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

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. Copyright (C) 2010 S. Karger AG, Basel