Trigeminal Nociceptors Express TLR-4 and CD14: a Mechanism for Pain due to Infection

Wadachi, R.; Hargreaves, Kenneth M.

doi:10.1177/154405910608500108

“…These activated microglia, in turn, release TNF-α, which induces neuron apoptosis in a caspase-3 dependent pathway [70]. There is a growing body of evidence that many neuronal subpopulations express TLRs, including TLR4 [132][133][134][135]. Mice with a defect in TLR4 are generally more resistant to CNS trauma [62], suggesting that TLR4 activation is detrimental to neuronal survival.…”

Section: Neuronsmentioning

confidence: 99%

Neuroimmune Response in Ischemic Preconditioning

McDonough

¹

,

Weinstein

²

2016

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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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“…In neuronal cells, LPS-induced inflammation causes neuronal loss and impaired memory (Hauss-Wegrzyniak et al, 1998;Monje et al, 2003). Recent studies have indicated that TLR-3 or TLR-4 is expressed in neurons (Maoeliñska et al, 2004;Wadachi and Hargreaves, 2006); however, the detailed processes regulated by these receptors remain unknown. In this study, the prefrontal cortex in rats and cultured cortical neurons were treated with LPS to assess the relationship between neuroinflammation and NR1 expression.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-Inducible Factor-1α Protects Cultured Cortical Neurons from Lipopolysaccharide-Induced Cell Death via Regulation of NR1 Expression

Yeh¹,

Hung²,

Gean³

et al. 2008

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Inflammation is involved in some neurodegenerative disorders. NMDA glutamate receptors play an important role in neuronal development. Here, we show that NR1 expression in the cerebral cortex and primary neurons of rats was upregulated after lipopolysaccharide (LPS) treatment. This increase in NR1 expression was considered to be strongly associated with hypoxia-inducible factor-1␣ (HIF-1␣) activation because the treatment of primary neurons with either echinomycin or small interfering RNA (siRNA) targeting HIF-1␣ could block NR1 expression. HIF-1␣ could be induced by an increase in the translational efficiency of the cells. After this, it was transported into the nucleus where it bound to the NR1 promoter and regulated the induction of NR1 transcriptional activity by LPS. LPS injection into the prefrontal cortex caused neuronal death, and this condition was aggravated by intracerebroventricular injection of echinomycin. Furthermore, knockdown of HIF-1␣ and NR1 by the appropriate siRNAs reduced the neurite outgrowth and viability of the primary neurons. These results suggest that NR1 expression is regulated by HIF-1␣ and plays a protective role in neurons during LPS challenge.

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“…These activated microglia, in turn, release TNF-α, which induces neuron apoptosis in a caspase-3 dependent pathway [70]. There is a growing body of evidence that many neuronal subpopulations express TLRs, including TLR4 [132][133][134][135]. Mice with a defect in TLR4 are generally more resistant to CNS trauma [62], suggesting that TLR4 activation is detrimental to neuronal survival.…”

Section: Neuronsmentioning

confidence: 99%

Correction to: Neuroimmune Response in Ischemic Preconditioning

McDonough

¹

,

Weinstein

²

2018

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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 Tolllike receptors and type 1 interferons. Brain ischemia results in release of pro-and anti-inflammatory cytokines and chemokines that orchestrate the neuroinflammatory 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. Keywords PreconditioningIschemic preconditioning (IPC) is an experimental phenomenon in which a brief period of ischemia confers robust neuroprotection against subsequent ischemic events [1-3]. It is important to note that preconditioning does not reduce the incidence of stroke, but rather ameliorates the pathophysiologic response to cerebral ischemia and results in a smaller infarct volume and improved poststroke recovery [4][5][6]. Clinical studies suggest that patients with stroke who suffered a recent prior transient ischemic attack have better outcomes than those who did not, implying that a human correlate to experimental IPC exists [7,8]. Elucidating the mechanisms of IPC is considered a critical challenge in stroke research [9,10]. Recent literature has implicated innate immune pathways, including Toll-like receptors (TLRs) [11,12] and type 1 interferon (IFN) signaling [5,11,13] in IPC-mediated protection.Due to a technical error in the production process, the earlier version of this article contained numerous errors in the reference numbering. We are reprinting the entire article in the correction for readabilityThe online version of the original article can be found at https://doi

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Trigeminal Nociceptors Express TLR-4 and CD14: a Mechanism for Pain due to Infection

Cited by 217 publications

References 34 publications

Neuroimmune Response in Ischemic Preconditioning

Neuroimmune Response in Ischemic Preconditioning

Hypoxia-Inducible Factor-1α Protects Cultured Cortical Neurons from Lipopolysaccharide-Induced Cell Death via Regulation of NR1 Expression

Correction to: Neuroimmune Response in Ischemic Preconditioning

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