Toll-like receptors 2 and 4 in ischemic stroke: outcome and therapeutic values - PubMed (original) (raw)

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

David Brea et al. J Cereb Blood Flow Metab. 2011 Jun.

Abstract

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)1β, IL6, tumor necrosis factor α, 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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Figures

Figure 1

Figure 1

TLR2 (A) and TLR4 (B) expression by the score of the Rankin scale evaluated at 3 months. CI, confidence interval; mRs, Modified Rankin Scale; TLR, Toll-like receptor.

Figure 2

Figure 2

Graphic representations of Pearson coefficients between the expression of TLR2 and 4 on admission (n_=110 patients), and levels of inflammatory (interleukin (IL)1_β, tumor necrosis factor α (TNF_α_), IL6, and matrix metalloproteinases 9 (MMP9)) and adhesion molecules (VCAM1 and ICAM1) at baseline, 24 hours, 72 hours, and 7 days. Gray-shadowed points represent coefficients that were not statistically significant. Hollowed points represent statistically significant coefficients. ICAM1, Intercellular Cell Adhesion Molecule 1; TLR, Toll-like receptor; VCAM1, Vascular Cell Adhesion Molecule 1.

Figure 3

Figure 3

Graphical representation of levels of inflammatory markers in the supernatant of monocytes (left graphic) and human umbilical vein endothelial cells (HUVECs) (right graphic) cultured during 18 hours. (A) With culture medium (left bars labeled as ‘only medium'), with culture medium plus serum from healthy control subjects (bars on the center of the chart, labeled as ‘negative control') and with culture medium plus serum from ischemic patients (bars on the right of the chart, labeled as ‘positive control'); (B) with culture medium without any treatment (only medium), with culture medium with anti-TLR2 (medium+anti-TLR2), with culture medium with anti-TLR4 (medium+anti-TLR4), with culture medium with anti-cFN (medium+anti-cFN), with culture medium with anti-HSP60 (medium+anti-HSP60), and with culture medium with anti-HSP70 (medium+anti-HSP70); (C) with culture medium without pretreatment (positive control), and previously treated with anti-TLR2 (TLR2 blockade) anti-TLR4 (TLR4 blockade) and anti-TLR2 and 4 (TLR2/4 blockade); (D) with culture medium and serum from patients (positive control) and culture medium and serum from patients treated to block cFN blockade), HSP60 (HSP60 blockade), HSP70 (HSP70 blockade) and the three ligands at once (three ligands blockade) (*P<0.01). cFN, cellular fibronectin; IL, interleukin; TLR, Toll-like receptor; TNF, tumor necrosis factor.

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