Abstract:
Bacterial meningitis is a life-threatening infectious disease with high morbidity and mortality worldwide, among which meningitic Escherichia coli is a common Gram-negative pathogenic bacterium causing meningitis. It can penetrate the blood-brain barrier (BBB), invoke local inflammatory responses and consequently disrupt the integrity of the BBB. Interleukin-17A (IL-17A) is recognized as a pro-inflammatory cytokine that is released during meningitic E. coli infection. It has been reported that IL-17A is involved in several pathological tissue injuries. However, the function of IL-17A in BBB breakdown remains rarely discussed. Here, our study found that E. coli-induced IL-17A led to the degradation of tight junction proteins (TJs) and adherens junction proteins (AJs) in human brain microvascular endothelial cells (hBMECs) through inhibiting protease proteinase 3 (PRTN3)/protease-activated receptor 2 (PAR-2) axis, thus increasing the permeability of BBB. In summary, this study uncovered the involvement of IL-17A in regulating BBB integrity and proposed a novel regulatory mechanism, which could be potential therapeutic targets of E. coli meningitis.
摘要:
细菌性脑膜炎是一种危及生命的传染病,在全球范围内发病率和死亡率都很高,其中脑膜炎性大肠杆菌是引起脑膜炎的常见革兰氏阴性致病菌。它可以穿透血脑屏障(BBB),引起局部炎症反应,从而破坏BBB的完整性。白细胞介素-17A(IL-17A)被认为是在脑膜炎大肠杆菌感染期间释放的促炎细胞因子。据报道,IL-17A参与多种病理组织损伤。然而,IL-17A在血脑屏障分解中的功能仍很少讨论。这里,我们的研究发现大肠杆菌诱导的IL-17A通过抑制蛋白酶蛋白酶3(PRTN3)/蛋白酶激活受体2(PAR-2)轴,导致人脑微血管内皮细胞(hBMECs)中紧密连接蛋白(TJs)和粘附连接蛋白(AJs)的降解,从而增加BBB的渗透性。总之,这项研究揭示了IL-17A参与调节BBB完整性,并提出了一种新的调节机制,这可能是大肠杆菌脑膜炎的潜在治疗靶点。