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

Abstract

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.

Integrated Transcriptional Profiling Analysis and Immune-Related Risk Model Construction for Intracranial Aneurysm Rupture

“…Inflammation and immune cell infiltration, including macrophages, mast cells ( Furukawa et al, 2020 ), and monocytes, play important roles in the formation and rupture of IAs. A previous study confirmed that inflammation-accelerated Toll-like receptor 4 (TLR4) pathway in aneurysmal walls promoted the development of IA rupture ( Mitsui et al, 2020 ). Similarly, Kanematsu et al (2011) reported that the infiltration and polarization of macrophages were closely related to the rupture of IAs.…”

“…Higher TNF-α expression is associated with increased expression of intracellular calcium ions (Ca 2+ ) and intracellular calcium release channels ( Jayaraman et al, 2008 ), which are related to the NF-κB signaling pathway and TLR signaling pathway. Moreover, the TLR4 pathway has been found to promote the development of IA rupture by accelerating inflammation in IA walls ( Mitsui et al, 2020 ).…”

Association between longitudinal blood pressure and prognosis after treatment of cerebral aneurysm: A nationwide population-based cohort study

“…The normalization of blood pressure in a mice model with aneurysm formation significantly reduced the risk of aneurysmal rupture [ 7 ]. Beyond mechanical stress, activation of the local renin-angiotensin system and toll-like receptor 4 pathway by systemic hypertension can induce vascular inflammation and remodeling, contributing to aneurysm rupture [ 35 ]. Increased activity and imbalances of the metalloproteinase/tissue inhibitors of metalloproteinase system in hypertensive patients predisposes them to cerebral aneurysm formation and growth [ 36 , 37 ].…”

Involvement of Microglia in the Pathophysiology of Intracranial Aneurysms and Vascular Malformations—A Short Overview

“…Regarding the molecular aspects of macrophage polarization, it has already been shown that toll-like receptor 4 (TLR4) compels macrophages skewedly toward the M1 phenotype in intracranial aneurysms [ 32 , 33 , 34 ]. The signaling cascade via the myeloid differentiation primary response gene 88 (MyD88) leads to the activation of inhibitor kappa B kinase β (IKK β ), which in turn triggers the phosphorylation and successive degradation of inhibitor kappa B (I κ B).…”