Macrophages are the biggest type of white blood cells - about 21 micrometers - or 0. Still too small to see with your eyes, but big enough to do the important job of cleaning up unwanted viruses, bacteria, and parts of dead cells. Instead, the eating machines engulf viruses and bacteria. This is called phagocytosis. First, the macrophage surrounds the unwanted particle and sucks it in. Then, the macrophage breaks it down by mixing it with enzymes stored in special sacs called lysosomes.
The leftover material is then pushed out of the cell as waste. Phagocytosis: Once a macrophage engulfs a virus , it's broken down with enzymes from the lysosomes 4,5 then released from the cell as harmless waste material 6. Video from Judith Behnsen on Wikimedia Commons. By volunteering, or simply sending us feedback on the site. Scientists, teachers, writers, illustrators, and translators are all important to the program.
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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. In the healthy organism, the innate immune system provides the first line of defense against external or internal danger signals, by initiating a protective inflammatory response that develops during time through different phases, from initiation and full inflammation, to resolution and re-establishment of tissue integrity.
The first phase of an inflammatory response is aimed at destroying pathogens, and is followed by a phase in which dead and dying cells, damaged extracellular matrix material, and cellular debris are removed, to end up with a recovery phase in which the tissue is repaired and restored to a healthy fully functional condition.
In fact, if the defense against harmful threats is a priority for avoiding tissue damage, maintaining homeostasis i. In this perspective, inflammation presumably evolved as an adaptive response to tissue malfunction or homeostatic imbalance 2. Thus, while the disease state is a displacement from homeostasis, inflammation is the tissue response for restoring homeostasis.
However, since the inflammatory activities are potentially harmful to the host, these need to be tightly controlled to avoid excessive tissue damage 3. The mononuclear phagocyte system MPS plays major roles in development, scavenging, inflammation, and anti-pathogen defenses, both by the direct elimination of foreign agents and in organizing each different phase of the inflammatory process 4.
Under the term, MPS are grouped lineage-committed bone marrow precursors, circulating monocytes, resident macrophages, and dendritic cells DC 5. The development, homeostatic maintenance, proliferation, differentiation, and function of the MPS are regulated by the growth factors colony-stimulating factor CSF -1 and interleukin IL , the second ligand for the CSF-1R 6 , 7.
The issue of heterogeneity in the MPS still leads to a confusion and debate about DC as truly distinct cells from macrophages, with separate lineage and functions 8. In fact, macrophages and myeloid DC possibly represent alternative differentiation options of bone marrow progenitors and blood monocytes 9 , with overlapping functions and marker expression. Reviewing this issue is beyond the scope of this essay [we refer the reader to recent excellent reviews on the topic; 9 — 11 ], and will only focus on monocytes and their relationship with macrophages.
The traditional view of the MPS suggests that recruited monocytes that become macrophages in tissues are key players during inflammation and pathogen challenge, whereas tissue-resident macrophages have important roles in development, tissue homeostasis, and the resolution of inflammation. A basic concept of the MPS is that blood monocytes are precursors that replace tissue macrophages within a single developmental lineage 4. This dogma needs now to be revised in the light of new evidence that macrophages are endowed with self-renewal capacity and can populate tissues before birth, deriving from early hematopoiesis in the yolk sac 12 , The discovery of new macrophage progenitors of embryonic origin forces us to reassess definitions, functions, and cell—cell relationships within the MPS.
We can synthesize it in three key new questions:. Are monocytes more than circulating precursors and can they have effector functions?
Is there a functional difference between the monocyte-derived macrophages and the yolk sac-derived self-renewing resident macrophages? What is the relationship between monocytes and macrophages and which are their mutual roles in different phases of inflammatory reactions? Another new perspective arises from the description of macrophage polarization, i. This highlights the central role of macrophages in immune defense, overturning the long-held notion that macrophages need to be activated by T-cells We will consider key studies that have been carried out in mice, with reference to the human situation when data are available.
