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Can a macrophage differentiate back into a monocyte?

Can a macrophage differentiate back into a monocyte?



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I know that monocytes differentiate into macrophages when they enter the tissues, but do macrophages stay in those same tissues for the remainder of their lifespan, or do they differentiate back into monocytes and re-enter the bloodstream at some point?


No, macrophages can not turn back into monocytes, usually once a monocyte travels around the bloodstream for 1-3 days, it then leaves the bloodstream and travel to a tissue where it will differentiate to a macrophage or dendritic cell. It undergoes a conformational change, this usually happens during inflammation as the macrophages travel over a chemical gradient, macrophages can still enter the bloodstream, however, they won't re-differentiate to a monocyte. So to answer your question directly, macrophages don't stay in the same tissue forever as their life span is pretty long(1-2 months) so most likely an inflammation will occur and force the macrophages to diffuse across the chemical gradient, but they usually patrol around the tissue area where they differentiated.

source: http://www.histology.leeds.ac.uk/blood/blood_wbc.php


This paper found dedifferentiation of macrophages back to monocytes https://mbio.asm.org/content/10/5/e01743-19

"Bordetella Adenylate Cyclase Toxin Inhibits Monocyte-to-Macrophage Transition and Dedifferentiates Human Alveolar Macrophages into Monocyte-like Cells" Jawid Nazir Ahmad, Jana Holubova, Oldrich Benada, Olga Kofronova, Ludek Stehlik, Martina Vasakova, Peter Sebo mBio Sep 2019, 10 (5) e01743-19; DOI: 10.1

Found by searching with keywords macrophage dedifferentiation


From Monocytes to M1/M2 Macrophages: Phenotypical vs. Functional Differentiation

Studies on monocyte and macrophage biology and differentiation have revealed the pleiotropic activities of these cells. Macrophages are tissue sentinels that maintain tissue integrity by eliminating/repairing damaged cells and matrices. In this M2-like mode, they can also promote tumor growth. Conversely, M1-like macrophages are key effector cells for the elimination of pathogens, virally infected, and cancer cells. Macrophage differentiation from monocytes occurs in the tissue in concomitance with the acquisition of a functional phenotype that depends on microenvironmental signals, thereby accounting for the many and apparently opposed macrophage functions. Many questions arise. When monocytes differentiate into macrophages in a tissue (concomitantly adopting a specific functional program, M1 or M2), do they all die during the inflammatory reaction, or do some of them survive? Do those that survive become quiescent tissue macrophages, able to react as naïve cells to a new challenge? Or, do monocyte-derived tissue macrophages conserve a "memory" of their past inflammatory activation? This review will address some of these important questions under the general framework of the role of monocytes and macrophages in the initiation, development, resolution, and chronicization of inflammation.

Keywords: functional phenotypes inflammation monocyte-derived macrophages monocytes tissue-resident macrophages.


Introduction

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 [1].

Inflammatory monocytes selectively traffic to the sites of inflammation, produce inflammatory cytokines and contribute to local and systemic inflammation [2]. 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 [3].

Murine monocyte subset classification and their functional determinations have been consistent and well accepted [4]. 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, [5] a clinical condition reflecting an increased number of circulating monocytes.

Emerging clinical analysis revealed a higher prevalence of monocytosis in cardiovascular diseases (CVD) (Table 1). Monocyte count is increased in acute myocardial infarction (AMI) patients compared to patients with stable coronary arterial disease (CAD) [6]. Peripheral monocytosis is associated with left ventricular (LV) dysfunction and LV aneurysm, suggesting a possible role of monocytes in the development of LV remodeling after reperfused AMI [7]. Monocytosis is also associated with reduced high-density lipoprotein (HDL) levels and impaired renal function in CAD patients [8]. It has been demonstrated that monocyte count is a better independent risk factor of CVD than several conventional risk factors such as C-reactive protein (CRP), inflammatory cytokine interleukin-6 (IL-6), fibrinogen, hypertension, and cigarette smoking [9]. The treatment of coronary arterial disease patients with pravastatin, a cholesterol lowering medication, for 6 months reduces plaque volume and monocyte count, implying that monocytosis is a potential target for coronary atherosclerotic regression [10].

Following the defining of monocytosis, reduced phagocytic capacity of monocytes was found in patients with rheumatoid arthritis and cutaneous vasculitis [11]. Patients with lymphopenia have suppressor monocytes, which are unable to activate T-cells [12]. 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 [13]. The CD16 + monocytes has been considered an inflammatory monocyte subset in humans [14].

Mouse monocyte subsets

Monocyte subsets in mice were first identified by differential expression of chemokine receptors CCR2. CCR2 + subset shows higher migratory and infiltration capacity than CCR2 - subset and was initially considered as murine inflammatory monocyte [15]. Later on, mouse monocyte subsets are characterized by differential expression of an inflammatory monocyte marker Ly6C (Gr1). It is now accepted that mouse monocyte subsets are grouped as Ly6C + (further divided as Ly6C high + Ly6C middle ) and Ly6C - (also called Ly6C low ) monocyte subsets based on expression levels of Ly6C on cell surface (Table 2). The surface markers and chemokine receptors for Ly6C + subsets are CD11b + CD115 + and CCR2 high CX3CR1 low . Whereas, the surface markers and chemokine receptors for Ly6C - monocytes are CD11b + CD115 + and CCR2 low CX3CR1 high [16].

