Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice

Can-xiang, Cao; Yang, Qingwu; Lv, Fenglin; Cui, Jie; Fu, Hua-bin; Wang, Jing-Zhou

doi:10.1016/j.bbrc.2006.12.057

Cited by 223 publications

(191 citation statements)

References 30 publications

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“…However, the full extent and mechanisms of IFN signaling in IPCmediated protection remain to be explored. The cellular source of IFN-β in the postischemic brain is unknown, but there are several possible sources such as peripheral macrophages [53,54] and astrocytes [55][56][57][58]. Published studies also suggest neurons [59] are capable of releasing IFN-β under specific conditions.…”

Section: Molecular Mediators Of Preconditioningmentioning

confidence: 99%

Neuroimmune Response in Ischemic Preconditioning

McDonough

Weinstein

2016

Neurotherapeutics

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Ischemic preconditioning (IPC) is a robust neuroprotective phenomenon in which a brief period of cerebral ischemia confers transient tolerance to subsequent ischemic challenge. Research on IPC has implicated cellular, molecular, and systemic elements of the immune response in this phenomenon. Potent molecular mediators of IPC include innate immune signaling pathways such as Toll-like receptors and type 1 interferons. Brain ischemia results in release of proand anti-inflammatory cytokines and chemokines that orchestrate the neuroinflammtory response, resolution of inflammation, and transition to neurological recovery and regeneration. Cellular mediators of IPC include microglia, the resident central nervous system immune cells, astrocytes, and neurons. All of these cell types engage in cross-talk with each other using a multitude of signaling pathways that modulate activation/ suppression of each of the other cell types in response to ischemia. As the postischemic neuroimmune response evolves over time there is a shift in function toward provision of trophic support and neuroprotection. Peripheral immune cells infiltrate the central nervous system en masse after stroke and are largely detrimental, with a few subtypes having beneficial, protective effects, though the role of these immune cells in IPC is largely unknown. The role of neural progenitor cells in IPC-mediated neuroprotection is another active area of investigation as is the role of microglial proliferation in this setting. A mechanistic understanding of these molecular and cellular mediators of IPC may not only facilitate more effective direct application of IPC to specific clinical scenarios, but also, more broadly, reveal novel targets for therapeutic intervention in stroke.

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Section: Molecular Mediators Of Preconditioningmentioning

confidence: 99%

Neuroimmune Response in Ischemic Preconditioning

McDonough

Weinstein

2016

Neurotherapeutics

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“…TLR4 may also contribute the process of neuronal death (Lehnardt et al, 2003). Recent reports indicate that brain infarct size and inflammatory responses are reduced in TLR4 deficient mice after occlusion of the middle cerebral artery (Cao et al, 2006;Caso et al, 2007). However, the mechanisms by which TLR4 signaling in ischemia-induced neuronal death/apoptosis remain unknown.…”

Section: Discussionmentioning

confidence: 99%

“…TLR4 is also involved in the pathogenesis of I/R injury in liver (Zhai et al, 2004), kidney (Kim et al, 2005) and lung tissues (Shimamoto et al, 2006), TLRs have been identified in the central nervous system (CNS) and are thought to play an important role in the brain's response to pathogens as well as toxic cell debris (Bottcher et al, 2003;Bsibsi et al, 2002;Maslinska et al, 2004) and inflammatory or autoimmune CNS diseases (Chakravarty and Herkenham, 2005;Kerfoot et al, 2004). Recent studies (Cao et al, 2006;Caso et al, 2007) using a permanent and longstanding focal cerebral ischemia model have shown that infarct size is reduced in TLR4-deficient mice compared with wild type (WT) mice. It is still unclear why TLR4 deficiency results in the protection of brain from ischemic injury.…”

