Monocytes in Inflammation and Cardiovascular Disease

By Nadezhda Glezeva PhD

Monocytes

Monocytes are components of the innate immune system with primary functions in immune defense, inflammation and tissue remodelling. As regulators of immune responses, monocytes protect the host against foreign pathogens in a non-antigen-specific manner either by direct pathogen elimination (depending on specific interactions between pattern recognition receptors (PRRs) including toll-like receptors (TLR), lipopolysaccharide (LPS) co-receptor CD14, and scavenger receptors) or indirectly via the production of numerous cytokines like TNFα, IL1, and IL12.

Upon relevant stimuli, monocytes differentiate into macrophages or dendritic cells to initiate innate and adaptive immune responses. Monocytes are also the main cellular source of pro-inflammatory cytokines (TNFα, IL1β, IL6, IL12) and, at the same time, the major targets of such cytokines, with only tiny amounts of cytokine sufficient to recruit monocytes from the blood into the tissue and activate them to undergo differentiation into macrophages.

Monocytes and CVD

There is significant evidence to date, which links monocytes with various cardiovascular disorders associated with HF [59, 60]. Being major regulators of systemic inflammatory reactions, monocytes have an important role in cytokine signalling in the cardiovascular system, both in its healthy and diseased states.However, their role is not restricted solely to cytokine signalling. Monocytes are also associated with processes of destructive (tissue infiltration, tissue damage) and constructive nature (tissue regeneration and healing) in the heart and the vascular system, which attributes a complex dual role for these cells in HF [59].
Monocytes are the major cell type implicated in atherosclerosis, the pathophysiological process underlying coronary artery disease (CAD) and ischaemic cardiomyopathy [61, 62]. The disease is characterized by inflammatory activation of monocytes, significantly increased release of pro-inflammatory cytokines and an oxidative state which favors oxidation of low-density lipoprotein (LDL) and activation of endothelial cells.

The initially protective monocyte inflammatory response with time begins to damage the arterial wall, a process triggered and sustained by the excessive release of cytokines, chemokines, and growth factors by dysfunctional endothelial cells (P- and E-selectins, VCAM, ICAM, MCP1) and macrophages (MCP1, myeloperoxidase (MPO), TNFα, reactive oxygen species (ROS), MMP). These conditions promote the migration of SMCs into the intima of the arterial wall which results in the formation of a fibro-fatty lesion and which is followed by extensive remodelling of the vessel wall. Thus, the mobilization of monocytes is majorly implicated in the subsequent processes of atherogenesis and the development of the atherosclerotic plaque, pre-events in the pathophysiological source of myocardial infarction and stroke.

Monocyte Activation

Monocyte activation, infiltration into damaged tissue, and undue inflammation has also been associated with ischaemia-induced myocardial damage, myocardial remodelling and HF [63, 64]. Low tissue oxygen levels could directly activate monocytes and macrophages, which will produce pro-inflammatory mediators and thus cause severe tissue damage. In a rat model of
myocardial ischaemia and reperfusion, it was shown that depletion of monocytes from the infarcted heart via neutralization of MCP1 can prevent from reperfusion injury [65]. In addition, patients with acute myocardial infarction (AMI) had elevated peripheral monocyte counts (monocytosis) and had an increased infiltration of monocytes and macrophages into the necrotic myocardium visible at 3 days post infarction [66]. Peripheral monocytosis was strongly associated with LV dysfunction (i.e. LV end-diastolic volume, ejection fraction) which suggested a role of monocytes in the development of LV remodelling after AMI. Altogether, these models and studies have pinpointed that inhibition of monocyte activation may be a valuable therapeutic strategy for prevention of ischaemia-related HF. The significance of monocyte activation in the pathogenesis of chronic heart diseases, like HTN and CHF hasn’t so far been fully investigated.

Monocyte subsets and their role in inflammation and cardiovascular disease

Even though monocytes seem to be regarded as a uniform entity with common cellular functions it is now well established that, in fact, at least two distinct types of monocytes exist in human peripheral blood. Monocyte subsets are best differentiated on the basis of expression of the surface Fcγ receptor CD16 and are either characterized as classical, CD14++CD16- or alternative, CD14+CD16++ monocytes [67-69]. Very recently a third subset of monocytes, termed intermediate as it shares characteristics with both the classical and the alternative monocyte subsets, has also been described [70, 71]. It is known that these monocytes express CD16 and also low-to-intermediate levels of CD14 (CD14+(+)CD16+) but so far not much is known about their characteristics and function.

