© Schattauer 2017 Thrombosis and Haemostasis 1/2017 7 Review Article Pathophysiological relevance of macrophage subsets in atherogenesis Luca Liberale 1 ; Franco Dallegri 1,2 ; Fabrizio Montecucco 1,2,3 ; Federico Carbone 1 1 First Clinic of Internal Medicine Department of Internal Medicine, University of Genoa, Genoa, Italy; 2 First Clinic of Internal Medicine, IRCCS AOU San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; 3 Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy Summary Macrophages are highly heterogeneous and plastic cells. They were shown to play a critical role in all stages of atherogenesis, from the initiation to the necrotic core formation and plaque rupture. Lesional macrophages primarily derive from blood monocyte, but local macro- phage proliferation as well as differentiation from smooth muscle cells have also been described. Within atherosclerotic plaques, macro- phages rapidly respond to changes in the microenvironment, shifting between pro- (M1) or anti-inflammatory (M2) functional phenotypes. Furthermore, different stimuli have been associated with differenti- ation of newly discovered M2 subtypes: IL-4/IL-13 (M2a), immune- complex (M2b), IL-10/glucocorticoids (M2c), and adenosine receptor agonist (M2d). More recently, additional intraplaque macrophage phenotypes were also recognized in response to CXCL4 (M4), oxidized phospholipids (Mox), haemoglobin/haptoglobin complexes (HA- mac/M(Hb)), and heme (Mhem). Such macrophage polarization was described as a progression among multiple phenotypes, which reflect the activity of different transcriptional factors and the cross-talk be- tween intracellular signalling. Finally, the distribution of macrophage subsets within different plaque areas was markedly associated with cardiovascular (CV) vulnerability. The aim of this review is to update the current knowledge on the role of macrophage subsets in athero- genesis. In addition, the molecular mechanisms underlying macro- phage phenotypic shift will be summarised and discussed. Finally, the role of intraplaque macrophages as predictors of CV events and the therapeutic potential of these cells will be discussed. Keywords Monocyte, macrophage, polarisation, atherosclerosis Correspondence to: Fabrizio Montecucco, MD, PhD Department of Internal Medicine University of Genoa School of Medicine 6 viale Benedetto XV, 16132 Genoa, Italy Tel.: +39 010 353 8694, Fax: +39 010 353 8686 E-mail: fabrizio.montecucco@unige.it Financial support: This study was supported by European Commission (FP7-INNOVATION I HEALTH-F2–2013–602114; Athero-B-Cell: Targeting and exploiting B cell function for treatment in cardiovascular disease). This work was supported by a Swiss National Science Foundation Grant to Dr. F. Montecucco (#310030_152639/1). Received: August 1, 2016 Accepted after minor revision: September 12, 2016 Epub ahead of print: September 29, 2016 https://doi.org/10.1160/TH16-08-0593 Thromb Haemost 2017; 117: 7–18 Introduction Atherosclerosis is a low-grade chronic inflammatory disease that might be complicated by some acute life-threatening conditions, such as myocardial infarction and ischaemic stroke (1). Athero- sclerotic plaque rupture is the result of a “perfect storm” scenario in which an arterial stimulus for clinically relevant thrombosis overlaps a prothrombotic milieu at the site of rupture or erosion (2). Transition to symptomatic plaque rupture is supported by a chronic maladaptive inflammation involving several immune cell subsets. Due to their heterogeneity and plasticity, monocytes and macrophages were described to play a critical role in atherogenesis and its acute complications (3). Circulating monocytes derived from the bone marrow were traditionally considered as a major source of intraplaque macrophages. However, other extra-medul- lary niches may contribute to monocyte recruitment, especially in the early stages of atherosclerosis (4). Macrophage turnover within established atherosclerotic plaques is largely sustained by local proliferation (5). Differentiation of smooth muscle cells (SMC) into foam cell-like cells may further contribute to this process (6). As reported in vitro and in genetically engineered mice, SMC ex- posed to cholesterol acquire typical macrophage features such as phagocytosis and antigen presentation (7). Macrophages are pres- ent in different regions of the plaque: next to the necrotic core, in the plaque shoulder, or even near to the blood vessel and calcified zone. Furthermore, they respond to change in their intracellular milieu by specific adaptive mechanisms and reactions. The aim of this narrative review is to update evidence on mac- rophage heterogeneity and plasticity in the atherosclerotic en- vironment. Then, we will update the pathophysiological relevance of a wide spectrum of macrophage polarisation, focusing on plaque vulnerability. Monocyte in atherosclerosis Monocyte subset in mice Differential expression of trans membrane molecules has been used to identify monocyte subsets in mice and humans (8) (▶Table 1). Mouse monocytes may be distinguished according to the expression For personal or educational use only. No other uses without permission. All rights reserved. Downloaded from www.thrombosis-online.com on 2017-10-27 | IP: 54.70.40.11