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.2011 Feb 8;108(6):2372-7.
doi: 10.1073/pnas.1018515108. Epub 2011 Jan 10.

Unexpected protective role for Toll-like receptor 3 in the arterial wall

Affiliations

Unexpected protective role for Toll-like receptor 3 in the arterial wall

Jennifer E Cole et al. Proc Natl Acad Sci U S A..

Abstract

The critical role of Toll-like receptors (TLRs) in mammalian host defense has been extensively explored in recent years. The capacity of about 10 TLRs to recognize conserved patterns on many bacterial and viral pathogens is remarkable. With so few receptors, cross-reactivity with self-tissue components often occurs. Previous studies have frequently assigned detrimental roles to TLRs, in particular to TLR2 and TLR4, in immune and cardiovascular disease. Using human and murine systems, we have investigated the consequence of TLR3 signaling in vascular disease. We compared the responses of human atheroma-derived smooth muscle cells (AthSMC) and control aortic smooth muscle cells (AoSMC) to various TLR ligands. AthSMC exhibited a specific increase in TLR3 expression and TLR3-dependent functional responses. Intriguingly, exposure to dsRNA in vitro and in vivo induced increased expression of both pro- and anti-inflammatory genes in vascular cells and tissues. Therefore, we sought to assess the contribution of TLR3 signaling in vivo in mechanical and hypercholesterolemia-induced arterial injury. Surprisingly, neointima formation in a perivascular collar-induced injury model was reduced by the systemic administration of the dsRNA analog Poly(I:C) in a TLR3-dependent manner. Furthermore, genetic deletion of TLR3 dramatically enhanced the development of elastic lamina damage after collar-induced injury. Accordingly, deficiency of TLR3 accelerated the onset of atherosclerosis in hypercholesterolemic ApoE(-/-) mice. Collectively, our data describe a protective role for TLR signaling in the vessel wall.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
AthSMC exhibit enhanced expression and response to TLR3. (A) Concentration of IL-6 in the supernatants of SMC stimulated with various TLR agonists for 24 h are shown. Bars show mean ± SEM (n = 6 donors per group). AthSMC displayed enhanced expression of IL-6 when stimulated with Poly(I:C) and FSL-1 compared with AoSMC (**P < 0.01 and ***P < 0.001, respectively; rank ANCOVA). (B) The same data as inA are shown as fold change in IL-6 production between AthSMC and AoSMC following TLR agonist stimulation. Bars show mean ± SEM (n = 6 donors per group). (C) AthSMC and AoSMC were stimulated for 5 h with 25 μg/mL Poly(I:C) or left unstimulated. Genes induced by dsRNA in AoSMC (n = 3) and AthSMC (n = 7) were examined by quantitative PCR analysis using an Atherosclerosis RT2 Profiler PCR Array (SA Biosciences). Data are shown as mean ± SEM. Genes with a fold regulation greater than two are shown here. AthSMC displayed an enhanced expression of the indicated genes when stimulated with Poly(I:C) (*P < 0.05, **P < 0.01, ***P < 0.001; pairedt test vs. unstimulated). (D) Atherosclerosis-related and TLR-pathway–related genes were assessed using quantitative PCR gene arrays (SA Biosciences) with cDNA from unstimulated AoSMC and AthSMC. Genes with a statistically significant up-regulation greater than twofold are displayed here. Data shown are mean fold changes of gene expression ± SEM of AthSMC (n = 9) vs. AoSMC (n = 4) (*P < 0.05, **P < 0.01, ***P < 0.001; AthSMC vs. AoSMC; pairedt test). BIRC3, baculoviral inhibitor of apoptosis repeat-containing 3; CCL2, chemokine (C-C motif) ligand 2; CCL5, chemokine (C-C motif) ligand 5; ICAM1, intercellular adhesion molecule 1; LIF, leukemia inhibitory factor; SELE, E-selectin; VCAM1, vascular cell adhesion molecule 1; A20/TNFAIP3, tumor necrosis factor alpha-induced protein 3; IL-1R1, interleukin-1 receptor-1.
