI 的皮质控制撞击模型中，发现 TLR2/4 和 CD44 的信使在损伤皮质中迅速且持续上调。在 BBB 模型中，重组人 PRG4（rhPRG4）通过高容量、饱和转运系统穿过内皮单层。在发生 TBI 的大鼠中，BBB 通透性增加增强了 PRG4 向大脑的输送。TBI 后 1 小时静脉内注射 rhPRG4 可强力抑制核因子 kappa B 和细胞外信号调节激酶 1/2 的创伤后激活，这两种与 TLR2/4 和 CD44 相关的主要信号转导途径，并减少创伤后单核细胞的涌入。此外，PRG4 通过防止创伤后紧密连接蛋白 claudin 5 的丢失和减少神经元死亡，在 TBI 后恢复 BBB 的正常功能。我们的观察结果为针对 TBI 中 TLR 的治疗策略提供了支持。
