Toll Like Receptor 2 and 4 stimulation elicits an enhanced inflammatory response in human obese patients with atherosclerosis.

Abstract

Abstract Objective. The innate immune response elicited by activation of toll like receptors (TLR) plays an important role in the pathogenesis of atherosclerosis. We hypothesized that cardiovascular risk factors are associated with the activation status of the innate immune system. We therefore assessed the responsiveness of TLR’s on circulating cells in 2 groups of patients with established atherosclerosis and related this to the presence of cardiovascular risk factors. Methods. TNF-alpha release induced by TLR 2 and 4 activation was measured in patients with established coronary (PCI study n=78) or carotid artery disease (CEA study n=104), by stimulating whole blood samples with Lipopolysaccharide (TLR4) and Pam3Cys-Ser-(Lys)4 (TLR2). As an early activation marker, CD11b expression was measured by flow-cytometry on CD14 positive cells. Results. Obesity was the only risk factor that correlated with TLR response. In both studies, obese patients had significantly higher TNF- alpha levels after stimulation of TLR2, compared with non-obese patients (median [IQR]pg/ml): coronary artery disease 16.9 [7.7 – 49.4] versus 7.5 [1.5 – 19.2] (p = 0.008) and carotid artery disease 14.6 [8.1 – 28.4] versus 9.5 [6.1 – 15.7] (p = 0.015). Similar results were obtained following TLR4 stimulation. The enhanced inflammatory state in obese patients, was also confirmed by an significant increased expression of the activation marker CD11b on circulating monocytes. Conclusion. Obesity is associated with an enhanced TLR response in patients suffering from established atherosclerotic disease.