Classical Monocytes

The classical and alternative monocytes (85-90% and 10-15% of all monocytes respectively) have distinct phenotypic and functional characteristics. Classical monocytes have high expression of CD14, are highly phagocytic, actively migrate to MCP1 (also known as C-C ligand 2 (CCL2)) gradients to inflamed tissue, have high MPO activity and high antibody-dependent cell-mediated toxicity, and produce very high levels of IL1.

Alternative Monocytes

Alternative monocytes have similar or lower levels of CD14, higher levels of the human leukocyte antigen- MHC class II cell surface receptor (HLA-DR), are less phagocytic, and migrate in a CCL2-independent fashion preferentially to fractalkine (also known as CXC-linked 3 chemokine receptor 1(CX3CR1)), primarily to non-inflamed tissue. They are also allegedly involved in tissue surveillance and are more likely to become dendritic cells. Alternative monocytes produce high levels of TNFα, IL1, IL6 and IL12 and low-to-no IL10 and are expanded in acute and chronic inflammatory diseases (atherosclerosis, CAD, rheumatoid arthritis (RA), inflammatory bowel disease, asthma, sarcoidosis, peridontitis, eczema, pancreatitis), neoplastic diseases, and in severe infection (bacterial sepsis, tuberculosis, human immunodeficiency virus (HIV) infection) [72, 73]. These monocytes are also referred to as “resident” monocytes and are considered more mature as they share phenotypic characteristics with tissue macrophages.

It was suggested that different blood monocyte subsets may give rise to specific subtypes of tissue macrophages; however this hypothesis is still highly disputed. Although alternative monocytes have important functions in inflammation, their role in hypertension, cardiac fibrosis, and diastolic heart failure hasn’t been clarified so far.

From monocytes to macrophages – macrophage subsets and relevance to disease

Monocytes and tissue macrophages are immune system cells with indispensable roles in innate and adaptive responses of the host to foreign agents. Macrophages have numerous functions related to immunity, inflammation, tissue remodelling, thrombosis, tumorigenesis, etc. They can be phenotypically polarized by the microenvironment to become M1 or M2 macrophages with unique phenotypic and functional properties [73-76].

M1 Macrophages

M1 macrophages, also known as classically-activated macrophages, are induced by interferon γ (IFNγ) with or without microbial stimuli (LPS) or by cytokines such as TNFα and granulocyte macrophage colony stimulating factor (GM-CSF). They are classified as IL12++IL23++IL10+, have high capacity for antigen presentation, are very efficient producers of toxic intermediates (nitric oxide and reactive oxygen intermediates) and inflammatory cytokines (TNFα, IL1β, IL6), stimulate and sustain polarized T helper lymphocyte (Th) type 1 responses and type 1 inflammation, and mediate resistance against intracellular parasites and tumours. In contrast, the alternative, M2 phenotype is more heterogeneous.

M2 Macrophages

Three different subclasses of M2 macrophages have been described: M2a, M2b, and M2c. M2a macrophages form following exposure to IL4 and IL13, M2b are stimulated by immune complexes together with TLR or IL1 receptor (IL1R) agonists, and M2c are regulated by IL10, TGFβ, and glucocorticoids. All M2 macrophages share a IL12+IL23+IL10++ phenotype, have higher phagocytic activity and high expression of scavenger (CD204, CD163, CD36), mannose (CD206, CD209) and galactose-type receptors, participate in polarized Th2 responses, and mediate type 2 inflammation, parasite clearance, tissue remodelling, angiogenesis, tumour progression, and immunoregulation.M2 macrophages are increasingly associated with fibrotic and chronic inflammatory disorders including pulmonary fibrosis, hepatic fibrosis, systemic sclerosis, viral myocarditis [76-80] which makes the study of M2 in the context of cardiac fibrosis, hypertension and LVDD a particularly attractive concept.

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