Impaired LPS tolerance in monocytes of coronary atherosclerosis patients is associated with the intermediate subset

Endotoxin tolerance in monocytes is a mechanism that reduces the secretion of inflammatory cytokines upon repeated pathogen exposure, thereby protecting tissues from hyperinflammation. Previously, we demonstrated that monocytes from patients with asymptomatic carotid atherosclerosis exhibit impaired LPS tolerance. In this study, we aimed to investigate monocyte tolerance impairments in coronary atherosclerosis in greater detail. The study included 46 male patients with ischemic heart disease, divided into two groups based on coronary angiography results with and without coronary atherosclerosis. CD14 + monocytes were isolated from patients' blood and subjected to LPS stimulation on days 1 and 7 of culture. Transcriptomic analysis of monocytes was conducted. Monocyte subpopulations were assessed and sorted based on CD14 and CD16 expression. Patients with coronary atherosclerosis exhibited disrupted inflammatory responses in monocytes, characterized by elevated basal and LPS-induced IL-1β secretion. These patients demonstrated impaired LPS tolerance, as evidenced by increased CCL2 secretion upon repeated stimulation. Transcriptomic analysis revealed upregulation of inflammatory genes, particularly those associated with minor CD16 + monocyte subpopulations. The proportions of non-classical and intermediate monocytes were elevated in patients with atherosclerosis, with IL-1β and CCL2 secretion levels correlating predominantly with the intermediate monocyte subset. Functional analysis revealed that non-classical monocytes from healthy donors developed stable endotoxin tolerance. In contrast, intermediate and classical monocytes from some donors exhibited a non-tolerant response to LPS, as evidenced by secretion of IL-1β, IL-6, and CCL2. The differentiation of classical monocytes into intermediate monocytes may play a key role in the impaired endotoxin tolerance observed in atherosclerosis.