Toll-Like Receptor 4 Immunohistochemical Expression Is Enhanced in Macrophages of Symptomatic Carotid Atherosclerotic Plaques

Abstract

Background: A growing body of evidence supports a role for Toll-like receptor 4 (TLR4), a primary receptor of the innate immune system, in atherosclerosis initiation and progression. Carotid atheroma macrophages (MACs) and smooth muscle cells (SMCs) express TLR4; nevertheless, correlations with epidemiological and clinical variables and especially cerebrovascular symptomatology remain unsettled. Methods: Carotid atherosclerotic plaques were obtained by standard carotid endarterectomy on 157 patients with carotid artery disease (84 asymptomatic – 73 symptomatic). TLR4 expression in MACs and SMCs of carotid atheroma was detected by immunohistochemistry techniques. TLR4 positivity, overexpression and intensity of immunostaining in MACs and SMCs were correlated with cerebrovascular symptomatology, epidemiological and clinical variables. Results: MAC TLR4 positivity was noted in 129 (82.2%) patients. Patients receiving statins had significantly lower TLR4 expression. Rates of MAC TLR4 positivity were higher among symptomatic patients (odds ratio, OR = 5.1; 95% confidence interval, CI = 1.8–14.3; p < 0.001); the association was stronger for transient ischemic attacks. TLR4 overexpression was also significantly enhanced among symptomatic patients (OR = 2.3; 95% CI = 1.02–5.03; p < 0.05). No correlations were detected between SMC TLR4 expression and cerebrovascular symptoms. In multivariate models adjusting for age, gender, body mass index, hyperlipidemia and smoking, MAC TLR4 positivity was associated with a cerebrovascular event during the last 6 months (OR = 4; 95% CI = 1.2–13.3; p = 0.02). Conclusions: Symptomatic carotid artery plaques are characterized by increased expression of TLR4 in macrophages supporting a potential role for TLR4 in the pathophysiology and clinical presentation of cerebrovascular disease. Further investigation is warranted.

Correlation between thyroid autoantibodies and intracranial arterial stenosis in stroke patients with hyperthyroidism

“…Some studies have shown that immune responses contribute to atherosclerosis [8]. In autoimmune thyroiditis with euthyroidism, vascular studies of the brachial artery showed that endothelium-mediated arterial dilation was negatively correlated with TPO-Ab, which suggests that immune responses may cause endothelial dysfunction [9].…”

Augmented Osteogenic Responses in Human Aortic Valve Cells Exposed to oxLDL and TLR4 Agonist: A Mechanistic Role of Notch1 and NF-κB Interaction

“…Currently, it remains unclear whether oxLDL plays a role in the osteogenic responses in aortic valve cells. Interestingly, several studies indicate that oxLDL modulates TLR4 expression or signaling in macrophages, resulting in an enhanced cytokine response to TLR4 stimulation [18], [19], [20], [21], [22]. While oxLDL and bacterial products may co-exist in diseased aortic valves, the effect of oxLDL on TLR4-mediated osteogenic responses in human AVICs has not been determined.…”

Oxidized Low Density Lipoprotein Induces Bone Morphogenetic Protein-2 in Coronary Artery Endothelial Cells via Toll-like Receptors 2 and 4

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