Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases
© Yang et al.; licensee BioMed Central Ltd. 2014
Received: 23 November 2013
Accepted: 20 December 2013
Published: 7 January 2014
Monocytes express various receptors, which monitor and sense environmental changes. Monocytes are highly plastic and heterogeneous, and change their functional phenotype in response to environmental stimulation. Evidence from murine and human studies has suggested that monocytosis can be an indicator of various inflammatory diseases. Monocytes can differentiate into inflammatory or anti-inflammatory subsets. Upon tissue damage or infection, monocytes are rapidly recruited to the tissue, where they can differentiate into tissue macrophages or dendritic cells. Given the rapid progress in monocyte research from broad spectrum of inflammatory diseases, there is a need to summarize our knowledge in monocyte heterogeneity and its impact in human disease. In this review, we describe the current understanding of heterogeneity of human and murine monocytes, the function of distinct subsets of monocytes, and a potential mechanism for monocyte differentiation. We emphasize that inflammatory monocyte subsets are valuable biomarkers for inflammatory diseases, including cardiovascular diseases.
The primary role of monocytes was considered to sense the environment and replenish the pool of tissue macrophages and dendritic cells. Recent advances in immunology research have discovered that monocytes are heterogenic and can be divided into three subsets based on specific surface markers and that each subset displays specific functions. During steady state, circulating monocytes have a half-life of about one to three days, and maintain a steady composition of monocyte subsets.
Identified monocyte subsets exhibit distinct pathophysiological roles. Classical inflammatory monocytes are equipped with a set of Toll-like receptors (TLRs) and scavenger receptors, recognizing pathogen-associated molecular patterns (PAMPs) and removing microorganisms, lipids, and dying cells via phagocytosis. They produce effector molecules such as cytokines, myeloperoxidase and superoxide, and initiate inflammation .
Inflammatory monocytes selectively traffic to the sites of inflammation, produce inflammatory cytokines and contribute to local and systemic inflammation . They are highly infiltrative and can be differentiated into inflammatory macrophages, which remove PAMPs and cell debris. In steady state, the patrolling anti-inflammatory monocytes patrol the vasculature to monitor PAMPs and become tissue resident macrophages. During inflammation, they differentiate into anti-inflammatory macrophages, which repair damaged tissues .
Murine monocyte subset classification and their functional determinations have been consistent and well accepted . However, classification of human monocyte subsets in relevance to their inflammatory or anti-inflammatory functional phenotypes remains partially undefined. Here, we intend to review the current understanding regarding monocyte heterogeneity, and to integrate the knowledge of murine and human monocyte classification.
Monocytosis and heterogeneous monocytes
It was first reported in the 1970s that monocytes increase proliferative activity in bone marrow (BM) in response to inflammatory stimuli, leading to monocytosis,  a clinical condition reflecting an increased number of circulating monocytes.
Monocytosis in human disease
Monocyte counts comparison
HDL, 2 nmol/L vs. <1 nmol/L
3.65 × 108 vs. 4.5× 108 cells/dL
CT vs. AMI
4.97 × 108 vs. 7.93 × 108 cells/dL
5 h AMI vs. 1–2 day AMI
4.56 × 108 vs. 7.11 × 108 cells/dL
None vs. Pump failure
6.05 × 108 vs. 9.41 ×108 cells/dL
None vs. LV aneurysm
6.82 × 108 vs. 8.61 × 108 cells/dL
CKD without CVD vs. CKD with CVD
5.71 × 108 vs. 6.97 × 108 cells/dL
LVF recovery vs. LVF no recovery
6.42 × 108 vs. 10.13 × 108 cells/dL
Healthy vs. CAD vs. AMI
5.17 × 108 vs. 5.42 × 108 vs. 6.72 × 108 cells/dL
Following the defining of monocytosis, reduced phagocytic capacity of monocytes was found in patients with rheumatoid arthritis and cutaneous vasculitis . Patients with lymphopenia have suppressor monocytes, which are unable to activate T-cells . These findings suggested the existence of heterogeneous monocyte populations. Further studies for different functional properties of such populations identified that CD16 (Leu-11), a Fc receptor (FcR) as it binds to the Fc region (constant region) of antibody, is expressed on the surface of monocytes and correlated with atherosclerosis and CVD in patients and an inflammatory phenotype in cultured monocytes and circulating monocytes . The CD16+ monocytes has been considered an inflammatory monocyte subset in humans .