Functional properties of mouse monocyte subsets

As shown in Figure 1, mouse Ly6C + monocytes have a high antimicrobial capability due to their potent capacity for phagocytosis, secrete ROS, TNFα, nitric oxide, IL-1β, little IL-10 upon bacterial infection [17] and large amount of type 1 interferon (IFN) in response to viral ligands [18]. CCR2-CCL2 signaling in Ly6C + monocytes alters the conformational change of VLA-4 (α4β1 integrin), the ligand for VCAM-1, leading to high affinity interaction and monocyte transmigration (Figure 1). In vascular inflammation, Ly6C + monocytes are preferentially recruited into inflamed tissue via interaction of chemokine receptor CCR2 [19] and more likely to mature to inflammatory M1 macrophages, which are distinguished by secretion of pro-inflammatory cytokine, TNFα, and IL-6 and contribute to tissue degradation and T cell activation.

Murine MC and M ϕ differentiation, and distinct subset functions. Mouse Ly6C + MCs leave the bone marrow in a CC-chemokine receptor 2 (CCR2)-dependent manner. In the steady state, Ly6C + MCs differentiate into Ly6C - MCs in the circulation. Ly6C - MCs are recruited into normal tissue by interaction of complementary pair CX3CR1/CCL3 via a LAF/ICAM1-dependent manner and become tissue resident Mϕ/DCs. Ly6C + MCs have a high antimicrobial capability due to their potent capacity for phagocytosis, and secrete ROS, TNFα, and IL-1β, whereas Ly6C - MCs secrete anti-inflammatory cytokine IL-10 upon in vivo bacteria infection. In vascular inflammation, Ly6C + MCs are tethered and invade tissue by interaction complimentary pair of CCR2/CCL2(MPC-1) via a VLA-1/VCAM1-dependent manner, then mature to inflammatory M1Mϕ. M1Mϕ are distinguished by secretion of pro-inflammatory cytokines, TNFα and IL-6 and contribute to tissue degradation and T cell activation. Ly6C - MCs are recruited to tissue and differentiate into M2Mϕ, which secrete anti-inflammatory cytokine and contribute to tissue repair. TC, T cell MC, monocyte M ϕ, macrophage EC, endothelial cells DC, dendritic cell inf., inflammatory α-inf. Anti-inflammatory TCR, T cell receptor HLA-DR, human leukocyte antigen DR (a major histocompatibility complex class II (MHC-II)).

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) [20].

Recruited monocytes/macrophages may emigrate from vessels and enter lymph nodes, which are associated with regression of atherosclerotic lesions [21]. Notably, CD62L (L-selectin) expressed by leukocytes, including Ly6C + monocytes, is important for circulation to lymph nodes through high endothelial venules (HEV) [15]. Chemokine receptor CCR7 and CCR8, responsible for lymph node traffic, were selectively expressed by Ly6C middle monocytes [22].

Human monocyte subsets

Because CD14 is abundantly expressed on the surface of human monocytes and macrophages, it is used to mark human monocytes. Compared to CD14 + CD16 - (also described as CD14 bright CD16 - ) monocytes, the human CD14 + CD16 + (also described as CD14 dim CD16 + ) monocyte subset has reduced phagocytic capacity, produces less reactive oxygen species (ROS) and expresses lower levels of CCR2, a chemokine receptor mediating monocyte chemotaxis during inflammation and higher levels of CX3CR1, a chemokine receptor mediating resident monocyte accumulation [23]. Because the chemokine expression pattern implies CD16 + monocyte has an anti-inflammatory function, there was confusion on the characterization of human monocyte subsets [23]. However, CD14 + CD16 + monocytes also express CCR2 and are associated with Crohn’s disease [24] and CVD [25]. Several earlier clinical studies used CD14 + CD16 + as the inflammatory monocyte criteria and established the association of increased levels of CD14 + CD16 + monocyte in human inflammatory diseases, including rheumatoid arthritis, coronary arterial disease, atherosclerosis, hemophagocytic syndrome, and Crohn’s disease (Table 3). Moreover, circulating CD16 + monocyte levels are positively correlated with levels of atherogenic lipids [26] and plaque vulnerability [27], whereas it is negatively correlated with cardiac function such as left ventricular (LV) ejection fraction after AMI [28]. Significant increases in CD16 + monocyte levels have been described in human chronic pathologies in obesity as well [29]. In the same study, several groups reported differential expression of CD14 dim and CD14 high within CD16 + monocytes [26, 30], which was related to distinct functional properties of the chemokine receptor expression pattern [31]. A panel of leading experts in monocyte biology proposed consensus nomenclature for human monocyte subsets in 2010, and classified human monocytes subsets as classical monocytes (CD14 ++ CD16 - ), intermediate monocytes (CD14 ++ CD16 + ), and non-classical monocytes (CD14 + CD16 ++ ) [32].

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 [31].

