Upregulated Expression of Toll-Like Receptor 4 in Monocytes Correlates with Severity of Acute Cerebral Infarction

Yang, Qingwu; Li, Jingcheng; Lü, Fenglin; Wen, Aiyou; Xiang, Jun; Zhang, Lili; Huang, Zhiyu; Wang, Jing-Zhou

doi:10.1038/jcbfm.2008.50

Cited by 100 publications

(84 citation statements)

References 36 publications

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“…Earlier studies have shown that poor outcome after stroke is associated with innate responses signaled through TLR4 in monocytes (Urra et al, 2009a;Yang et al, 2008). In this study, the expression of TLR4 disclosed no significant differences between monocyte subtypes, suggesting that other differences in monocyte subtypes affect stroke outcome.…”

Section: Figurecontrasting

confidence: 41%

“…Stroke may also induce monocyte deactivation, which is characterized by decreased HLA-DR expression and impaired production of proinflammatory cytokines on stimulation with lipopolysaccharide (Emsley et al, 2007;Haeusler et al, 2008). A higher expression of Toll-like receptor (TLR)4 in monocytes of patients with acute stroke was recently associated with poor prognosis (Urra et al, 2009a;Yang et al, 2008), in agreement with experimental data showing that TLR4-deficient mice have minor infarctions and less inflammatory response after an ischemic insult (Caso et al, 2007).…”

Section: Introductionmentioning

confidence: 61%

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Monocyte Subtypes Predict Clinical Course and Prognosis in Human Stroke

Urra

Villamor

Amaro

et al. 2009

J Cereb Blood Flow Metab

182

164

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The number of circulating monocytes increases after stroke. In this study, we assessed the time course and phenotype of monocyte subsets and their relationship with the clinical course and outcome in 46 consecutive stroke patients and 13 age-matched controls. The proportion of the most abundant 'classical' CD14 high CD16À monocytes did not change after stroke, whereas that of CD14 high CD16 + monocytes increased and CD14 dim CD16 + monocytes decreased. CD14 high CD16 + monocytes had the highest expression of TLR2, HLA-DR and the angiogenic marker, Tie-2; CD14 dim CD16 + monocytes had the highest expression of costimulatory CD86 and adhesion molecule CD49d. Platelet-monocyte interactions were highest in CD14 high CD16À monocytes and lowest in CD14 dim CD16 + monocytes. In adjusted models, 1/CD14 high CD16À monocytes were associated with poor outcome (OR: 1.38), higher mortality (OR: 1.40) and early clinical worsening (OR: 1.29); 2/CD14 high CD16 + monocytes were inversely related to mortality (OR: 0.32); and 3/CD14 dim CD16 + monocytes were inversely related to poor outcome (OR: 0.74) and infarction size (r = À0.45; P = 0.02). These results illustrate that the predominant monocyte subtype conveys harmful effects after stroke, which include stronger interaction with platelets. Alternatively, rarer subpopulations of monocytes are beneficial with a phenotype that could promote tissue repair and angiogenesis. Therefore, monitoring of monocyte subtypes may emerge as a useful tool at the bedside for stroke patients.

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Section: Figurecontrasting

confidence: 41%

Section: Introductionmentioning

confidence: 61%

Monocyte Subtypes Predict Clinical Course and Prognosis in Human Stroke

Urra

Villamor

Amaro

et al. 2009

J Cereb Blood Flow Metab

182

164

View full text Add to dashboard Cite

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“…However, these studies were conducted using recombinant proteins (Lasarte et al, 2007) or selected serum (Yang et al, 2008), instead of a pool of serum from ischemic stroke patients. Besides, they have used transformed cells instead of cells from human origin.…”

Section: Discussionmentioning

confidence: 99%

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

Brea

Blanco

Ramos‐Cabrer

et al. 2011

J Cereb Blood Flow Metab

154

103

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Stroke triggers an intense inflammatory response that could be a consequence of Toll-like receptors (TLRs) activation. However, the clinical significance and the therapeutic possibilities of TLR in stroke is not completely clear. In this study, we analyze the association between the expression of TLR2 and TLR4, inflammatory molecules and endogenous ligands, and clinical outcome of ischemic stroke patients, and we test the potential of TLR2/TLR4 and their endogenous ligands as therapeutic targets. For this purpose, we included 110 patients with ischemic stroke finding that TLR2 and TLR4 are independently associated to poor outcome and correlated with higher serum levels of interleukin (IL)1b, IL6, tumor necrosis factor a, and VCAM1, and that TLR4 was independently associated to lesion volume. In addition, we have developed an in vitro model to test the potential therapeutic value of blocking TLR2/TLR4 or their endogenous ligands. Cultured cells (monocytes and human umbilical vein endothelial cells) were treated with serum from ischemic stroke patients, showing a strong inflammatory response that was blocked when TLR2/4 or cellular fibronectin (cFN) or HSP60 were blocked. In conclusion, TLR2 and TLR4 are associated to outcome in stroke patients and TLR2/ 4 or their endogenous ligands, cFN/HSP60 could be new therapeutic targets for ischemic stroke.

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“…During the preparation of the manuscript, a work has been published 43 showing an increase in circulating TLR4 ϩ monocytes in a group of 19 patients with acute ischemic stroke. Moreover, the expression of TLR4 correlated with stroke severity at 10 days.…”

Section: Disclosuresmentioning

confidence: 99%

Monocytes Are Major Players in the Prognosis and Risk of Infection After Acute Stroke

Urra

Cervera

Obach

et al. 2009

Stroke

178

151

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Background and Purpose-Monocytes participate in adaptive and innate immune responses. Monocyte numbers increase in patients with stroke associated infection (SAI) or severe stroke. Whether changes in monocytes are related to specific effects, or simply mark brain damage, remains unsettled. Methods-We used flow cytometry in 45 consecutive strokes and 12 healthy controls to assess the time course of monocytes, their phenotype, and the production of cytokines after stimulation. Cortisol, TNF-␣, IFN-␥, and IL-10 were measured in serum and metanephrine in plasma. The effects of humoral and cellular parameters on the risk of SAI and poor outcome were tested in multivariate analyses adjusted for confounders (NIHSS score, age, and tube feeding). Results-Surface expression of human leukocyte antigen-DR, Toll-like receptor-2, and production of TNF-␣ in monocytes were independently associated with stroke. Distinct immune mechanisms were related with functional outcome and the risk of SAI; the signature of SAI included an increase of cortisol, metanephrine, and IL-10 in serum, and reduced production of TNF-␣ in monocytes; poor outcome was associated with increased expression of Toll-like receptor-4 in monocytes (OR, 9.61; 95% CI, 1.27-72.47). SAI did not predict poor outcome (OR, 5.63; 95% CI, Pϭ0.18). Conclusions-In human stroke, poor outcome is associated to innate responses mediated by Toll-like receptor-4 in monocytes. SAI may result from the immunosuppressive and antiinflammatory effects of corticoids, catecholamines, IL-10, and deactivated monocytes. Early treated SAI does not contribute significantly to additional brain damage. These findings encourage the exploration of strategies aimed to inhibit Toll-like receptor-4 signaling in acute stroke. (Stroke.

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Upregulated Expression of Toll-Like Receptor 4 in Monocytes Correlates with Severity of Acute Cerebral Infarction

Cited by 100 publications

References 36 publications

Monocyte Subtypes Predict Clinical Course and Prognosis in Human Stroke

Monocyte Subtypes Predict Clinical Course and Prognosis in Human Stroke

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

Monocytes Are Major Players in the Prognosis and Risk of Infection After Acute Stroke

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