They have typical morphological features, such as irregular cell shape, oval- or kidney-shaped nucleus, cytoplasmic vesicles, and high cytoplasm-to-nucleus ratio. Monocytes can remain in the circulation for up to 1—2 days, after which time, if they have not been recruited into a tissue for facing a danger, they die and are removed. Monocytes originate in the bone marrow from hematopoietic stem cells HSCs and develop through a series of sequential differentiation stages: the common myeloid progenitor CMP 15 , the granulocyte-macrophage progenitor GMP 15 , the common macrophage and DC precursor MDP 16 , and finally the committed monocyte progenitor cMoP , a recently identified bone marrow precursor that differs from MDP as it lacks CD expression Monocytes have been considered as the systemic reservoir of myeloid precursors for renewal of tissue macrophages and DC.
However, many DC and macrophage subpopulations [for example, lymphoid organ DC, plasmacytoid DC, skin Langerhans cells LC , and brain microglia] originate from the MDP independent of monocytes 11 , 18 , and in some cases, they can even develop directly from the bone marrow Unlike broadly expressed CSF-1, IL expression is restricted to the epidermis and central nervous system 24 , where it supports the steady-state proliferation of macrophages LC and microglia, respectively.
Granulocyte-macrophage colony-stimulating factor GM-CSF is another factor involved in the development of mononuclear phagocytes but only during the inflammatory state and not under homeostatic conditions 25 , Abundant experimental evidence indicates that recruited monocytes are innate effectors of the inflammatory response to microbes, and they kill pathogens via phagocytosis, production of reactive oxygen species ROS , nitric oxide NO , myeloperoxidase, and inflammatory cytokines In some circumstances, monocytes can trigger and polarize T-cell responses 27 , 28 and may also contribute to angiogenesis and atherogenesis Human peripheral blood monocytes are not a homogeneous population.
In recent years, investigators have identified three functional subsets of human monocytes, the characterization of which is still in its infancy. Likewise, it is still unclear which are the specific roles that they exert in homeostasis and inflammation in vivo , in comparison with those of the previously described classically and alternatively activated macrophages see below. The new nomenclature that groups monocytes into three subsets, based on the expression of the surface markers CD14 and CD16, has recently been approved by the Nomenclature Committee of the International Union of Immunologic Societies Over the recent years, an increasing amount of knowledge has been gained in the field of monocyte subpopulations.
Many authors demonstrated that the three subsets express different transcriptomes 32 — 38 , although discrepancies between studies were evident. These discrepancies may be due to differences in cell isolation methodology and in the purity of the cell populations isolated, and the microarray methodologies, which use different amounts of total RNA for the hybridization, different probes to identify the genes, and even distinct solid supports for the probes However, there is stronger agreement for the proximity of relationship between the intermediate and non-classical monocyte subsets, while the classical subset is the most distant subset The close relationship between intermediate and non-classical monocytes suggests a direct developmental relationship between them, although this has yet to be formally proven.
Recent data suggested a sequential developmental relationship between the two subsets based on the observation that, in time course studies in inflammatory diseases, an increase in the intermediate monocytes is followed by an increase of non-classical monocytes The physiological role of the monocyte subsets in vivo is not fully defined.
The phenotypic and functional differences between the monocyte subsets were recently discussed in an exhaustive review Both human and mouse inflammatory monocytes express high levels of the chemokine receptor CCR2 and low levels of the chemokine receptor CX3CR1, whereas patrolling monocytes show a reverse pattern. Overall, it is clear that the subsets between human being and mouse are similar but not identical 42 , Table 1 summarizes the main features of monocytes in human beings and mice.
This hypothesis still needs experimental proof. To date, a relevant question that is still open concerns the origin of the various monocyte subpopulations. It should be kept in mind that the majority of current knowledge derives from mouse studies.