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 [34]. 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

As shown in Figure 2, human CD14 ++ CD16 - classical monocytes express high levels CCR2 and CD62L (L-selectin), and low levels of CX3CR1. Their major function is phagocytosis. They are phagocytic, exhibit high peroxidase activity, and produce high levels of IL-10 and low levels of TNF-α in response to LPS [23, 35]. Gene expression profiling analysis indicates that human classical monocytes preferentially express genes involved in angiogenesis, wound healing, and coagulation [36]. Human CD14 ++ CD16 + intermediate monocytes display inflammatory function. This subset has low peroxidase activity but higher capacity to produce and release IL-1β, and TNFα in response to LPS [35]. Gene signature links CD14 ++ CD16 + monocytes to antigen presentation and T cell activation (Figure 2) [36]. During inflammation, classical and intermediate monocytes are tethered and invade tissue by interaction of complementary pair of CCR2/CCL2 (termed monocyte chemoattractant protein, MCP) or/and CCR5/CCL5 in a Very Late Activation Antigen-1 (VLA1)/VCAM1 dependent manner.

Human MC and M ϕ differentiation, and distinct subset functions. Human CD14 ++ CD16 - classical MCs leave the bone marrow in a CC-chemokine receptor 2 (CCR2)-dependent manner. In the steady state, classical MCs can differentiate into intermediate MCs, then differentiate into patrolling non-classical MCs in circulation. Classical MCs have a high antimicrobial capability due to their potent capacity of phagocytosis, and secrete ROS and IL-10 upon LPS stimulus, whereas intermediate and non-classical MCs secrete inflammatory cytokines, TNFα and IL-1β upon inflammatory stimulation. During inflammation, classical and intermediate MCs are tethered and invade tissue by interaction of complementary pair CCR2/CCL2(MCP1) or/and CCR5/CCL5(RANTES) in a VLA1/VCAM1 dependent manner. MCs then mature to M1Mϕ in tissue and present self-antigen via MHC-I/II to TCR leading to TC activation. Non-classical MCs patrol the vessel wall and invade by interaction of complementary pair of CX3CR1/CCL3 via LAF/ICAM1-dependent manner. TC, T cell MC, monocyte Mϕ, macrophage EC, endothelial cells inf., inflammatory α-inf. Anti-inflammatory TCR, T cell receptor HLA-DR, human leukocyte antigen DR (a major histocompatibility complex class II (MHC-II)).

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 [35].

In human CVD and inflammatory conditions, inflammatory intermediate CD14 ++ CD16 + monocyate is increased (Tables 3 & 4). However, the change of CD14 + CD16 ++ non-classical monocyte count is inconsistent CD14 + CD16 ++ monocyte count is increased in chronic kidney disease (CKD), abdominal aortic aneurysms (AAA), sepsis, hepatitis B, human immunodeficiency virus (HIV) infection and tuberculosis, but decreased in congestive heart failure, stroke and sepsis. It was suggested that CD14 ++ CD16 - and CD14 ++ CD16 + monocytes resemble mouse Ly6C + inflammatory monocyte subset, whereas CD14 + CD16 ++ monocytes may resemble Ly6C - anti-inflammatory monocytes and have potential role of patrolling vascular endothelium [23]. However, some studies emphasize the inflammatory role of CD14 + CD16 ++ cells because of the production of inflammatory cytokines. Nevertheless, much attention has been focused on the changes of CD14 ++ CD16 + intermediate monocyte count in patients with inflammatory diseases. Since CD14 ++ CD16 + monocyte count increases are consistently associated with human inflammatory disease (Tables 3 & 4), it is a sufficient biomarker of chronic and acute inflammatory diseases.

Monocyte differentiation

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: CX3CR1 high CCR2 low Ly6C - and CX3CR1 low CCR2 high Ly6C + . However, it is unclear whether Ly6C - monocyte is differentiated from CX3CR1 low CCR2 high Ly6C + or directly from bone marrow MDP. After maturation, Ly6C + monocytes leave bone marrow and enter into the blood stream via CCR2 mediated migration [37]. After leaving the bone marrow, mouse Ly6C + monocytes differentiate into Ly6C - monocytes in circulation [38]. 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 [39]. 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 [40].

Monocyte to macrophage differentiation

CCR2 hi Ly6C + inflammatory and CCR low Ly6C - resident monocytes are generally thought to preferentially differentiate into M1 inflammatory and M2 anti-inflammatory macrophages, respectively, during early inflammation [20]. 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) Ly6C middle 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 CX3CR1 high macrophages [44] 4) M2 macrophages are generated by alternative activation of tissue-resident macrophages rather than recruited monocytes during infection with Litomosoides sigmodontis [45] 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 [46]. 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 [47]. 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 [48]. 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 [49]. 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 [50]. 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 [51]. 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 [52].

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 [53]. CD40 signaling induced the expression of adhesion molecules, matrix metalloproteinases and proinflammatory cytokines in macrophages and foam cell formation [54]. It was reported that monoclonal antibodies against CD40L reduced atherosclerosis rendered thromboembolic complications [55]. 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 [56]. Inflammation accompanying stroke plays an important role in secondary ischemic injury [57]. 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 [58]. 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 [59] and infectious encephalitis caused by West Nile virus [60]. 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 [61]. 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 [62]. 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.