Mouse monocyte subsets
Markers and functions of MC subsets in human and mouse
% in MNC
Phagocytosis & Pro-inflammatory
Patrolling; tissue repair
Functional properties of mouse monocyte subsets
In steady state, Ly6C+ monocytes differentiate into Ly6C- monocytes in the circulation. This subset patrols the luminal side of endothelium of small blood vessels and bind to endothelium by chemokine receptor CX3CR1 via LAF-1/ICAM1-dependent manner. The patrolling behavior of monocytes may be due to low levels expression of adhesion molecules. Ly6C- monocytes secrete anti-inflammatory cytokine, IL-10 upon in vivo bacterial infection. In vascular inflammation, Ly6C- monocytes are recruited to tissue and more likely to differentiate into M2 macrophages, which secrete anti-inflammatory cytokine and contribute to tissue repair (Figure 1) .
Recruited monocytes/macrophages may emigrate from vessels and enter lymph nodes, which are associated with regression of atherosclerotic lesions . Notably, CD62L (L-selectin) expressed by leukocytes, including Ly6C+ monocytes, is important for circulation to lymph nodes through high endothelial venules (HEV) . Chemokine receptor CCR7 and CCR8, responsible for lymph node traffic, were selectively expressed by Ly6Cmiddle monocytes .
Human monocyte subsets
Frequency of two MC subsets in human diseases
CD14 ++CD16 -(classical, phagocytic)
CD14 +CD16 +(Non-classical, inflammatory)
Functional changes associated with CD14 ++CD16 +MC expansion
HLA-DR and CCR5↑ Counts of tender/swollen joints↑ Rheumatoid factors ↑
Serum TNFα ↑
Serum TNFα & IL-6↑
As indicated in Table 2, CD14++CD16+ monocytes express CCR2 and selectively CCR5, which react with macrophage inflammatory protein-1α (MIP-1α), a chemotactic chemokine for macrophages and CCL5 (termed regulated on activation, normal T cell expressed and secreted, RANTES). CCR5, known as a co-receptor for human immunodeficiency virus entry into macrophages, is also associated with CVD [31, 33]. CD14++CD16- monocytes express highest levels of CCR2 and CD14+CD16++ monocytes express highest levels of CX3CR1 .
Although much more evidence supports that Ly6C+ and CD14+CD16- classical monocytes are pro-inflammatory monocytes, their high expressions of CD62L imply a possible role of lymph node migration and differentiate into a variety of macrophages and dendritic cell subtypes that could inhibit immune response . Understanding the functions of subsets provides an insight in extrapolating results from clinical studies of inflammatory monocytosis found in patients’ blood with various inflammatory diseases.
Functional properties of human monocyte subsets
Human CD14+CD16++ non-classical monocytes, patrol the vessel wall and invade by interaction of complementary pair of CX3CR1/CCL3 via the Leu-CAM family integrin lymphocyte functional antigen-1 (LFA-1)/ICAM1-dependent manner (Figure 2). This subset releases IL-1β, and TNFα in response to DNA, RNA particles, implicating the pathological role in autoimmune disease such as rheumatoid arthritis .
