Inflammation is emerging as a critical factor in the pathophysiology of intracranial aneurysm. TLR4 (toll-like receptor 4) contributes not only to the innate immune responses but also to the inflammatory processes associated with vascular disease. Therefore, we examined the contribution of the TLR4 pathway to the development of the rupture of intracranial aneurysm. We used a mouse model of intracranial aneurysm. TLR4 inhibition significantly reduced the development of aneurysmal rupture. In addition, the rupture rate and levels of proinflammatory cytokines were lower in TLR4 knockout mice than the control littermates. Macrophage/monocyte-specific TLR4 knockout mice had a lower rupture rate than the control littermate mice. Moreover, the deficiency of MyD88 (myeloid differentiation primary-response protein 88), a key mediator of TLR4, reduced the rupture rate. These findings suggest that the TLR4 pathway promotes the development of intracranial aneurysmal rupture by accelerating inflammation in aneurysmal walls. Inhibition of the TLR4 pathway in inflammatory cells may be a promising approach for the prevention of aneurysmal rupture and subsequent subarachnoid hemorrhage.

中文翻译：

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TLR4（Toll-Like Receptor 4）介导颅内动脉瘤破裂的发展

炎症正在成为颅内动脉瘤病理生理学中的一个关键因素。TLR4（toll 样受体 4）不仅有助于先天免疫反应，还有助于与血管疾病相关的炎症过程。因此，我们检查了 TLR4 通路对颅内动脉瘤破裂发展的贡献。我们使用了颅内动脉瘤的小鼠模型。TLR4 抑制显着减少了动脉瘤破裂的发展。此外，TLR4 敲除小鼠的破裂率和促炎细胞因子水平低于对照同窝小鼠。巨噬细胞/单核细胞特异性 TLR4 敲除小鼠的破裂率低于对照同窝小鼠。此外，TLR4 的关键介质 MyD88（髓样分化初级反应蛋白 88）的缺乏，降低了破裂率。这些发现表明 TLR4 通路通过加速动脉瘤壁的炎症促进颅内动脉瘤破裂的发展。抑制炎症细胞中的 TLR4 通路可能是预防动脉瘤破裂和随后的蛛网膜下腔出血的一种有前景的方法。