The latter hypothesis seems to be the most reliable. Indeed, the primary function of these cells seems to be that of patrolling the vascular endothelium and monitoring its integrity 45 , The original concept of MPS implicated that classical monocytes are recruited in the tissue to become tissue-resident macrophages in homeostatic conditions, and inflammatory activated macrophages during an infection 27 , We will examine more in detail the role of recruited cells during the inflammatory response later, while here we will focus on the recruitment of monocytes in homeostasis and their contribution to maintaining the pool of tissue macrophages.
In order to avoid misunderstandings, it is important to agree on the definition of monocyte. In our view, bona fide monocytes are restricted to the blood compartment, and to the bone marrow and spleen 55 , where they wait to be released in the blood.
For obvious reasons, in both these compartments, monocytes should not initiate any inflammatory reaction, but they must be ready to be recruited into the blood first and subsequently to all organs and tissues.
Conversely, in the dermis are present both resident dermal macrophages and monocyte-derived macrophages 60 , A recent work suggests that the number of macrophages is partially replenished by monocytes also in the heart 62 and in the lung It is unknown why some tissue macrophages are constantly maintained by circulating monocytes, whereas other populations are independent on circulating monocytes see below. These monocytes can enter non-lymphoid organs without obligatory differentiation into macrophages or DC.
The authors propose that these monocytes can upregulate MHC class II expression and subsequently recirculate to lymph nodes, where they are able to present antigens to T-cells. This study contributes to revising the role of circulating monocytes, suggesting that they are not only precursors of macrophages but also effector cells.
The patrolling monocytes mainly respond via Toll-like receptor 7 TLR7 to local danger signals while they are poorly responsive to bacterial products such as LPS by producing inflammatory mediators They are able to induce the intravascular recruitment of neutrophils, which trigger endothelial necrosis, and subsequently they clear the resulting debris A summary of the roles of monocyte subsets in steady state vs.
Table 2. Functions of monocyte subsets in steady state and inflammatory conditions. This number can increase further in response to inflammatory stimuli. The specialization of macrophages in particular microenvironments explains their heterogeneity. Macrophages take different names according to their tissue location, such as osteoclasts bone see Box 1 , alveolar macrophages lung , microglial cells CNS , histiocytes connective tissue , Kupffer cells liver , and LC skin.
These populations have such highly different transcriptional profiles that they could be considered as many different and unique classes of macrophages On the other hand, the functions of macrophages are the same in all tissues.
They are key players in tissue development by shaping the tissue architecture , in immune response to pathogens by generating and resolving the inflammatory reaction , in surveillance and monitoring of tissue changes by acting as sentinel and effector cells , and especially in maintenance of tissue homeostasis by clearing apoptotic or senescent cells, and by remodeling and repairing tissues. Osteoclasts are multinuclear giant cells with a hematopoietic origin, commonly known as bone macrophages.
They function in bone resorption and are involved in a normal skeletal development, growth, and modeling, for the maintenance of its integrity throughout life, and for remodeling through calcium metabolism Moreover, osteoclasts are able to interact with the hematopoietic system and the adaptive immune system Excessive bone loss mediated by osteoclasts plays a major role in certain pathologic conditions, such as rheumatoid arthritis RA and osteoporosis 67 , On the other hand, insufficient bone resorption due to the lack of functional osteoclasts as in CSF-1R knock-out mice leads to excessive bone apposition and osteopetrosis Osteoclasts really seem a class of macrophages on their own.
Recently, it has been shown that also IL is involved in the osteoclast development Thus, culture of unfractionated peripheral blood monocytes with M-CSF and RANKL is sufficient to induce their differentiation into osteoclasts, and it has been assumed that osteoclast precursors are monocytes, although this has not been shown in vivo. The question arises as to why osteoclasts, unlike other macrophages, have their own lineage of commitment and differentiation.
The view that tissue macrophages originate from circulating peripheral blood monocytes that migrate into tissues under a variety of stimuli, proposed and strongly supported by van Furth in the s 4 , 75 , 76 , needs to be reconsidered.