Frequency of three monocyte subsets in different diseases
CD14 ++CD16 -(Classical, phagocytic)
CD14 ++CD16 +(Intermediate, inflammatory)
CD14 +CD16 ++(Non-classical, patrolling)
Functional change associated with CD14 ++CD16 -MC expansion
CD143 (ACE) ↑, Creatine↑, GFR↓, albumin↓
42 → 70 cells/μl
55 → 130 cells/μl
Th17 cells expansion
Myeloid dendritic cell depletion
Phagocytosis↓, CD86↑, HLA-DR↓, IL-1β↓, IL-10↑
HLA-DR↓, TNFα & IL-1β ↓,IL-10↑
HLA-DR↑,TNF α ↑, IL-6↑, IL1β ↑, Th17 cells expansion
12 ~ 18%↓
3 ~ 7%↑
HLA-DR ↓, ICAM ↑, serum TNFα↑, IL-18 ↑, IFNγ ↑ ,
TNFα ↑, apoptosis↑, Il-10↓
Monocytes are differentiated from the committed precursor termed macrophage-DC precursor (MDP) mainly resident in bone marrow and differentiate into either dendritic cells or macrophages. They consist of two main subpopulations: CX3CR1highCCR2lowLy6C- and CX3CR1lowCCR2highLy6C+. However, it is unclear whether Ly6C- monocyte is differentiated from CX3CR1lowCCR2highLy6C+ or directly from bone marrow MDP. After maturation, Ly6C+ monocytes leave bone marrow and enter into the blood stream via CCR2 mediated migration . After leaving the bone marrow, mouse Ly6C+ monocytes differentiate into Ly6C- monocytes in circulation . A recent monocyte fate mapping study strongly supported that in the steady state, Ly6C+ monocyte is the obligatory precursor for generation and lifespan control of Ly6C- monocyte in the bone marrow, peripheral blood and spleen. In a competitive setting of mixed CCR2-proficient (CD45.1) and CCR2-deficient (CD45.2) (Ly6C+ monocytes are reported to be selectively reduced) BM chimeras, CD45.1+ WT Ly6C- monocytes outcompeted their CD45.2 mutant Ly6C- counterparts . In the same study, Ly6C+ monocytes restored regained Ly6C- half-life and the population.
Similarly, in human monocyte differentiation, it is accepted that CD14++ classical monocytes leave bone marrow and differentiate into CD14++CD16+ intermediate monocytes and sequentially to CD14+CD16++ non-classical monocytes in peripheral blood circulation .
Monocyte to macrophage differentiation
CCR2hiLy6C+ inflammatory and CCRlowLy6C- resident monocytes are generally thought to preferentially differentiate into M1 inflammatory and M2 anti-inflammatory macrophages, respectively, during early inflammation . Ly6C+ monocytes dominate the early phase of myocardial infarction and exhibit phagocytic, proteolytic, inflammatory function and digest damaged tissue. On the other hands, Ly6C- monocytes, recruited at later phase of inflammation, attenuate inflammatory properties and differentiate toward M2 macrophages and contribute to angiogenesis, genesis of my fibroblasts, and collagen deposition (Figure 1). It is possible that monocytes and macropahge are highly plastic and can be crossly differentiated into different subsets in response to environment changes. Several studies revealed “unusual” cascades of monocytes to macrophage transition: 1) Infiltrated Ly6C+ monocytes in inflamed skeletal muscle or brain tissues acquire phenotypic features of anti-inflammatory monocytes by down-regulating Ly6C expression, thereby displaying anti-inflammatory M2 macrophages function; [41, 42] 2) Ly6Cmiddle monocytes emigrate to lymph nodes via CCR7 and CCR8 and differentiate into dendritic cells; [22, 43] 3) During steady state, Ly6C+ monocytes are recruited to healthy lamina propria and differentiate into tissue resident CX3CR1high macrophages;  4) M2 macrophages are generated by alternative activation of tissue-resident macrophages rather than recruited monocytes during infection with Litomosoides sigmodontis;  and 5) Inflammatory monocyte recruitment to allergic skin is essential to alleviate allergic inflammation in order to acquire an anti-inflammatory M2 phenotype via basophil-derived IL-4 . These findings demonstrated the multiple capacities of monocytes to differentiate into either regulatory or inflammatory mature macrophages/dendritic cells.
Inflammatory monocytosis in CVD and stroke
Inflammatory monocytes are the major cellular component in atherosclerotic plaque . Accumulation of activated immune cells, including inflammatory monocytes and macrophages, and T lymphocytes in the vessel wall produce inflammatory cytokines and facilitate vascular inflammation.
