Toll-like receptors 2 and 4 in ischemic stroke: Outcome and therapeutic values

Brea, David; Blanco, Miguel; Ramos‐Cabrer, Pedro; Moldes, Octavio; Arias, Susana; Pérez‐Mato, María; Leira, Rogelio; Sobrino, Tomás; Castillo, José

doi:10.1038/jcbfm.2010.231

Cited by 155 publications

(111 citation statements)

References 21 publications

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“…Post-ischemic inflammation and subsequent ischemic damage depend on TLR2 and TLR4, but not TLR9 (Hyakkoku et al 2010), because TLR2-or TLR4-deficiency significantly attenuates ischemic brain damage and suppresses inflammatory cytokine expression in infiltrating immune cells on day 1 after ischemia-reperfusion in mice (Shichita et al 2012). The clinical relevance of TLR2 and TLR4 in stroke patients has been also demonstrated (Brea et al 2011). Despite these findings about the importance of TLR, the mechanisms responsible for activating them in infiltrating immune cells, such as macrophages and T cells, are not yet fully understood.…”

Section: Tlrs As Damps Receptorsmentioning

confidence: 93%

Novel therapeutic strategies targeting innate immune responses and early inflammation after stroke

Shichita

Ago

Kamouchi

et al. 2012

Journal of Neurochemistry

129

102

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Post-ischemic inflammation is an essential step in the progression of ischemic stroke. This review focuses on the function of infiltrating immune cells, macrophages, and T cells, in ischemic brain injury. The brain is a sterile organ; however, the activation of Toll-like receptor (TLR) 2 and TLR4 is pivotal in the beginning of post-ischemic inflammation. Some endogenous TLR ligands are released from injured brain cells, including high mobility group box 1 and peroxiredoxin family proteins, and activate the infiltrating macrophages and induce the expression of inflammatory cytokines. Following this step, T cells also infiltrate into the ischemic brain and mediate postischemic inflammation in the delayed phase. Various cytokines from helper T cells and cdT cells function as neurotoxic (IL-23/IL-17, IFN-c) or neuroprotective (IL-10, IL-4) mediators. Novel neuroprotective strategies should therefore be developed through more detailed understanding of this process and the regulation of post-ischemic inflammation. Keywords: cytokine, DAMPs, macrophage, T cell, TLR. J. Neurochem. Stroke is a leading cause of death and disability worldwide, and approximately, 70-80% of all cases are ischemic stroke. The only globally approved treatment for ischemic stroke is the intravenous administration of alteplase [tissue plasminogen activator (tPA)], which is a time-dependent therapy that must be provided within 4.5 h after the stroke onset. Thus, the beneficial effect of tPA is limited to a small proportion of stroke patients. There is a need for an efficacious therapy that can be administered beyond this time window (Lo 2010;Moskowitz et al. 2010).Post-ischemic inflammation is an essential step in ischemic brain injury (Eltzschig and Eckle 2011;Iadecola and Anrather 2011). The primary (acute) and secondary (delayed) progression of the infarct lesion are directly linked to the prognosis of ischemic stroke patients. The deprivation of oxygen, glucose, and other nutrients caused by the insufficient blood supply results in the dysfunction of cerebrovascular units, which consist of glial cells, endothelial cells, Received May 31, 2012; revised manuscript received July 9, 2012; accepted July 20, 2012. Address correspondence and reprint requests to Hiroaki Ooboshi, Department of Internal Medicine, Fukuoka Dental College Medical and Dental Hospital, 2-15-1 Tamura, Sawara-ku, Fukuoka 814-0193, Japan. E-mail: ooboshi@college.fdcnet.ac.jp Abbreviations used: BBB, blood-brain barrier; BM, bone marrow; DAMPs, danger-associated molecular patterns; HMGB1, high mobility group box 1; ICAM-1, intercellular adhesion molecule-1; MMPs, matrix metalloproteinases; NKT, natural killer T; Prx, peroxiredoxin; ROS, reactive oxygen species; S1P, Sphingosine-1-phosphate; TCR, T-cell receptor; TLRs, Toll-like receptors; TNF, Tumor necrosis factor; tPA, tissue plasminogen activator. pericytes, and neurons (del Zoppo 2006;Iadecola 2004;Kamouchi et al. 2011). Brain cells fail to maintain the neuronal microenvironment, leading to blood-brain barrier (B...

