TLR4 (Toll-Like Receptor 4) Mediates the Development of Intracranial Aneurysm Rupture

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2020-02, Vol.75 (2), p.468-476
• Main Authors: Mitsui, Kazuha, Ikedo, Taichi, Kamio, Yoshinobu, Furukawa, Hajime, Lawton, Michael T., Hashimoto, Tomoki
• Format: Article
• Language: English
• Subjects: Aneurysm, Ruptured - genetics; Aneurysm, Ruptured - metabolism; Animals; Cytokines - biosynthesis; Cytokines - genetics; Disease Models, Animal; Gene Expression Regulation; Intracranial Aneurysm - genetics; Intracranial Aneurysm - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; RNA - genetics; Toll-Like Receptor 4 - antagonists & inhibitors; Toll-Like Receptor 4 - biosynthesis; Toll-Like Receptor 4 - genetics
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.118.12595

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.