Features of Gene Regulation in Violation of the Inflammatory Response of Monocyte-like Cells Bearing Mitochondrial Mutations Associated with Atherosclerosis.

Abstract

Inflammation plays an important, if not decisive, role in the occurrence of atherosclerotic lesions and then accompanies it throughout its further development. Thus, atherogenesis is a chronic inflammatory process. Chronification of inflammation is a consequence of disruption of the normal inflammatory response at the cell level of the vascular wall. In this study, we used cytoplasmic hybrids or cybrids carrying atherosclerosis-associated mitochondrial mutations to study gene regulation of inflammatory response. The main goal of the study was to identify the key genes responsible for the impaired inflammatory response revealed for some cybrids. Inflammatory stimulation of cybrids was induced with bacterial lipopolysaccharide, and assessed through secretion of pro-inflammatory cytokines CCL2, IL8, IL6, IL1b. A transcriptome analysis was performed to identify the key genes (master regulators) in the normal (tolerant) and intolerant response of cybrid cells. Normal inflammatory response after re-stimulation elicited a much smaller secretion of pro-inflammatory cytokines. In an intolerant response, the level of secretion upon re-stimulation was the same or even higher than after the first stimulation. Normal and intolerant responses differed significantly both in terms of the number of signaling pathways involved and qualitatively, since the signaling pathways for normal and intolerant responses are completely different. Master regulators controlling normal and intolerant inflammatory response were identified. For a normal response to the first inflammatory stimulation, no common master up-regulators and 3 master down-regulators were identified. The reverse situation was observed with the intolerant inflammatory response: 6 master up-regulators, and no master down regulators were identified. After the second inflammatory stimulation, no master regulator common to all studied cytokines was found. Thus, key genes involved in the development of intolerant inflammatory response have been identified. In addition, other key genes were identified that were initially associated with an intolerant inflammatory response and thus determine disorders of the inflammatory reaction leading to chronification of inflammation. We identified disturbances in gene associated with the development of intolerant immune response that may be relevant to atherosclerosis. Key genes responsible for the chronification of inflammation were discovered.