Impaired tolerance of monocyte-macrophages to lipopolysaccharide in patients with coronary atherosclerosis

Atherosclerosis is a chronic disease in which lipids, cells and various proteins accumulate in the walls of the arteries, forming atherosclerotic plaques. The growth of plaques leads narrowing of the lumen of the blood vessels. Atherosclerosis is accompanied by local inflammation, while the number of hematogenous macrophages are derived from monocytes increases in the vascular wall. The reasons why the inflammatory reaction cannot be completed and becomes chronic are not clear. To resolve inflammation and protect tissues from high concentrations of cytokines that can cause apoptosis, there is a mechanism of immune tolerance of innate immunity. Lipopolysaccharide (LPS) tolerance of monocyte-macrophages is a phenomenon in which cells reduce their sensitivity to repeated exposure to LPS. This condition is characterized by a decrease in the ability of macrophages to produce proinflammatory cytokines and promotes resolution of inflammation. We hypothesized that in atherosclerosis, tolerance violations in monocyte-macrophages are possible. The study included patients who were admitted to the department of cardiac surgery, Moscow Regional Research and Clinical Institute (MONIKI). Patients were divided into patients with coronary atherosclerosis (CAD) with detected stenosis in 2 or more arteries and healthy controls without stenosis in the arteries according to the results of coronary angiography. In the present study, we examined the ability of macrophages from 13 patients with CAD and 11 patients without CAD to develop tolerance to LPS. To do this, we isolated CD14⁺ monocytes from the blood by positive selection using immunomagnetic separation and subjected them to two sequential LPS stimulations, immediately after cell isolation and after 6 days of culture. The secretion of cytokines TNFα, IL-1b, IL-6, IL-10, IL-8, and CCL2 was measured in cell culture supernatants using by ELISA. Our results showed impaired macrophage tolerance for CCL2 secretion and improved tolerance for IL-8 secretion in macrophages from patients with CAD compared with patients without. Since IL-8 and CCL2 are chemoattractants for other immune cells, it can be assumed that the observed impairment of macrophage tolerance to LPS in atherosclerosis increases the infiltration of other monocytes into the inflammatory site, contributing to the chronicity of inflammation.

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