Use Cases for Macrophages

Because macrophages can have suppressive effects on tumors, they are used to study various infections and immunotherapies. You can use your macrophages to:

  • Study chemotaxis
  • Study effects of drugs on macrophage functions
  • Study their role in wound healing

Author: Anne Lodge, Ph.D.

Dr. Lodge is the Chief Science and Innovation Officer at Cellero. She has a strong background in cell-based therapeutics and immunology, including a Ph.D. in Cell and Molecular Biology from the University of Vermont and a postdoctoral fellowship with the Multiple Sclerosis Society studying the role of T cells in the disease process. Learn more about Dr. Lodge.

11 Comments

Pigment cells are called melanocytes. There are probably other cell types with pigment but those are the ones that first come to mind.

Hi Dr. Lodge. I am confused between these different cell types: lymphocytes, leukocytes, monocytes, white blood cells, and macrophages. They all seem to be extremely similar and I am having trouble with the hierarchy. Another question I had is regarding infiltrating macrophages in the brain. We use markers such as CD11b and CD45 (low and high), to stain for infiltrating macrophages and resting/activated microglia, but I am a bit confused on what the “low” and “high” really means, and what cell type t specifically targets. I apologize for such the loaded questions, and I would very much appreciate it if you take your time to give me some clarity. Thank you!

Hi Andrew, thanks for your questions. It can be quite confusing and the nomenclature doesn’t help. Leukocytes and white blood cells are the same thing. Leukocyte is just the scientific term. Leuko means “white” and cyte means cell. Lymphocytes and monocytes are both white blood cells but they are different in many ways, including morphology, development and function. The post you’ve just commented on discusses the difference between monocytes and macrophages and it is again, more of a naming problem. Monocytes are found in blood, macrophages are found in solid tissue.
When you are looking at cells infiltrating the brain you will find any white blood cell will be positive for CD45 and the macrophages will be CD11b positive. You may be trying to distinguish the microglia with the CD45 stain since they have a lower expression of CD45. It is hard to see the difference if you are staining tissue sections but if you stain with fluorescent antibodies and analyze by flow cytometry the difference is pretty obvious.

Hi,
Can exogenous macrophages (isolated from one animal) cross the blood-brain barrier after the intravenous injection?

I would predict that they would. I think that this has been shown in fact. Richard Ransohoff published some nice papers on trafficking through the brain back in the 90’s. You might take a look at that work.

Hi Anne lodge, pls I difference between recruited Macrophages and resident Macrophages..
I also want to know their distinct functions in the heart.

Hi Rita, I can tell you that tissue resident macrophages arise from cells in the yolk sac, early in development. The recruited macrophages originate in the bone marrow. As for the functions of the two, I am not certain that they function differently. They may only traffic differently since the tissue resident macrophages arrive in the tissues during fetal development and recruited macrophages move about the body through the lymphatic system.

I want to distinguish between monocytes and macrophages in oncological patients’ effusions, but my biggest challenge is which markers to choose (they express almost the same markers)?


Contents

Monocytes are amoeboid in appearance, and have nongranulated cytoplasm. [1] Thus they are classified as agranulocytes. Containing unilobar nuclei, these cells are one of the types of mononuclear leukocytes which shelter azurophil granules. The archetypal geometry of the monocyte nucleus is ellipsoidal metaphorically bean-shaped or kidney-shaped, although the most significant distinction is that the nuclear envelope should not be hyperbolically furcated into lobes. Contrast to this classification occurs in polymorphonuclear leukocytes. Monocytes compose 2% to 10% of all leukocytes in the human body and serve multiple roles in immune function. Such roles include: replenishing resident macrophages under normal conditions migration within approximately 8–12 hours in response to inflammation signals from sites of infection in the tissues and differentiation into macrophages or dendritic cells to effect an immune response. In an adult human, half of the monocytes are stored in the spleen. [2] These change into macrophages after entering into appropriate tissue spaces, and can transform into foam cells in the endothelium.

Subpopulations Edit

In humans Edit

There are at least three types of monocytes in human blood: [3]

  1. The classical monocyte is characterized by high level expression of the CD14 cell surface receptor (CD14 ++ CD16 − monocyte)
  2. The non-classical monocyte shows low level expression of CD14 and additional co-expression of the CD16 receptor (CD14 + CD16 ++ monocyte). [4]
  3. The intermediate monocyte with high level expression of CD14 and low level expression of CD16 (CD14 ++ CD16 + monocytes).

While in humans the level of CD14 expression can be used to differentiate non-classical and intermediate monocytes, the slan (6-Sulfo LacNAc) cell surface marker was shown to give an unequivocal separation of the two cell types. [5] [6]

Ghattas et al. state that the "intermediate" monocyte population is likely to be a unique subpopulation of monocytes, as opposed to a developmental step, due to their comparatively high expression of surface receptors involved in reparative processes (including vascular endothelial growth factor receptors type 1 and 2, CXCR4, and Tie-2) as well as evidence that the "intermediate" subset is specifically enriched in the bone marrow. [7] After stimulation with microbial products the CD14 + CD16 ++ monocytes produce high amounts of pro-inflammatory cytokines like tumor necrosis factor and interleukin-12.

