Inhibition of Toll-like Receptor and Cytokine Signaling—A Unifying Theme in Ischemic Tolerance

Karikó, Katalin; Weissman, Drew; Welsh, Frank A.

doi:10.1097/01.wcb.0000145666.68576.71

Cited by 240 publications

(217 citation statements)

References 173 publications

(153 reference statements)

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“…The TLR family includes receptors for bacterial cell wall/membrane components such as lipotechoic acid (TLR2), peptidoglycan (TLR2), and LPS (TLR4) [16]. Activation of TLRs by endogenous ligands, also known as danger-associated molecular patterns (DAMPs), released from ischemia-injured cerebral vasculature and parenchyma is a possible mechanism for initiation of inflammatory responses in stroke [2,61]. A number of putative DAMPs, including heat shock proteins (HSPs) [62,63], especially HSP70 [64] and HSP60 [62]both will activate TLRs-have been identified in the brain.…”

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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“…A recent study has also shown a role of TLR3 in the recognition of RNA released by dying or dead cells (11,55,56). In this case, it was demonstrated that secondary structure creating hairpin loops within the mRNA was responsible for TLR3 activation.…”

Section: Discussionmentioning

confidence: 91%

Recognition of Double-stranded RNA by Human Toll-like Receptor 3 and Downstream Receptor Signaling Requires Multimerization and an Acidic pH

Bouteiller¹,

Merck²,

Hasan³

et al. 2005

Journal of Biological Chemistry

237

214

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Studies involving Toll-like receptor 3 (TLR3)-deficient mice suggest that this receptor binds double-stranded RNA. In the present study, we analyzed ligand/receptor interactions and receptor-proximal events leading to TLR3 activation. The mutagenesis approach showed that certain cysteine residues and glycosylation in TLR3 amino-terminal leucine-rich repeats were necessary for ligand-induced signaling. Furthermore, inactive mutants had a dominant negative effect, suggesting that the signaling module is a multimer. We constructed a chimeric molecule fusing the amino-terminal ectodomain of TLR3 to the transmembrane and carboxyl terminal domains of CD32a containing an immunoreceptor tyrosine-based motif. Expression of TLR3-CD32 in HEK293T cells and the myeloid cell line U937 resulted in surface localization of the receptor, whereas the nonrecombinant molecule was intracellularly local- Mammalian Toll-like receptors (TLRs) 7 belong to a family of receptors that recognize pathogen-associated molecular patterns. TLRs play a key role in host defense during pathogen infection by regulating and linking the innate and adaptive immune responses (1-3). TLRs are expressed in dendritic cells (DC), sentinels of the immune system, endowing them with the capacity to sense pathogen-derived products and to alert the immune system (4). Members of the TLR family are also variably expressed on nonhematopoietic cells. TLR-deficient mice and transfected cell lines have been the keys to understanding TLR function. Ligand specificity has been elucidated for most TLRs; thus, TLR2 and TLR4 recognize Gram-positive and Gram-negative bacterial cell wall products, respectively. TLR5 recognizes a structural epitope of bacterial flagellin, and TLR7, TLR8, and TLR9 have been demonstrated to recognize different forms of microbial-derived nucleic acid (5). Host-derived ligands for the TLRs have also been identified; in particular, TLR4 recognizes heat shock proteins and pulmonary surfactant (6), and TLR9 recognizes chromatin-IgG complexes (7).TLR3 has been extensively characterized to be a receptor for poly(I-C), a synthetic double-stranded RNA (dsRNA) mimic (8); recently, it has been shown to mediate responses to West Nile virus (9) as well as dsRNA derived from the helminth parasite Schistosoma (10). Additionally, host-derived mRNA has recently been shown to activate TLR3, suggesting that activation via TLR3 can occur in a variety of situations (11). Whereas most TLRs recruit myeloid differentiation factor 88 (12), with some variation in the signaling profile mediated by the additional recruitment of Toll/interleukin-1 receptor-containing adapter protein and TRIF-related adaptor molecule, TLR3 recruits only TRIF (13-15). TRIF can activate both NF-B through TRAF6 and receptor-interacting protein-1 (16) and interferon-regulatory factor 3 through IB kinase/ TANK-binding kinase 1 (17) and phosphoinositide 3-kinase (18). Although the signaling pathway of TLRs is increasingly well characterized, the parameters controlling interactions between the recept...

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“…Cytokines such as interleukin-1 (IL-1), and TNF-α are important mediators of the inflammatory reactions seen in cerebral ischemia. The importance of the cytokine system in the setting of ischemia was emphasized by Kariko et al [28] . TNF-α is one of the pro-inflammatory cytokines and is expressed in the ischemic brain.…”

Section: Inflammatory Cytokinesmentioning

confidence: 99%

The neuroprotective mechanism of brain ischemic preconditioning

2009

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Brain ischemia is one of the most common causes of death and the leading cause of adult disability in the world. Brain ischemic preconditioning (BIP) refers to a transient, sublethal ischemia which results in tolerance to later, otherwise lethal, cerebral ischemia. Many attempts have been made to understand the molecular and cellular mechanisms underlying the neuroprotection offered by ischemic preconditioning. Many studies have shown that neuroprotective mechanisms may involve a series of molecular regulatory pathways including activation of the N-methyl-D-aspartate (NMDA) and adenosine receptors; activation of intracellular signaling pathways such as mitogen activated protein kinases (MAPK) and other protein kinases; upregulation of Bcl-2 and heat shock proteins (HSPs); and activation of the ubiquitin-proteasome pathway and the autophagic-lysosomal pathway. A better understanding of the processes that lead to cell death after stroke as well as of the endogenous neuroprotective mechanisms by which BIP protects against brain ischemic insults could help to develop new therapeutic strategies for this devastating neurological disease. The purpose of the present review is to summarize the neuroprotective mechanisms of BIP and to discuss the possibility of mimicking ischemic preconditioning as a new strategy for preventive treatment of ischemia.

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Inhibition of Toll-like Receptor and Cytokine Signaling—A Unifying Theme in Ischemic Tolerance

Cited by 240 publications

References 173 publications

Neuroimmune Response in Ischemic Preconditioning

Neuroimmune Response in Ischemic Preconditioning

Recognition of Double-stranded RNA by Human Toll-like Receptor 3 and Downstream Receptor Signaling Requires Multimerization and an Acidic pH

The neuroprotective mechanism of brain ischemic preconditioning

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