Section: Introductionmentioning

confidence: 99%

Activation of Toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion

Fang

et al. 2007

Journal of Neuroimmunology

191

156

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Toll-like receptors (TLRs) play a critical role in the induction of innate immune responses which have been implicated in neuronal death induced by global cerebral ischemia/reperfusion (GCI/R). The present study investigated the role and mechanisms-of-action of TLR4 signaling in ischemiainduced hippocampal neuronal death. Neuronal damage, activation of the TLR4 signaling pathway, expression of pro-inflammatory cytokines and activation of the PI3K/Akt signaling pathway in the hippocampal formation (HF) were assessed in wild type (WT) mice and TLR4 knockout mice (TLR4 -/-) mice after GCI/R. GCI/R increased expression of TLR4 protein in the hippocampal formation (HF) and other brain structures in WT mice. Phosphorylation of the inhibitor of kappa B (p-IκB) as well as activation of nuclear factor kappa B (NFκB) increased in the HF of WT mice. In contrast, there were lower levels of p-IκB and NFκB binding activity in TLR4 -/-mice subjected to GCI/R. Pro-inflammatory cytokine expression was also decreased, while phosphorylation of Akt and GSK3β were increased in the HF of TLR4 -/-mice after GCI/R. These changes correlated with decreased neuronal death/apoptosis in TLR4 -/-mice following GCI/R. These data suggest that activation of TLR4 signaling contributes to ischemia-induced hippocampal neuronal death. In addition, these data suggest that modulation of TLR4 signaling may attenuate ischemic injury in hippocampal neurons.

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“…TLR4 signaling activation is actively involved in tissue damage following CNS ischemia (24,25). We further clarified the role of TLR4 in the development of IOP-induced retinal ischemia by using wildtype (WT) and TLR4 −/− mice.…”

Section: Tlr4 Signaling Is Involved In the Development Of Iop-inducedmentioning

confidence: 99%

Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1β production in acute glaucoma

Chi

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

264

222

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Acute glaucoma is a sight-threatening condition characterized by a sudden and substantial rise in intraocular pressure (IOP) and consequent retinal ganglion cell (RGC) death. Angle closure glaucoma, a common cause of glaucoma in Asia that affects tens of millions of people worldwide, often presents acutely with loss of vision, pain, and high IOP. Even when medical and surgical treatment is available, acute angle closure glaucoma can cause permanent and irreversible loss of vision. Toll-like receptor 4 (TLR4) signaling has been previously implicated in the pathogenesis of IOP-induced RGC death, although the underlying mechanisms are largely unknown. In the present study, we used an acute IOP elevation/glaucoma model to investigate the underlying mechanism of RGC death. We found that TLR4 leads to increased caspase-8 expression; this elevation increases IL-1β expression and RGC death via a caspase-1-dependent pathway involving Nod-like receptor family, pyrin domain containing 1 (NLRP1)/NLRP3 inflammasomes and a caspase-1-independent pathway. We show that inhibition of caspase-8 activation significantly attenuates RGC death by down-regulating the activation of NLRP1 and NLRP3, thus demonstrating the pivotal role of caspase-8 in the TLR4-mediated activation of inflammasomes. These findings demonstrate collectively a critical role of caspase-8 in transducing TLR4-mediated IL-1β production and RGC death and highlight signal transduction in a caspase-1-dependent NLRP1/NLRP3 inflammasome pathway and a caspase-1-independent pathway in acute glaucoma. These results provide new insight into the pathogenesis of glaucoma and point to a treatment strategy.retinal ischemia/reperfusion injury | cell apoptosis A cute glaucoma is a significant cause of permanent vision loss and irreversible blindness worldwide (1). It is most common among people of Asian descent, in part due to their having a more crowded anterior chamber (2, 3). With a rapid increase in intraocular pressure (IOP) to levels exceeding retinal perfusion pressure, there is resulting retinal ischemia and retinal ganglion cell (RGC) death. Individuals with angle closure glaucoma are much more likely to lose vision and become blind than those with primary open-angle glaucoma (4). The precise mechanisms by which elevated IOP leads to RGC death are not well understood. Accumulating evidence suggests that overactivated microglia have pivotal roles in triggering neurotoxicity in the CNS, including retinal inflammatory responses (5, 6), by producing proinflammatory factors such as IL-1β. IL-1β production is tightly controlled as part of the innate immune response in the CNS (7).Toll-like receptors (TLRs) and Nod-like receptors (NLRs) are two key pattern recognition receptors (PRRs) in the initiation of the innate immune response (8-10). TLR4 has been shown to have a central role in retinal and CNS ischemia/reperfusion (I/R) injuries (11-13). Neuronal death following ischemic injury activates intense inflammation, which triggers TLR4 signaling. It has been demonstrated that ...

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Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice

Cited by 223 publications

References 30 publications

Neuroimmune Response in Ischemic Preconditioning

Neuroimmune Response in Ischemic Preconditioning

Activation of Toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion

Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1β production in acute glaucoma

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