TLR2 has a detrimental role in mouse transient focal cerebral ischemia

Ziegler, Gina; Harhausen, Denise; Schepers, C.; Hoffmann, Olaf; Röhr, Christina; Prinz, Vincent; König, Janett; Lehrach, Hans; Nietfeld, Wilfried; Trendelenburg, George

doi:10.1016/j.bbrc.2007.05.157

Cited by 218 publications

(235 citation statements)

References 23 publications

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“…TLR2 has been reported to be expressed in vascular endothelial cells and response to TLR2 ligands (Chen et al 2007). In addition, weak TLR2 expression has also been observed in cerebral vascular endothelial cells in the ischemic brain (Ziegler et al 2007). In the present study, we investigated whether Pam3CSK4 preconditioning modulated the expression of TJ proteins.…”

Section: Discussionmentioning

confidence: 99%

Preconditioning with a TLR2 specific ligand increases resistance to cerebral ischemia/reperfusion injury

Fang

et al. 2008

Journal of Neuroimmunology

118

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The brain's resistance to ischemic injury can be transiently augmented by prior exposure to a sublethal stress stimulus, i.e. preconditioning. It has been reported that Toll-like receptors (TLRs) are involved in the preconditioning-induced protective effect against ischemic brain injury. In this study, we investigated the effect of preconditioning with a TLR2 specific ligand, Pam3CSK4, on focal cerebral ischemia/reperfusion (I/R) injury in mice. Pam3CSK4 was administered systemically 24 hrs before the mice were subjected to focal cerebral ischemia (1 hr) followed by reperfusion. Cerebral infarct size was determined, blood brain barrier (BBB) permeability was evaluated, and expression of tight-junction proteins were examined after focal cerebral I/R. Results showed that pre-treatment with Pam3CSK significantly reduced brain infarct size (1.9 ± 0.5% vs 9.4 ± 2.2%) compared with the untreated I/R group. Pam3CSK4 pre-treatment also significantly reduced acute mortality (4.3% vs 24.2%), preserved neurological function (8.22 ± 0.64 vs 3.91 ± 0.57), and attenuated brain edema (84.61 ± 0.08% vs 85.29 ± 0.09%) after cerebral I/R. In addition, Pam3CSK4 pre-treatment preserved BBB function as evidenced by decreased leakage of serum albumin (0.528 ± 0.026 vs 0.771 ± 0.059) and Evans Blue (9.23 ± 0.72 μg/mg vs 12.56 ± 0.65μg/mg) into brain tissue. Pam3CSK4 pretreatment also attenuated the loss of the tight junction protein occludin in response to brain I/R injury. These results suggest that TLR2 is a new target of ischemic preconditioning in the brain and preconditioning with a TLR2 specific ligand will protect the brain from I/R injury.

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Section: Discussionmentioning

confidence: 99%

Preconditioning with a TLR2 specific ligand increases resistance to cerebral ischemia/reperfusion injury

Fang

et al. 2008

Journal of Neuroimmunology

118

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“…The expression of TLR2 is upregulated in cerebral ischaemia and similar to TLR4, mice lacking TLR2 had smaller infarct size compared to WT mice [64]. The scavenger receptor CD36 is a coreceptor for TLR1/2 and TLR2/6 heterodimers and cerebral injection of ligands for TLR1/2, but not ligands for TLR2/6 or TLR4, produced an inflammatory response that was dependent on CD36.…”

Section: Page 18 Of 62mentioning

confidence: 96%

Evaluating the role of Toll-like receptors in diseases of the central nervous system

Carty

Bowie

2011

Biochemical Pharmacology

134

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A key part of the innate immune system is a network of pattern recognition receptors (PRRs) and their associated intracellular signalling pathways. Toll-like receptors (TLRs) are one such group of PRRs that detect pathogen associated molecular patterns (PAMPs). Activation of the TLRs with their respective agonists results in the activation of intracellular signalling pathways leading to the expression of proinflammatory mediators and anti-microbial effector molecules. Activation of the innate immune system through TLRs also triggers the adaptive immune response, resulting in a comprehensive immune program to eradicate invading pathogens. It is now known that immune surveillance and inflammatory responses occur in the central nervous system (CNS). Furthermore it is becoming increasingly clear that TLRs have a role in such CNS responses andare also implicated in the pathogenesis of a number of conditions in the CNS, such as Alzheimer's, stroke and multiple sclerosis. This is likely due to the generation of endogenous TLR agonists in these conditions which amplifies a detrimental neurotoxic inflammatory response. However TLRs in some situations can be neuroprotective, if triggered in a favourable context. This review aims to examine the recent literature on TLRs in the CNS thus demonstrating their importance in a range of infectious and non-infectious diseases of the brain.

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“…In the recent work, Lehnardt et al [83] and Ziegler et al [147] reported smaller infarction size in the mice lacking TLR2 receptors, yet, on the other hand, the same signaling pathway has been reported instrumental for brain neurogenesis [117]. From the experimental results, it is conceivable that in acute response to injuries activated microglial cells may play an early detrimental role that can be converted into supportive role in the later, chronic phase of the brain response to ischemic injury.…”

Section: Tlrs Response To Ischemic Injury and Neurogenesismentioning

confidence: 96%

“…More particularly, TLR2 and TLR4 can interact with endogenous alarm signals such as heat shock proteins (Hsp60 and 70), extracellular breakdown product of hyaluron lipoproteins, etc., suggesting that TLRs may be involved in the regulation of inXammatory response following brain injuries [5,47,106] and neurodegeneration [99,105]. Recent studies demonstrated that TLRs, in particular TLR2 may be an important mediator of CNS ischemic injury [83,147]. The induction of TLR2 has been also observed in the activated microglial cells in other types of brain injuries.…”

Section: Tlrs Response To Ischemic Injury and Neurogenesismentioning

confidence: 99%

Inflammation, plasticity and real-time imaging after cerebral ischemia

2009

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With an incidence of approximately 350 in 100,000, stroke is the third leading cause of death and a major cause of disability in industrialized countries. At present, although progress has been made in understanding the molecular pathways that lead to ischemic cell death, the current clinical treatments remain poorly eVective. There is mounting evidence that inXammation plays an important role in cerebral ischemia. Experimentally and clinically, brain response to ischemic injury is associated with an acute and prolonged inXammatory process characterized by the activation of resident glial cells, production of inXammatory cytokines as well as leukocyte and monocyte inWltration in the brain, events that may contribute to ischemic brain injury and aVect brain recovery and plasticity. However, whether the post-ischemic inXammatory response is deleterious or beneWcial to brain recovery is presently a matter of debate and controversies. Here, we summarize the current knowledge on the molecular mechanisms underlying post-ischemic neuronal plasticity and the potential role of inXammation in regenerative processes and functional recovery after stroke. Furthermore, because of the dynamic nature of the brain inXammatory response, we highlight the importance of the development of novel experimental approaches such as real-time imaging. Finally, we discuss the novel transgenic reporter mice models that have allowed us to visualize and to analyze the processes such as neuroinXammation and neuronal repair from the ischemic brains of live animals.

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TLR2 has a detrimental role in mouse transient focal cerebral ischemia

Cited by 218 publications

References 23 publications

Preconditioning with a TLR2 specific ligand increases resistance to cerebral ischemia/reperfusion injury

Preconditioning with a TLR2 specific ligand increases resistance to cerebral ischemia/reperfusion injury

Evaluating the role of Toll-like receptors in diseases of the central nervous system

Inflammation, plasticity and real-time imaging after cerebral ischemia

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