In addition to a wealth of old data 77 , 78 , two new pieces of evidence have further weakened the view that monocytes are the precursors of tissue macrophages in steady-state conditions: 1 the finding of the macrophage origin from embryonic progenitors that seed developing tissues before birth and give rise to fetal tissue macrophages 79 and 2 the self-maintaining ability of tissue-resident macrophages through local proliferation in adulthood The latter finding will be discussed hereafter.
Two main phases of embryonic hematopoiesis have been described in the mouse: primitive hematopoiesis and definitive hematopoiesis. The former takes place in the ectoderm of the yolk sac and gives rise to macrophages without going through a monocytic progenitor. The latter takes place in the fetal liver, which is initially seeded by hematopoietic progenitors from the yolk sac and subsequently by HSCs from endothelium of the aorta-gonads-mesonephros 80 , The fetal liver subsequently becomes the source of definitive hematopoiesis that generates circulating monocytes during embryogenesis.
Spleen and bone marrow are also colonized via the circulatory system by hematopoietic progenitors that will ultimately differentiate there. After birth, upon bone formation, hematopoiesis passes from the fetal liver to the bone marrow. The human embryonic hematopoietic system is organized roughly in the same way as in the mouse 82 , and early studies propose that macrophages could arise in the embryo independent of bone marrow progenitors in human beings [for more extensive reading, see Ref.
In summary, macrophages in fetal and adult tissues derive from at least three sources: yolk sac giving rise to some tissue-resident yolk sac-derived macrophages , fetal liver giving rise to fetal liver-derived macrophages , and bone marrow giving rise to tissue-resident bone marrow-derived macrophages and inflammatory bone marrow-derived macrophages, see below Figure 1.
The primitive yolk sac-derived macrophages have two distinct characteristics: 1 their pattern of differentiation does not go through a monocytic intermediate state but they directly become mature macrophages in fetal tissues 85 and 2 unlike macrophages derived from definitive c-Myb-dependent hematopoiesis, they are independent of the transcriptional factor c-Myb during development, while depending on the transcriptional factor PU. Figure 1. Origin of tissue-resident macrophages in the mouse.
In adult tissues, macrophages derive from three sources. Later during fetal development, hematopoiesis shifts from the yolk sac to the fetal liver that seems to contribute to the LC pool in the skin, possibly through a yolk sac-derived progenitor. It is unknown whether other resident macrophages in other tissues may also derive from fetal liver hematopoiesis.
Based on different experimental approaches, from lineage tracing 12 , 48 to experiments carried out in parabiotic mice 64 , 86 , it is evident that monocytes do not contribute or contribute only minimally to the maintenance of peripheral tissue-resident macrophages in steady-state conditions in many adult tissues.
Fate-mapping experiments have shown that the adult microglial cell population is exclusively derived from yolk sac progenitors 87 , 88 , whereas for LC in adult skin it was clearly demonstrated a mixed origin, from the yolk sac and from the fetal liver 12 , Also, for splenic red pulp macrophages, alveolar, and peritoneal macrophages, an embryonic origin has been confirmed, rather than a monocyte origin All these experiments show that early embryonic progenitor-derived macrophages can persist in tissues to adulthood.
As mentioned previously, an exception is the gut, which contains a large population of resident macrophages that are all blood monocyte-derived cells, in steady-state conditions How the mutual contribution of yolk sac-derived macrophages and fetal liver-derived monocytes is regulated in each tissue is unknown, and likewise it is not known how these two distinct populations of macrophages are functionally and ontogenically related.
Regarding how much yolk sac progenitors contribute to originating adult tissue macrophages vs. One hypothesis is that fetal liver-derived monocytes proliferate and differentiate into adult tissue macrophages markedly diluting the population of yolk sac-derived macrophages e.