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Section: Tlrs As Damps Receptorsmentioning

confidence: 93%

Novel therapeutic strategies targeting innate immune responses and early inflammation after stroke

Shichita

Ago

Kamouchi

et al. 2012

Journal of Neurochemistry

129

102

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“…Some authors have reported improved survival and functional outcome associated with statin treatment, but these findings have not been consistently replicated. [15][16][17][18][19][20][21][22][23][24][25][26][27][28][31][32][33][34][35][36] Interpretations can be difficult because of limited sample sizes in some reports and possible bias in statin allocation in other studies, particularly those in which statins were allocated in a nonrandomized fashion. Some authors have also reported worse outcomes in patients treated with the combination of acute statins and intravenous thrombolysis.…”

mentioning

confidence: 99%

Statin Therapy and Outcome After Ischemic Stroke

Chróinín

Asplund

Åsberg

et al. 2013

Stroke

206

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Background and Purpose-Although experimental data suggest that statin therapy may improve neurological outcome after acute cerebral ischemia, the results from clinical studies are conflicting. We performed a systematic review and meta-analysis investigating the relationship between statin therapy and outcome after ischemic stroke. Methods-The primary analysis investigated statin therapy at stroke onset (prestroke statin use) and good functional outcome (modified Rankin score 0 to 2) and death. Secondary analyses included the following: (1) acute poststroke statin therapy (≤72 hours after stroke), and (2) thrombolysis-treated patients. Results-The primary analysis included 113 148 subjects (27 studies). Among observational studies, statin treatment at stroke onset was associated with good functional outcome at 90 days (pooled odds ratio [OR], 1.41; 95% confidence interval [CI], 1.29-1.56; P<0.001), but not 1 year (OR, 1.12; 95% CI, 0.9-1.4; P=0.31), and with reduced fatality at 90 days (pooled OR, 0.71; 95% CI, 0.62-0.82; P<0.001) and 1 year (OR, 0.80; 95% CI, P=0.01). In the single randomized controlled trial reporting 90-day functional outcome, statin treatment was associated with good outcome (OR, 1.5; 95% CI, 1.0-2.24; P=0.05). No reduction in fatality was observed on meta-analysis of data from 3 randomized controlled trials (P=0.9). In studies restricted to of thrombolysis-treated patients, an association between statins and increased fatality at 90 days was observed (pooled OR, 1.25; 95% CI, 1.02-1.52; P=0.03, 3 studies, 4339 patients). However, this association was no longer present after adjusting for age and stroke severity in the largest study (adjusted OR, 1.14; 95% CI, 0.90-1.44; 4012 patients). Conclusion-In the largest meta-analysis to date, statin therapy at stroke onset was associated with improved outcome, a finding not observed in studies restricted to thrombolysis-treated patients. 5-12 Experimental and clinical data also provide some evidence that statins may have neuroprotective effects after acute cerebral ischemia. [7][8][9][10][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] In animal models, treatment with statins either before, or early after, cerebral arterial occlusion has been associated with reduced infarct volume and improved neurological function. [5][6][7][8][9][10]13,14 Data are conflicting regarding the relationship between acute statin therapy and outcome after human ischemic stroke. Some authors have reported improved survival and functional outcome associated with statin treatment, but these findings have not been consistently replicated. [15][16][17][18][19][20][21][22][23][24][25][26][27][28][31][32][33][34][35][36] Interpretations can be difficult because of limited sample sizes in some reports and possible bias in statin allocation in other studies, particularly those in which statins were allocated in a nonrandomized fashion. Some authors have also reported worse outcomes in patients treated with the combination of acute statins and intravenous thro...

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“…A significant role for TLR4 in the pathogenesis of stroke has been reported by several studies [47,48]. There are several animal models for ischemia, and the role of TLR4 in ischemia and stoke has been investigated in these models.…”

Section: Tlr4 and Strokementioning

confidence: 99%

The Possible Role of Toll-Like Receptor 4 in the Pathology of Stroke

Hakimizadeh

Arababadi

Shamsizadeh

et al. 2016

Neuroimmunomodulation

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Stroke is a prevalent and dangerous health problem, which triggers an intense inflammatory response to Toll-like receptor (TLR) activation. TLRs are the essential components of the response of the innate immunity system, and, therefore, they are one of the key factors involved in recognizing pathogens and internal ligands. Among TLRs, TLR4 significantly participates in the induction of inflammation and brain functions; hence, it has been hypothesized that this molecule is associated with several immune-related brain diseases such as stroke. It has also been proved that animals with TLR4 deficiency have higher protection against ischemia and that the absence of TLR4 reduces neuroinflammation and injuries associated with brain trauma. TLR4 deficiency may play a neuroprotective role in the occurrence of stroke. This article reviews recent information regarding the impact of TLR4 on the pathogenicity of stroke.

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Toll-like receptors 2 and 4 in ischemic stroke: Outcome and therapeutic values

Cited by 155 publications

References 21 publications

Novel therapeutic strategies targeting innate immune responses and early inflammation after stroke

Novel therapeutic strategies targeting innate immune responses and early inflammation after stroke

Statin Therapy and Outcome After Ischemic Stroke

The Possible Role of Toll-Like Receptor 4 in the Pathology of Stroke

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