Inflammation and immune system interactions in atherosclerosis

Abstract

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, accounting for 16.7 million deaths each year. The underlying cause of the majority of CVD is atherosclerosis. In the past, atherosclerosis was considered to be the result of passive lipid accumulation in the vessel wall. Today's picture is far more complex. Atherosclerosis is considered a chronic inflammatory disease that results in the formation of plaques in large and mid-sized arteries. Both cells of the innate and the adaptive immune system play a crucial role in its pathogenesis. By transforming immune cells into pro- and anti-inflammatory chemokine- and cytokine-producing units, and by guiding the interactions between the different immune cells, the immune system decisively influences the propensity of a given plaque to rupture and cause clinical symptoms like myocardial infarction and stroke. In this review, we give an overview on the newest insights in the role of different immune cells and subtypes in atherosclerosis.

Fig. 1

Role of monocytes and neutrophils in atherosclerosis. a Lipoproteins enter the intima, bind to proteoglycans, accumulate, become modified and activate the endothelium. b Platelets deposit C–C motif chemokine ligand 5 (CCL5) on the endothelium, promoting neutrophil recruitment to the vessel wall. Activated neutrophils secrete granule proteins such as myeloperoxidase, azurocidin, and proteinase-3 that will enhance endothelial activation and dysfunction by inducing adhesion molecule expression, permeability changes and limiting the bioavailability of nitric oxide. Moreover, granule proteins secreted or deposited on the endothelium induce adhesion and recruitment of inflammatory monocytes, but can also modify chemokines, enhancing their ability to attract monocytes. c Activated endothelial cells release chemokines, such as MCP-1, that attract circulating monocytes. Monocytes bind to P and E selectin on endothelial cells, roll and finally come to arrest by adherence of their adhesion molecules (VLA-4, LFA-1) to VCAM-1 and ICAM1 on the endothelium. Platelets promote monocyte-endothelial interactions by expression of P-selectin, but can also form monocyte-platelet aggregates that further promote recruitment. Eventually, monocytes enter the intima through trans-endothelial diapedesis. d Infiltrated monocytes differentiate to macrophages, involving M-CSF, after which they polarize into various macrophage subsets (Ml, M2, M4 or MOX) that exert numerous effects and can become foams cells. Subset functions reviewed in Butcher et al. e Plaque neutrophils trap LDL in the vessel wall by secretion of α-defensin that binds LDL. f Neutrophils promote Ml polarization of macrophages. g Neutrophil-derived MMPs and MPO-dependent oxidative stress induces apoptosis of endothelial cells and degradation of basement membrane, leading to endothelial desquamation. h Neutrophil MMPs can also degrade ECM components affecting plaque stability. ECM extracellular matrix, MMP matrix metalloproteinase, MPO myeloperoxidase, LDL low-density lipoprotein, M-CSF macrophage colony stimulating factor, IFN interferon, TNF tumor necrosis factor, OxPAPC oxidation products of l-palmitoyl-2-arachidonoyl-sn-glycerol-3-phosphatidylcholine, EC endothelial cell, HOCI hypochlorous acid, PSGL-1 P-selectin glycoprotein ligand-1, VLA-4 very late antigen-4, VCAM-1 vascular cell adhesion molecule-1, LFA-1 leukocyte function-associated molecule 1, ICAM-1 intercellular adhesion molecule, SMC smooth muscle cell

Fig. 2

Dendritic cell functions in atherosclerosis. a Dendritic cells (DC) accumulate in the plaque through direct recruitment from the lumen, local proliferation and differentiation from either monocytes (preferentially Ly6C^low) or DC precursors. Recruitment of DCs from the plaque to the lumen is CX3CR1, CCR2 and VCAM-1 dependent. b Plaque DCs take up (atherosclerosis-specific) antigens, become activated and mature. c DCs take up oxLDL and can become foam cells. OxLDL induces DC maturation, but can also trigger DC apoptosis that might contribute to necrotic core formation. d Mature DCs are professional antigen presenting cells, whether direct antigen presentation occurs in the plaque is not known. e Dendritic cells can emigrate from the plaque into the lumen, a process that is inhibited by CCR7 deficiency and dyslipidemia. Dendritic cells can also emigrate from the plaque via lymphatics. f Emigrated DCs migrate towards secondary lymphoid organs (spleen and lymph nodes), where they present antigens to T and B lymphocytes. T cells become activated and clonally expand, after which they enter the blood stream and migrate to the plaque. After DC antigen presentation B cells divide and eventually differentiate into plasma cells. Plasma cells produce various types of immunoglobulin antibodies that affect immune responses. Stimulated T (and B cells) can enter the plaque where they exert different effector functions, either promoting or reducing atherosclerosis. g Dendritic cells inside the plaque can restimulate primed T cells entering the plaque, boosting immune responses. h Dendritic cells secrete several chemokines that influence leukocyte recruitment to the plaque. Most DC-derived chemokines, like CCL17 and CCL22, are involved in T cell recruitment. Dendritic cells also secrete various pro-inflammatory (e.g., TNFa, IFNy, IL-6, IL-12) and anti-inflammatory (e.g., IL-10) cytokines that either stimulate or dampen immune responses. i DC antigen presentation and cytokine production directly activate various B and T cell subsets that all affect atherosclerosis in specific ways. j DCs also contribute to the formation of arterial tertiary lymphoid organs (ATLOs), that affect plaque development remotely. MMP matrix metalloproteinase, LDL low-density lipoprotein, EC endothelial cell, VCAM-1 vascular cell adhesion molecule-1, pre-DC DC precursor, Ig immunoglobulin, SMC smooth muscle cell, Mcj macrophage, MHC major histocompatibility, TGF transforming growth factor