Toll-like receptor (TLR) and inflammasome actions in the central nervous system

Hanamsagar, Richa; Hanke, Mark L.; Kielian, Tammy

doi:10.1016/j.it.2012.03.001

Cited by 177 publications

(133 citation statements)

References 105 publications

(139 reference statements)

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“…The molecular signaling which triggers inflammasome assembly after SCI has been previously studied. It has been proposed that danger signals such as high plasma glucose, β-amyloid, Tolllike receptor (TLR) ligands, uric acid, and ATP induce inflammasome activation [47][48][49][50][51]. In particular, the engagement of ATP with P2X4 or P2X7 purinergic receptors induces inflammasome activation.…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Promotes Neuron Survival through Down-Regulation of Neuronal NLRP1 Expression after Spinal Cord Injury

Lin

Wang

2017

The Spine Journal

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Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Promotes Neuron Survival through Down-Regulation of Neuronal NLRP1 Expression after Spinal Cord Injury

Lin

Wang

2017

The Spine Journal

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“…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)(9)(10). TLR4 has been shown to have a central role in retinal and CNS ischemia/reperfusion (I/R) injuries (11)(12)(13).…”

mentioning

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.

265

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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“…Microglia TLRs have important functions in activating innate immunity and regulating the transition from innate to acquired immune responses (40). An increasing amount of data showed the involvement of TLRs not only in inflammation but also in the modulation of learning, memory, and mood on the pathogenesis of AD (41).…”

Section: Discussionmentioning

confidence: 99%

Xanthoceraside Inhibits Pro-inflammatory Cytokine Expression in Aβ25–35/IFN-γ–Stimulated Microglia Through the TLR2 Receptor, MyD88, Nuclear Factor-κB, and Mitogen-Activated Protein Kinase Signaling Pathways

Zou

Wang

et al. 2013

J Pharmacol Sci

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Abstract. An accumulating body of evidence suggests that Alzheimer's disease (AD) is associated with microglia-mediated neuroinflammation and pro-inflammatory cytokine expression. Therefore, the suppression of neuroinflammation and pro-inflammatory cytokine might theoretically slow down the progression of AD. Xanthoceraside, a novel triterpenoid saponin extracted from the husks of Xanthoceras sorbifolia Bunge, has potent anti-inflammatory and neuroprotective effects. However, the molecular mechanism underlying its anti-inflammatory action remains unclear. In the present study, we attempted to determine the effects of xanthoceraside on the production of pro-inflammatory mediators in amyloid b [25][26][27][28][29][30][31][32][33][34][35] ) / interferon-g (IFN-g)-stimulated microglia. Our results indicated that xanthoceraside (0.01 and 0.1 mM) significantly inhibited the release of nitric oxide (NO) and pro-inflammatory cytokines interleukin-1b and tumor necrosis factor-a in a concentration-dependent manner. Reverse transcriptase-polymerase chain reaction and western blotting analyses showed that xanthoceraside decreased the Ab 25-35 /IFN-ginduced production of cyclooxygenase-2 and inducible NO synthase. These effects were accompanied by inhibited activities of nuclear factor-kB and mitogen-activated protein kinase through Toll-like receptor 2 in a myeloid differentiation protein 88-dependent manner. Our results provide support for the therapeutic potential of xanthoceraside in AD.

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Toll-like receptor (TLR) and inflammasome actions in the central nervous system

Cited by 177 publications

References 105 publications

Heme Oxygenase-1 Promotes Neuron Survival through Down-Regulation of Neuronal NLRP1 Expression after Spinal Cord Injury

Heme Oxygenase-1 Promotes Neuron Survival through Down-Regulation of Neuronal NLRP1 Expression after Spinal Cord Injury

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

Xanthoceraside Inhibits Pro-inflammatory Cytokine Expression in Aβ25–35/IFN-γ–Stimulated Microglia Through the TLR2 Receptor, MyD88, Nuclear Factor-κB, and Mitogen-Activated Protein Kinase Signaling Pathways

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