Said et al. showed that activated monocytes express high levels of PD-1 which might explain the higher expression of PD-1 in CD14 + CD16 ++ monocytes as compared to CD14 ++ CD16 − monocytes. Triggering monocytes-expressed PD-1 by its ligand PD-L1 induces IL-10 production which activates CD4 Th2 cells and inhibits CD4 Th1 cell function. [8]

In humans a monocyte crawling behavior, similar to the patrolling in mice, has been demonstrated both for the classical and the non-classical monocytes. [9] [ clarification needed ]

In mice Edit

In mice, monocytes can be divided in two subpopulations. Inflammatory monocytes (CX3CR1 low , CCR2 pos , Ly6C high , PD-L1 neg ), which are equivalent to human classical CD14 ++ CD16 − monocytes and resident monocytes (CX3CR1 high , CCR2 neg , Ly6C low , PD-L1 pos ), which are equivalent to human non-classical CD14 + CD16 + monocytes. Resident monocytes have the ability to patrol along the endothelium wall in the steady state and under inflammatory conditions. [10] [11] [12] [13]

Monocytes are produced by the bone marrow from precursors called monoblasts, bipotent cells that differentiated from hematopoietic stem cells. Monocytes circulate in the bloodstream for about one to three days and then typically move into tissues throughout the body where they differentiate into macrophages and dendritic cells. They constitute between three and eight percent of the leukocytes in the blood. About half of the body's monocytes are stored as a reserve in the spleen in clusters in the red pulp's Cords of Billroth. [2] Moreover, monocytes are the largest corpuscle in blood. [14]

Monocytes which migrate from the bloodstream to other tissues will then differentiate into tissue resident macrophages or dendritic cells. Macrophages are responsible for protecting tissues from foreign substances, but are also suspected to be important in the formation of important organs like the heart and brain. They are cells that possess a large smooth nucleus, a large area of cytoplasm, and many internal vesicles for processing foreign material.

Dendritic cells Edit

In vitro, monocytes can differentiate into dendritic cells by adding the cytokines granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin 4. [15] Such monocyte-derived cells do, however, retain the signature of monocytes in their transcriptome and they cluster with monocytes and not with bona fide dendritic cells. [16]

Monocytes and their macrophage and dendritic cell progeny serve three main functions in the immune system. These are phagocytosis, antigen presentation, and cytokine production. Phagocytosis is the process of uptake of microbes and particles followed by digestion and destruction of this material. Monocytes can perform phagocytosis using intermediary (opsonising) proteins such as antibodies or complement that coat the pathogen, as well as by binding to the microbe directly via pattern-recognition receptors that recognize pathogens. Monocytes are also capable of killing infected host cells via antibody-dependent cell-mediated cytotoxicity. Vacuolization may be present in a cell that has recently phagocytized foreign matter.

Many factors produced by other cells can regulate the chemotaxis and other functions of monocytes. These factors include most particularly chemokines such as monocyte chemotactic protein-1 (CCL2) and monocyte chemotactic protein-3 (CCL7) certain arachidonic acid metabolites such as Leukotriene B4 and members of the 5-Hydroxyicosatetraenoic acid and 5-oxo-eicosatetraenoic acid family of OXE1 receptor agonists (e.g., 5-HETE and 5-oxo-ETE) and N-Formylmethionine leucyl-phenylalanine and other N-formylated oligopeptides which are made by bacteria and activate the formyl peptide receptor 1. [17]

Microbial fragments that remain after such digestion can serve as antigens. The fragments can be incorporated into MHC molecules and then trafficked to the cell surface of monocytes (and macrophages and dendritic cells). This process is called antigen presentation and it leads to activation of T lymphocytes, which then mount a specific immune response against the antigen.

Other microbial products can directly activate monocytes and this leads to production of pro-inflammatory and, with some delay, of anti-inflammatory cytokines. Typical cytokines produced by monocytes are TNF, IL-1, and IL-12.

Monocytic cells may contribute to the severity and disease progression in Covid-19 patients. [18]

A monocyte count is part of a complete blood count and is expressed either as a percentage of monocytes among all white blood cells or as absolute numbers. Both may be useful but these cells became valid diagnostic tools only when monocyte subsets are determined.

Monocytosis Edit

Monocytosis is the state of excess monocytes in the peripheral blood. It may be indicative of various disease states. Examples of processes that can increase a monocyte count include:

A high count of CD14 + CD16 ++ monocytes is found in severe infection (sepsis) [22]

In the field of atherosclerosis high numbers of the CD14 ++ CD16 + intermediate monocytes were shown to be predictive of cardiovascular events in at risk populations. [23] [24]

CMML patients are characterized by a persistent monocyte count of > 1000/ microL of blood. Analysis of monocyte subsets has demonstrated predominance of classical monocytes and absence of CD14lowCD16+ monocytes. [25] [26]

The absence of non-classical monocytes can assist in diagnosis of the disease and the use of slan as a marker can improve specificity. [27]

Monocytopenia Edit

Monocytopenia is a form of leukopenia associated with a deficiency of monocytes. A very low count of these cells is found after therapy with immuno-suppressive glucocorticoids. [28]

Also, non-classical slan+ monocytes are strongly reduced in patients with Hereditary diffuse leukoencephalopathy with spheroids (HDLS), a neurologic disease associated with mutations in the macrophage colony-stimulating factor receptor gene. [5]


<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More. </a></p> Function i

Involved in the dynamics of lysosomal membranes associated with microglial activation following brain lesion.