This hypothesis stems from the observation that generation of yolk sac-derived macrophages does not go through a monocytic intermediate, therefore being in contrast with normal adult hematopoiesis, while a fetal liver origin for tissue macrophages would be reminiscent of the adult scenario in inflammation Conversely, others believe that all tissue macrophages derive from yolk sac during the embryonic development, and circulating monocytes do not seed the majority of the adult tissues in mice except kidney and lung 12 , 91 Figure 2.
In conclusion, to which extent different populations of yolk sac-derived macrophages may be later replaced by fetal liver-derived macrophages or monocytes, and how yolk sac-derived tissue-resident macrophages can proliferate locally through life to maintain their own pool independently of adult monocyte input, these issues remain a matter of debate 90 , 91 , Thus, three main issues arise from all these findings:.
The origin of adult macrophages in steady-state conditions can vary considerably between tissues. Due to some limits and weaknesses of the published studies whole blood irradiation or other myelo-ablative treatments, parabiotic mice, engrafted bone marrow or monocytes, adoptive transfer of radiolabeled cells, Cre- loxP -based fate mapping, CCR2 or CSF-1 inactivation, etc.
Thus, more efficient and specific fate-mapping models of yolk sac-derived macrophages and fetal liver-derived monocytes are needed, along with further investigation, to determine which tissue macrophage populations are constantly replenished by circulating monocytes and which are not.
Figure 2. Distribution of tissue-resident macrophages and monocyte-derived macrophages in tissues and organs. Monocyte contribution to resident macrophages is highly tissue-dependent and varies from no contribution for brain microglia and epidermal LC to complete monocyte origin for intestinal lamina propria macrophages.
The tissues listed in the middle are those at the center of ongoing controversy see the main text , and for which a mixed contribution is probable. Here, we define yolk sac-derived macrophages as tissue-resident macrophages, and both fetal liver-derived macrophages and bone marrow-derived macrophages as monocyte-derived macrophages considering that bone marrow hematopoiesis derives from fetal liver hematopoiesis.
Given that it is currently not possible to discriminate the two populations of tissue macrophages yolk sac-derived and monocyte-derived during homeostasis, we will report their ability to proliferate without considering them as distinct subpopulations.
In any case, we will bear in mind the notion that the tissue macrophages can maintain their number in the absence of monocyte precursors both in steady-state conditions 12 , 48 , 64 , 86 as well as in genetically or experimentally monocytopenic situations 94 , It is important to clarify the difference between self-renewal and proliferative capacity.
As stated by Sieweke and Allen 13 , in immunology, self-renewal is understood as a replacement of a certain cell population, while in stem cell research as the capacity to generate with a cell division a daughter cell showing the same identity as the parental cell. Local proliferation of tissue macrophages can be considered as self-renewal in both senses [see Ref.
Having said that, recent evidence demonstrated that macrophages within the adult tissues self-renew via proliferation in homeostatic conditions rather than through an influx of progenitors. This has been shown for LC, which are able to proliferate 97 both in human beings 98 and in mice 99 , for brain microglia 19 , resident peritoneal macrophages , and alveolar macrophages Box 2. CSF-1 is constitutively produced by mesenchymal cells and is detectable in circulation in resting conditions Under homeostatic conditions , CSF-1 promotes monocyte development and macrophage proliferation , which is controlled in a negative feedback loop.
The decreased CSF-1 levels lead to a decrease in mononuclear cell proliferation, thereby maintaining the cell number to normal levels both systemically and locally [ 21 , 22 ; a model of CSFdependent local homeostasis of macrophage density has been described by Jenkins and Hume 9 ].
