Local immune activity in acute coronary syndrome: oxLDL abrogates LPS-tolerance in mononuclear cells isolated from culprit lesion

Abstract

BackgroundOxLDL plays a major role in the initiation and progression of atherosclerotic lesions even though further factors are needed to promote fibrous cap rupture and thrombotic occlusion of the arterial lumen. Pathogens have been implicated in this process but it remains unclear how they can cooperate with oxLDL in amplifying the destructive inflammatory response. ObjectiveTo phenotypically analyze culprit coronary inflammatory cells, evaluate their responsiveness to endotoxins and ascertain whether oxLDL alters the sensitivity of coronary mononuclear cells to bacterial components. MethodsMononuclear cells isolated from culprit and non-culprit coronary blood samples of patients with ST-segment elevation myocardial infarction (STEMI) and controls were analyzed for cell-specific surface markers and cytokines by flow-cytometry. Results and conclusionsCD14+ cells contained elevated levels of TLR4, expressed high CD80, and produced huge amounts of inflammatory cytokines in response to LPS. Using a well-established model of endotoxin tolerance, we next showed that mononuclear cells isolated from control coronary artery, but not from culprit coronary artery, were tolerant to LPS, but pre-treatment of such cells with oxLDL abrogated LPS tolerance. Flow-cytometry analysis also showed that IL-17A, IL-21 and IFN-γ were over-produced by CD4+ and CD56+ cells isolated from the culprit coronary artery. All this data indicate that monocytes circulating in the culprit coronary artery of patients with STEMI are primed to synthesize high levels of inflammatory cytokines and suggest that oxLDL can amplify the inflammatory response of such cells to endotoxins.