<p>The <a href="http://www.geneontology.org/">Gene Ontology (GO)</a> project provides a set of hierarchical controlled vocabulary split into 3 categories:<p><a href='/help/gene_ontology' target='_top'>More. </a></p> GO - Molecular function i

    Source: CACAO <p>Inferred from Direct Assay</p> <p>Used to indicate a direct assay for the function, process or component indicated by the GO term.</p> <p>More information in the <a href="http://geneontology.org/page/guide-go-evidence-codes#ida">GO evidence code guide</a></p> Inferred from direct assay i

      GO - Biological process i

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      Enzyme and pathway databases

      Pathway Commons web resource for biological pathway data

      Protein family/group databases

      Transport Classification Database


      Post-Inflammation Fate of Monocytes/Macrophages

      Antigen Presentation in Non-Lymphoid Organs

      The capacity of taking up and presenting antigen (i.e., the linking function between innate and adaptive immunity) is one of the most important features of tissue macrophages (208). It has been mentioned above that some monocytes that enter the tissue during inflammation do not differentiate into macrophages, and are able to take up antigen in the tissue and carry it to lymph nodes where they can present it to naïve T-cells (64). In addition to this population of monocyte-like cells, tissue macrophages are also able to present antigen, despite the fact that they do not recirculate to lymph nodes after antigen uptake. That tissue macrophages are highly phagocytic and can take up microorganisms and other matter in the tissue is well known, as this is their major function both in homeostasis and during inflammation. That antigen presentation may occur also in non-lymphoid organs has been suggested by several experimental evidence describing antigen-specific local activation and expansion of primed T-cells, but not of naïve T-cells (209�). Based on this evidence, the hypothesis proposed by Ley is that initial priming of naïve T-cells occurs in the lymph node (to which antigen-loaded tissue monocytes recirculate), but that the full activation and effector functions of T-cells occur in the tissue where the inflammatory reaction is taking place, upon the productive interaction and formation of immunological synapse between primed T-cells and the antigen-presenting tissue macrophages (the difference between monocyte-derived tissue DC and tissue macrophages is bleared, as they seem to be not much more than slightly different functional differentiation states from a common precursor). Most likely, the inflammatory monocyte-derived cells with an M1-like functional phenotype are the antigen-presenting cells (APC) that induce activation/polarization of effector Th1 and Th17 cells upon production of IL-12 and IL-23, respectively, and in a TNFRSF and TNFSF-dependent fashion (but independent of CD80, CD86, and CD28 co-stimulation). Likewise, M2-like tissue macrophages, which produce TGF-β and express the αV㬨 integrin are likely involved in the polarization of iTreg cells, whereas their role in Th2 polarization is less clear (208).

      Fate of Activated Resident Macrophages and Recruited Monocytes: Proliferation, Replacement, and M2-Like Polarization

      Based on what described above, the cell populations present in the tissue during the acute phase of an inflammatory reaction are the following:

      • Tissue-resident macrophages and monocyte-derived macrophages. These, after initial recognition of microbial or damage-associated molecules, drive the influx of blood-derived monocytes, which will become inflammatory macrophages. Their role in initiating the inflammatory reaction possibly depends on the nature and grade of challenge.

      • Monocyte-derived macrophages, newly recruited and rapidly occupying the inflammatory lesion, becoming the majority of the macrophages present in the tissue. These cells induce the inflammatory response by differentiating in the M1 functional phenotype.

      • Tissue monocytes, the recently described cells that can take up antigens in the tissue and move to lymph nodes, where they are able to present antigens to naïve T-cells.

      • Memory macrophages, or trained monocytes, cells functionally programed by a previously stimulus for either enhanced (training) or decreased (tolerance) cytokine production, depending on the type and concentration of the stimulus they encountered [(216) see below]. Here, we consider them as a kind of resident inflammatory monocyte-derived macrophage, able to react in a faster and stronger manner compared to other macrophages.

      A summary of the different macrophage types and of their fate after the acute inflammatory phase is given in Figure 4.

      Figure 4. Fate of the different monocyte/macrophage populations in the tissue during the post-inflammatory phase. Tissue-resident macrophages are in general maintained locally by proliferative self-renewal, and retain an M2-like functional phenotype. The same situation is hypothesized for monocyte-derived resident macrophages, since it is not possible to fully discriminate between the two populations. A number of cells of these two populations probably die during the inflammatory reaction. Inflammatory monocyte-derived macrophages can die killed by the NO they have produced, and the surviving cells can undergo in situ phenotype conversion and become M2-like tissue-resident macrophages. In addition, a number of these cells can conserve a “memory” of their past inflammatory activation, and become trained monocytes/memory macrophages. Monocytes recruited from the blood during the post-inflammatory phase can lose the expression of Ly6C and become Ly6C − cells, subsequently differentiating in M2 macrophages. They may also become memory macrophages. Memory macrophages that are present in the tissue, reminiscent of previous inflammatory events, would probably behave like naïve macrophages upon a new inflammatory challenge, except for a much quicker reaction, and will, therefore, mostly die or generate M2-like macrophages or again memory macrophages. Their life span in the tissue is presently unknown.

