The role of Toll-like receptor 4 in apoptosis of brain tissue after induction of intracerebral hemorrhage

Abstract

BackgroundInflammation and apoptosis caused by intracerebral hemorrhage (ICH) are two important factors that affect patient prognosis and survival. Toll-like receptor 4 (TLR4) triggers activation of the inflammatory pathway, causing synthesis and release of inflammatory factors. The inflammatory environment also causes neuronal apoptosis. However, no studies have reported the role of TLR4 in inflammation and apoptosis.MethodsWe performed survival curve analysis and behavioral scores on TLR4 knockout mice and wild-type mice after inducing ICH. We used TLR4 knockout mice and wild-type mice to make ICH models with type VII collagenase and explored the link between TLR4 in inflammation and apoptosis. We used Western blot to detect the expression of apoptosis-related proteins, inflammatory factors, and their receptors at different time points after ICH induction. The effects of TLR4 on apoptosis were observed by TUNEL, Hoechst, and HE staining techniques. The association with TLR4 in inflammation and apoptosis was explored using IL-1β and TNF-α antagonists. Data conforming to a normal distribution are expressed as mean ± standard deviation. Grade and quantitative data were compared with rank sum test and t test between two groups. P < 0.05 was considered statistically significant.ResultsTLR4 knockout significantly increased the survival rate of ICH mice. The scores of TLR4 knockout mice were significantly lower than those of wild-type mice. We found that TLR4 knockout mice significantly inhibited apoptosis and the expression of inflammatory factors after the induction of ICH. The apoptosis of ICH-induced mice was significantly improved after injecting IL-1β and TNF-α antagonists. Moreover, the anti-apoptotic effect of the antagonist in wild-type mice is more pronounced. A single injection of the antagonist failed to improve apoptosis in TLR4 knockout mice.ConclusionsWe conclude that TLR4-induced inflammation after ICH promotes neuronal apoptosis. IL-1β and TNF-α antagonists attenuate this apoptotic effect. Therefore, targeting TLR4 in patients with clinical ICH may attenuate inflammatory response, thereby attenuating apoptosis and improving prognosis.

The Beneficial Roles of SIRT1 in Neuroinflammation-Related Diseases

“…It has been confirmed that the TLR pathway is involved in the inflammation response and diseases of CNS. TLR4 knockout inhibits the expression of inflammatory factors IL-1 β and TNF- α and improves the survival rate after induction of intracerebral hemorrhage (ICH) compared with wild-type (WT) mice [ 108 ]. TLR4 deficiency suppresses the inflammatory factors IL-1 β and TNF- α and improves cognitive dysfunction in β 2-microglobulin- (B2M-) induced age-related cognitive decline compared with WT mice [ 109 ].…”

Characterization of a novel model of global forebrain ischaemia–reperfusion injury in mice and comparison with focal ischaemic and haemorrhagic stroke

“…Caspase3/7 activity doubled in the site ipsilateral to the transient 30 min occlusion but was 3 × in the site ipsilateral to the permanent occlusion, accurately mirroring the infarct volume data. Increased cytochrome c, a pre-cursor to caspase-3 cleavage in the intrinsic apoptosis pathway has been reported at 24 h in rat ICH models involving autologous blood-injection 31 and increased apoptotic activity has been reported at the same time point in rat 32 and mouse models 33 of collagenase injections. Caspase activity was increased fourfold in the ipsilateral cortex in our model, which was ~ 2 × that seen in the MCAo and DCAL models at the same timepoint.…”

Toll-Like Receptor Signaling Pathways: Novel Therapeutic Targets for Cerebrovascular Disorders

“…ICH occurs when blood vessels in the brain rupture due to various pathological conditions, such as hypertension and microangiopathy [ 192 ]. Blood leakage in the surrounding tissue leads to edema, changes in cerebral blow flow (CBF), and neuronal injury with various mechanisms, including activation of inflammatory cascades [ 193 , 194 ]. Both the primary ICH and the surrounded cerebral edema play a critical role in post-hemorrhagic secondary brain injury [ 195 , 196 ].…”