R Innate immunity and monocyte-macrophage activation in atherosclerosis (original) (raw)
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Vessel Plus, 2021
Atherosclerosis is the main pathological basis of most cardiovascular diseases and the leading health threat in the world. Of note, lipid-lowering therapy could not completely retard atherosclerosis progression, even in patients that treated with combined statins and PCSK9 inhibitors. This failure further impels researchers to explore other underlying therapeutic strategies except for lipid-lowering. Monocytes and macrophages are the major immune cell groups in atherosclerotic plaques. They play important roles in all stages of atherosclerosis, including the occurrence, advance and regression. It is interesting that macrophages are demonstrated to have plastic and heterogenous characteristics within the dynamic atherosclerotic plaque microenvironment. Furthermore, the phenotype of macrophages can switch upon different microenvironmental stimulus. Therefore, macrophages have become a potential therapeutic target for anti-atherosclerosis treatment. This article reviews the phenotypic diversity of macrophages and their roles in dynamic atherosclerotic plaque microenvironment, especially the related signaling pathways involved in macrophage polarization and compounds exhibited therapeutic effects.
Macrophages: An elusive yet emerging therapeutic target of atherosclerosis
Medicinal Research Reviews, 2008
Macrophages are central to the initiation and progression of atherosclerosis and thus can be very appropriate targets for therapy. Cell adhesion molecules mediating monocytes recruitment to the endothelium are attractive therapy targets and their inhibitors are in clinical trials. Macrophage scavenger receptors like SR-A and CD-36 mediate foam cell formation by facilitating the uptake of modified lipids. Peroxisome proliferator-activated receptors (PPAR), liver X receptor (LXR)-mediated signaling, mitogen-activated protein kinase (MAPK) induced phosphorylation events seem to play an important role in this phenomenon. Proteins affecting macrophage cholesterol metabolism and transport, including ATP-binding cassette (ABC) A1, ABCG1, acyl-CoA:cholesterol acyltransferase (ACAT), apolipoprotein A-1 (ApoA-1), neutral cholesteryl ester hydrolase (NCEH) also regulate foam cell formation and are being developed as therapeutic targets by many pharmaceutical companies. Macrophage proliferation and apoptosis are important events controlling inflammatory response, plaque vulnerability, and destabilization. Free cholesterol (FC) activates the macrophage endoplasmic reticulum (ER) stress pathway and apoptosis. Free radicals and nitric oxide also modulate macrophage foam cell formation and apoptosis. Various antioxidants like AGI-1067 and BO-653 are in clinical trials for atherosclerosis treatment. Macrophage matrix metalloproteinase's (MMP's) play a significant role in weakening and rupture of plaques. Efforts are on to develop isoform specific MMP inhibitor. CD-14, MMP-3, ABCA1, Toll-like receptor-4 (TLR-4), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), arachidonate lipoxygenase-15 (ALOX-15), and Connexin37 polymorphisms and macrophage dysfunction signify their importance in atherosclerosis. Deciphering the role of macrophages in regulating dyslipidemia and inflammation during atherosclerosis is important for developing them as therapeutic targets. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 4, 483–544, 2008
Innate immune signals in atherosclerosis
Clinical Immunology, 2010
Atherosclerosis is a chronic disease characterised by lipid retention and inflammation in the arterial intima. Innate immune mechanisms are central to atherogenesis, involving activation of pattern-recognition receptors (PRRs) and induction of inflammatory processes. In a complex tissue, such as the atherosclerotic lesion, innate signals can originate from several sources and promote atherogenesis through ligation of PRRs. The receptors recognise conserved molecular patterns on pathogens and endogenous products of tissue injury and inflammation. Activation of PRRs might affect several aspects of atherosclerosis by acting on lesion resident cells. Scavenger receptors mediate antigen uptake and clearance of lipoproteins, thereby promoting foam cell formation. Signalling receptors, such as Toll-like receptors (TLRs), lead to induction of pro-inflammatory cytokines and antigen-specific immune responses. In this review we describe the innate mechanisms present in the plaque. We focus on TLRs, their cross-talk with other PRRs, and how their signalling cascades influence inflammation within the atherosclerotic lesion.
Macrophage heterogeneity in atherosclerotic plaques
Current opinion in lipidology, 2009
The varied behaviour of macrophages and foam cells during atherosclerosis and its clinical sequelae prompt the question whether all these activities can be the property of a single cell population. Subsets of monocytes with distinct patterns of surface markers and behaviours during inflammation have recently been characterized and shown to have complementary roles during progression of atherosclerosis. A variety of macrophage phenotypes derived from these monocyte subsets in response to mediators of innate and acquired immunity have also been found in plaques. Based on functional properties and genomic signatures, they may have different impacts on facets of plaque development, including fibrous cap and lipid core formation. Monocyte and macrophage phenotypic diversity is important in atherogenesis. More work is needed to define consistent marker sets for the different foam cell phenotypes in experimental animals and humans. Cell tracking studies are needed to establish their relati...
Immunological aspects of atherosclerosis
Physiological research / Academia Scientiarum Bohemoslovaca, 2014
Atherosclerosis is a degenerative inflammatory disease of the vascular wall, which is characterized by the formation of atherosclerotic plaques that contain lipids, activated smooth muscle cells, immune cells, foam cells, a necrotic core and calcified sites. In atherosclerosis pathology, monocytes and macrophages play the most important role by accumulating redundant LDL particles in their oxidized form and producing proinflammatory cytokines. Atherosclerotic plaque macrophages reveal distinct phenotypes that are distinguished into M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages. Numerous environmental signals (cytokines, microbial cell molecules) that are received by macrophages drive their polarization, but it must be determined whether this classification reflects different macrophage subtypes or plasticity and phenotypic tissue changes, but the balance between subsets is crucial. M1 macrophages are dominant in symptomatic atherosclerotic plaques, while M2 macrophage...
Macrophages are key players in atherosclerotic lesions, regulating the local inflammatory milieu and plaque stability by the secretion of many inflammatory molecules, growth factors and cytokines. Monocytes have long been considered to be the main source of plaque macrophages. However, recent findings provide evidence for proliferation of local macrophages or transdifferentiation from other vascular cells as alternative sources. Recent years of research focused on the further identification and characterisation of macrophage phenotypes and functions. In this review we describe the advances in our understanding of monocyte and macrophage heterogeneity and its implications for specific therapeutic interventions, aiming to reduce the ever growing significant risk of cardiovascular events without any detrimental side effects on the patient's immune response.