      In general, tissue-resident macrophages are maintained locally by proliferative self-renewal (100, 106), and retain an M2-like phenotype, for example, in the peritoneal cavity, brain, and lung (86, 100, 161). The fate of monocyte-derived resident macrophages is hard to follow, considering that it is not possible to fully discriminate between them. However, we may hypothesize that they have the same fate of tissue-resident macrophages, i.e., they maintain an M2-like phenotype and a low self-renewal capacity. A number of cells of both populations probably die during inflammation, the extent of their survival possibly depending on the nature and magnitude of the insult.

      Generally, the inflammatory monocyte-derived macrophages are polarized toward M1, and the majority of them dies, killed by their own NO production (see above). In an experimental acute lung injury model, these cells undergo Fas-mediated death, while the resident alveolar cells persist (217). From that, we can argue that M1 likely is a terminal differentiation phenotype. However, there are reports that they can also undergo in situ phenotype conversation to become tissue-resident macrophages either during inflammation or after experimental deletion of tissue macrophages (48, 86). This underlines the notion that macrophage polarization is both transient and plastic.

      The survival in the tissue of inflammatory monocyte-derived macrophages raises important questions that need to be answered.

      Do monocyte-derived tissue macrophages conserve a “memory” of their past inflammatory activation, thereby becoming memory macrophages? And, do tissue macrophages resume their previous functional phenotype in response to a new inflammatory challenge? Or, do they react as naïve cells?

      Memory macrophages (also recently termed “trained monocytes”) have been described, which retain a memory of past challenges (see below). Their fate in the tissue is, however, unknown, since no long-term experiments have been performed in mammals. It is possible that a part of them dies after reacting to a new inflammatory challenge. If some of them survive (again, this possibly depends on the type and magnitude of the new challenge), they would probably behave like inflammatory monocyte-derived macrophages, i.e., they could become M2-like cells, having a low level of self-renewal, and may also form a new population of memory macrophages that retain the memory of multiple challenges.

      Another population that should be considered is that of monocytes recruited from the blood during the post-inflammatory phase. It is possible that these cells lose Ly6C expression when in the tissue, thereby becoming Ly6C − cells that subsequently differentiate in M2 macrophages.

      Memory Macrophages

      It is long known that innate immune responses are higher to a secondary infection/challenge, and that this higher reactive occurs whether the new challenge is the same or different from the first one (cross-protection). An old example is that of mouse peritoneal macrophages from BCG-infected mice that have little/no activity 7 days after infection, and acquire significant citocydal activity upon in vitro challenge with LPS or with a wealth of other stimuli, while naïve macrophages do not (218). Recently, this phenomenon has been re-named trained innate immunity (219). Innate memory plays an important defensive role in organisms lacking adaptive immunity, such as plants and invertebrates, but it is evident also in vertebrates lacking functional T and B lymphocytes (220). In these animals, this innate memory mechanism was shown to involve innate immune cells with low turnover [such as macrophages and NK cells (221, 222)] that would be responsible for improved pathogen recognition through pathogen recognition receptors, and for an enhanced protective inflammatory response (223, 224). NK cells could generate a memory response to viruses, while macrophages retain memory of both bacterial and viral challenges. A logical possibility is that the microorganisms encountered by the host on a regular basis may serve to differentiating and continually renewing a pool of memory-like macrophages with enhanced reactivity to infectious challenges. The molecular mechanisms responsible for shifting macrophages toward a memory status have not yet been elucidated. Putative mechanisms may involve differences in the monocyte/macrophage population (i.e., CD14 + and CD16 − ) or changes in the expression of lectin receptors on cell membrane (221), or in the functional phenotype (e.g., phagocytosis or protein production), but all are probably underlain by epigenetic reprograming that, through modification of DNA, post-translational modifications of histones (methylation), or microRNA, regulates gene expression by inducing dynamic alterations in the chromatin structure (220). Establishment of macrophage memory, depending on the experienced challenges, is likely to rely on epigenetic changes, as these can be at the basis of a rapid evolution of responsiveness and adaptation to incurring events, thereby allowing to surviving to new environmental threats (220, 225). Efficacy of many vaccines probably implies the induction of non-specific macrophage memory that contributes to the increased resistance to infections. Research in the field of memory macrophages needs a thorough re-assessment of a large body of old evidence accumulated in the past decades in the areas of macrophage activation and of adjuvanticity.


