Abstract
Atherosclerosis is a chronic inflammatory disease with atherosclerotic plaques containing inflammatory cells, including T-lymphocytes, dendritic cells (DCs) and macrophages that are responsible for progression and destabilization of atherosclerotic plaques. Stressed cells undergoing necrosis release molecules that act as endogenous danger signals to alert and activate innate immune cells. In atherosclerotic tissue the number of DCs increases with the progression of the lesion and produce several inflammatory cytokines and growth factors. Triggering receptor expressed on myeloid cells (TREM)-1 plays a crucial role in inflammation. However, relationship of DCs and the role of TREM-1 with the stability of atherosclerotic plaques have not been examined. In this study, we investigated the heterogeneity of the plaque DCs, myeloid (mDC1 and mDC2) and plasmacytoid (pDCs), and examined the expression of TREM-1 and their co-localization with DCs in the plaques from symptomatic (S) and asymptomatic (AS) patients with carotid stenosis. We found increased expression of HLA-DR, fascin, and TREM-1 and decreased expression of TREM-2 and α-smooth muscle actin in S compared to AS atherosclerotic carotid plaques. Both TREM-1 and fascin were co-localized suggesting increased expression of TREM-1 in plaque DCs of S compared to AS patients. These data were supported by increased mRNA transcripts of TREM-1 and decreased mRNA transcripts of TREM-2 in carotid plaques of S compared to AS patients. There was higher density of both CD1c+ mDC1 and CD141+ mDC2 in the carotid plaques from AS compared to S patients, where as the density of CD303+ pDCs were higher in the carotid plaques of S compared to AS patients. These findings suggest a potential role of pDCs and TREM-1 in atherosclerotic plaque vulnerability. Thus, newer therapies could be developed to selectively block TREM-1 for stabilizing atherosclerotic plaques.
Highlights
Cardiovascular disease is currently the principal cause of death in the western world [1,2]
We found an increased immunoreactivity and mRNA expression of Triggering receptor expressed on myeloid cells (TREM)-1 in S compared to AS and this increased reactivity may be due to the infiltrated monocytes, neutrophils and increased number of dendritic cells (DCs) in symptomatic atherosclerotic carotid plaque
We found that the majority of the DCs in S plaque belong to plasmacytoid DC (pDC) phenotype
Summary
Cardiovascular disease is currently the principal cause of death in the western world [1,2]. Atherosclerosis is a chronic cardiovascular inflammatory disease initiated by an infiltration of low-density lipoprotein cholesterol (LDL) into the intimal layer of the artery. The presence of LDL within the arterial wall leads to endothelial dysfunction and subsequent recruitment of leukocytes resulting in the formation of atheroma or plaque that can grow in size and cause occlusion of the arterial lumen [3,4]. Integral to the progression of atherosclerotic plaque formation are the innate and adaptive immune responses and misdirected activation of immune system mediating the chronic inflammatory process in the arterial wall [2, 4,5,6]. The recruited leukocytes include monocytes/macrophages, dendritic cells (DCs) and activated T cells. Libby et al [9] reported that thrombogenicity of the plaque and integrity of the fibrous cap of the plaque is regulated by inflammation and it provides a correlation between inflammation and thrombotic complications
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