Inflammatory monocytes may contribute to vascular inflammation not only by producing inflammatory cytokines, but also via CD40-mediated T cell activation. It was reported that CD40-CD40 ligand (CD40L) signaling, a T cell co-stimulatory receptor-ligand pair, plays a crucial role in atherosclerosis . The action of T cells in atherosclerosis is similar to a CD4+ T helper cell 1 (Th1)-mediated hypersensitivity reaction, which might use ox-LDL as a possible auto-antigenic stimulus . In human atherosclerotic lesions, CD40–CD40L are co-localized with epitopes of ox-LDL, scavenger receptor A (a mediator of foam cell formation), and CD16 . CD40 is a TNF receptor superfamily 5 member and is expressed in monocytes, macrophages, dendritic cells. CD40 ligand is found on CD4+ T cells and platelets in both secreted and membrane bound forms. CD40-CD40L expression on platelets enhances platelet activation and thrombosis . CD40 and CD40L are both expressed on endothelial cells and vascular smooth muscle cells. Either CD40 or CD40L deficiency in ApoE-/- mice abrogated atherosclerosis by increasing the extracellular matrix and promoting M2 macrophage polarization .
Classical CD14+ monocytes are critical for clearance of LDL, whereas CD16+ monocytes including intermediate and nonclassical monocytes have higher expression levels of major histocompatibility complex class II (MHC-II) and higher capacity to uptake ox-LDL . CD40 signaling induced the expression of adhesion molecules, matrix metalloproteinases and proinflammatory cytokines in macrophages and foam cell formation . It was reported that monoclonal antibodies against CD40L reduced atherosclerosis rendered thromboembolic complications . Thus, antagonizing CD40 signaling or suppressing CD40 expression might be future therapeutic alternatives for human CVD.
Similarly, monocytes are the major infiltrating immune cells in the ischemic brain in stroke. Monocyte infiltration is one of the earliest cellular response in stroke. It occurs 4 hours after stroke and reaches maximum infiltration in 7 days . Inflammation accompanying stroke plays an important role in secondary ischemic injury . Infiltrated inflammatory cells can produce ROS, inflammatory cytokines and matrix metalloproteinase, inducing neuron injury directly or indirectly by inducing blood brain barrier (BBB) disruption, which can lead to edema, cerebral hemorrhage and a vicious circle of continuous influx of myeloid cells. However, the inflammatory effects on the stroke process can be detrimental or protective, depending on the immune cell types, numbers and duration. A recently published paper indirectly supported the detrimental role of monocytes in stroke . Bone marrow transplantation from ApoE-/- CD36-/- (mostly expressed in monocytes) donor mice to ApoE-/- recipient mice decreased infarction volume and neurological deficits after stroke. But the roles of different monocyte subsets in the pathogenesis of stroke remain unclear. Ly6C+ monocytes have been proven to be responsible for many central nervous system diseases like autoimmune multiple sclerosis  and infectious encephalitis caused by West Nile virus . The chemokine receptor CCR2 deficiency, which is the main chemokine receptor for recruiting Ly6C+ monocytes, attenuates infarction size and neurological deficit after stroke in the transient middle cerebral artery occlusion (tMCAO) stroke mouse model, accompanying significantly reduced monocyte and neutrophil infiltration . Also, there is a report pointing out that the Ly6C- macrophages differentiated from infiltrating Ly6C+ monocytes are critical for preventing hemorrhagic infarct transformation in both the tMCAO and the photo thrombosis induced permanent stroke models . However, Ly6C+ monocyte depletion by clondronate liposome or by bone marrow transplantation from CCR2-/- donor mice to wild type recipient mice showed dramatically increased hemorrhage occurrence rates without changing infarction volume and neurological function. The reason why the same CCR2 deficiency mice display different results is unknown, it may be due to different mouse breeding methods since pure knockout mouse cross-breeding for several generations may lead to gene changes, which may compensate for the designated gene defect. To determine the roles of different monocyte subsets in stroke pathogenesis, more experiments should be conducted in the context of normal or combined disease settings like hyperlipidemia and hyperhomocysteinemia.
To date, many studies have demonstrated the key roles of inflammatory and anti-inflammatory monocytes in response to inflammation or steady state in mouse models. Inflammatory monocyte subset is a valuable biomarker for human inflammatory diseases, including cardiovascular diseases. Understanding the mechanism of monocyte differentiation will likely provide a potential therapeutic target for inflammatory monocytosis.
This work was supported in part by NIH Grants HL67033, HL77288, HL82774, HL110764 and HL117654 (HW); and HL9445, HL108910 and HL116917 (XFY).
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