      Volume II

      Ryoko Okamoto , H. Phillip Koeffler , in Vitamin D (Third Edition) , 2011

      Conclusions

      The secosteroid hormone 1,25(OH)2D3 has a role in normal hematopoiesis, enhancing the activity of monocyte– macrophage differentiation . It also has anti-proliferative and pro-differentiation effects against various myeloid leukemia cell lines by both genomic and non-genomic pathways. Nevertheless, hematopoiesis in vitamin D 3 receptor deletional mice is fairly normal, suggesting the vitamin D3 pathway has an adjunctive role in blood formation in mammals. The anti-proliferative activities of 1,25(OH)2D3 in vivo require supraphysiological levels of the secosteroid. Limited clinical trials with 1,25(OH)2D3 have been performed for the treatment of preleukemia/myelodysplastic syndrome but the in vitro effective dose caused hypercalcemia in vivo. Since the mid-1980s, many vitamin D analogs have been synthesized that possess reduced hypercalcemic activity and increased ability to induce cell differentiation and to inhibit proliferation of leukemic cells. Further studies have been performed in vitro and in vivo using these analogs with other differentiating and/or anti-proliferative agents in the hopes that their combination, working through different pathways, could lead to synergistic activity. Proof of principle that 1,25(OH)2D3 and its analogs are beneficial in leukemia has been shown in experiments conducted in vitro and in laboratory animals, but to date their therapeutic value in patients is unproven. Of interest, 1,25(OH)2D3 and its analogs can stimulate synthesis of CAMP and β-defensins in myeloid cells in humans and may represent an evolutionary important pathway to protect humans against microbes.


      Monocyte

      Assorted References

      …occur in two varieties—granulocytes and monocytes—and ingest and break down microorganisms and foreign particles. The circulating blood functions as a conduit, bringing the various kinds of cells to the regions of the body in which they are needed: red cells to tissues requiring oxygen, platelets to sites of injury, lymphocytes…

      Monocytes are the largest cells of the blood (averaging 15–18 μm in diameter), and they make up about 7 percent of the leukocytes. The nucleus is relatively big and tends to be indented or folded rather than multilobed. The cytoplasm contains large numbers of…

      …from the blood is the monocyte, a mononuclear cell larger than the lymphocyte and with different potentialities. These migratory cells can divide and, when appropriately stimulated, can transform into highly phagocytic macrophages. The reaction of the blood and connective-tissue cells to injury is called inflammation and is usually accompanied by…

      …and other organs produce the monocytes (4–8 percent of the white cells). The platelets, which are small cellular fragments rather than complete cells, are formed from bits of the cytoplasm of the giant cells (megakaryocytes) of the bone marrow.

      These precursors develop into monocytes and dendritic cells, phagocytic cells that are released into the bloodstream. Some monocytes and dendritic cells remain in the general blood circulation, but most of them enter body tissues. In tissues, monocytes develop into much larger phagocytic cells known as macrophages. The great majority…

      Role in

      Immune system

      …phagocytic white blood cells called monocytes. Studies have shown that upon severe tissue injury, such as that sustained during a heart attack, the spleen releases a legion of monocytes, which then travel through the bloodstream to the site of injury. There they serve to regulate inflammation and to facilitate tissue…

      …the mature form of the monocyte. Like granulocytes, monocytes are produced by stem cells in the bone marrow and circulate through the blood, though in lesser numbers. But, unlike granulocytes, monocytes undergo differentiation, becoming macrophages that settle in many tissues, especially the lymphoid tissues (e.g., spleen and lymph nodes) and…

      …wandering amoeboid cells, and the monocyte, a precursor of the macrophage, is found in the blood. The smaller phagocytes are chiefly neutrophils that are carried along by the circulating blood until they reach an area of infected tissue, where they pass through the blood vessel wall and lodge in that…

      …cells, neutrophilic leukocytes (microphages) and monocytes (macrophages), are phagocytic. Neutrophils are small, granular leukocytes that quickly appear at the site of a wound and ingest bacteria. Monocytes are larger, with a large, kidney-shaped nucleus they appear about three days after infection and scavenge for bacteria, foreign particles, dead cellular material,…

      Monocytes, which constitute between 4 and 8 percent of the total number of white blood cells in the blood, move from the blood to sites of infection, where they differentiate further into macrophages. These cells are scavengers that phagocytose whole or killed microorganisms and are…

      …following an inflammatory reaction, the monocytes may increase in number, and subsequently the lymphocytes will become more numerous.

      …of white blood cells, the monocytes, which eventually mature into cell-eating macrophages. Macrophages usually become more prevalent at the site of injury only after days or weeks and are a cellular hallmark of chronic inflammation.


      13061_2009_240_MOESM1_ESM.xls

      Additional file 1: The genes differentially expressed by CD16 + and CD16 - monocytes that were detected in common by Zhao et al. [6] and Ancuta et al. [7] (XLS 34 KB)

      13061_2009_240_MOESM2_ESM.xls

      Additional file 2: Genes differentially expressed by CD16 + and CD16 - monocytes (from [6, 7]) in common with a dataset of genes expressed during monocyte maturation (3 days and 7 days after stimulation with MCSF) and activation by the classical (M1) and alternative (M2) pathway [8]. (XLS 32 KB)


      Watch the video: USMLE Animated Immunology - Infection u0026 Acute Inflammation - Monocytes u0026 Macrophages (August 2022).