Fig. 2.
Fig. 2.
Aortic gene expression of both pro- and anti-inflammatory factors is induced by Poly(I:C) stimulation. Ten- and 30-wk-old C57BL/6, ApoE−/−, and TLR3−/− mice were stimulated with PBS or 250 μg Poly(I:C) in PBS. Twenty-four hours poststimulation, mice were killed, aortas harvested, and RNA extracted. Gene expression of CCL5 (A), IL-10 (B), VCAM-1 (C), and IFNβ (D) was examined by quantitative RT-PCR. Bars show overall mean ± SEM [n = 3–5 mice/group; *P < 0.05, **P < 0.01, ***P < 0.001; PBS vs. Poly(I:C); unpaired Student'st test].
Fig. 3.
Fig. 3.
TLR3 activation protects against neointima formation in response to carotid collar injury. (A) Representative photomicrographs of injured carotid arteries from C57BL/6 and TLR3−/− mice treated with PBS or Poly(I:C) stained for elastin and counterstained with hematoxylin. (Scale bars: 200 μm.) (B andC) Intima/media ratio (IMR) of carotid arteries 21 d after injury from C57BL/6 (B) and TLR3−/− (C) mice treated with PBS or Poly(I:C). Each dot represents the mean IMR per individual mouse. Line represents the mean IMR per group [n = 8–11; ***P < 0.001; PBS vs. Poly(I:C); unpaired Student'st test].
Fig. 4.
Fig. 4.
TLR3 activation protects against elastic lamina interruptions during carotid collar injury. (A) Representative photomicrographs of injured carotid arteries from C57BL/6 and TLR3−/− mice treated with PBS stained for elastin and counterstained with hematoxylin. Arrows denote area of breakage of the elastic laminae. (Scale bars: 200 μm.) (B) Table detailing number of mice in which a breakage in the elastic lamina was observed [n = 8–10 mice/group; *P < 0.05 C57BL/6 PBS vs. TLR3−/− PBS;§P < 0.05 TLR3−/− PBS vs. TLR3−/− Poly(I:C); χ2 test] and the average size of observed breaks [n = 8–10 mice/group; **P < 0.01 C57BL/6 PBS vs. TLR3−/− PBS;§P < 0.05 TLR3−/− PBS vs. TLR3−/− Poly(I:C); Mann–WhitneyU test]. (C) Graph showing the average number of segments of the injured carotid artery of the five examined for each mouse that were affected or unaffected by elastic lamina breakage [n = 8–10 mice/group; ***P < 0.001 C57BL/6 PBS vs. TLR3−/− PBS;§§§P < 0.001 TLR3−/− PBS vs. TLR3−/− Poly(I:C); χ2 test].
Fig. 5.
Fig. 5.
TLR3 deficiency accelerates early atherosclerotic lesion development in the aortic root. (A) Representative photomicrographs of aortic roots from 15-wk ApoE−/− and ApoE−/−TLR3−/− mice stained with Oil Red O and hematoxylin. (Scale bars: 500 μm.) (B) Cross-sectional aortic root lesion area (×103 μm2) in 15-wk ApoE−/− and ApoE−/−TLR3−/− mice. (C) Cross-sectional aortic root lesion area (%) in 15-wk ApoE−/− and ApoE−/−TLR3−/− mice. (B andC) Each circle represents the mean lesional area per individual mouse. Line represents the mean lesional area per group (n = 7–8; *P < 0.05; unpaired Student'st test).
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Comment in

  • Toll in the vessel wall--for better or worse?
    Hansson GK, Lundberg AM.Hansson GK, et al.Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2637-8. doi: 10.1073/pnas.1019722108. Epub 2011 Feb 3.Proc Natl Acad Sci U S A. 2011.PMID:21292987Free PMC article.No abstract available.

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