Thus, elevated production of CSF-1 can drive both an increased proliferation of resident macrophages and an increased recruitment of monocytes , via macrophage production of CCL2 CSF-1 deficiency in mice affects distinct tissues by different degrees, ranging from marked cell loss in the gut, kidney, peritoneal cavity, and in circulation, as compared to liver CSF-1 is also involved in the proliferation of splenic red pulp macrophages and bone marrow macrophages GM-CSF is also critical for macrophage homeostasis and proliferation, especially in the lung and in the peritoneal cavity in vivo , but it is less important in hematopoiesis, and, therefore, for monocyte development GM-CSF can support monocyte expansion and differentiation in vitro 25 , , and it seems to be mainly involved in induction of hematopoiesis during inflammation rather than in homeostasis , In summary, CSF-1 is mainly involved in self-renewal of tissue macrophages, consistent with its role in M2 polarization, while GM-CSF is involved in proliferation of monocyte-derived inflammatory macrophages, consistent with its role in M1 polarization.
Resident macrophages can proliferate at low levels in steady-state conditions, but proliferation rates strongly increase after macrophage depletion 86 or under inflammatory challenge To solve this issue, there is evidence that a macrophage that had previously divided has the same probability of entering the cell cycle as a cell that had not, suggesting the same proliferative ability for all macrophages This is consistent with the observation that macrophages genetically modified to have an indefinite self-renewal potential can be efficiently cloned During inflammation, things are quite different, especially because the tissue is enriched with monocyte-derived macrophages.
We will discuss later the replenishment of tissue macrophages by monocyte-derived macrophages and their ability to proliferate. Table 3 summarizes the functions of resident macrophages in the main body tissues. These functions, mirroring different phenotypes 74 , , are specific because depending on different tissue microenvironments. Different tissues define different phenotypes of both resident macrophages and monocyte-derived macrophages recruited from the reservoirs of blood, spleen, and bone marrow 10 , phenotypes that are necessary for the tissue-specific needs of defending, maintaining, and regaining homeostasis In pathological conditions, the distinction between tissue-resident macrophages and recruited inflammatory macrophages has not yet been possible.
For an in-depth analysis of these issues, the reader can refer to recent exhaustive reviews 99 , , Apart from tissue-specific functions, tissue macrophages share a series of common functions encompassing clearance of cell debris, immune surveillance, wound healing, defense against pathogens, and the initiation and resolution of inflammation. In this review, we will only focus on the role of macrophages in inflammatory responses, considering their capacity to polarize into different functional phenotypes in response to the tissue microenvironmental changes that occur during the different phases of an inflammatory response.
This polarization process is based on the M1—M2 paradigm see below. Table 3. Macrophage functions and the pathological consequences of their anomalous activation in the main tissues. During the first phases of an inflammatory reaction, there is in the tissue an increase of the effector cell number, necessary for increasing the immune defensive firepower.
These cells are monocyte-derived macrophages. To cope with the need of increasing the number of effector cells, two strategies come into play. First is the recruitment of blood monocytes, driven by resident macrophages alongside with other tissue cells. Recruited blood monocytes are a source of inflammatory macrophages, which take the name of bone marrow-derived or monocyte-derived inflammatory macrophages. The other strategy is the increase of tissue-resident macrophage proliferation by enhancement of their self-renewal ability.
Central to the issue of monocyte recruitment is the difference in monocyte subset trafficking. Such differences have been observed to occur during acute and chronic inflammation in mice, and underline the fact that the monocyte subsets are under the control of distinct trafficking mechanisms, with the classical subset being recruited via CCR2 and the non-classical one utilizing a CXCR1-dependent pathway see Box 3.
Box 3. Chemokines and monocyte recruitment mechanisms. Recently, it has been proposed that both mesenchymal cells and progenitor cells closely apposed to bone marrow vessels can produce CCL2 in inflammatory situations, to allowing the egress of monocytes from the tissue and their subsequent entry into the blood These studies underline the importance of monocyte recruitment from blood to the tissue in the injured cardiac or skeletal muscle.
Macrophage accumulation in skin wounds is also reduced in mice lacking CX3CR1 Intravenous administration of CCL2 leads to the mobilization of monocytes into the circulation, which is consistent with a role for peripheral CCL2 production responsible for replenishment of circulating monocytes from bone marrow In mice with myeloid cell-restricted Bmal 1-deficiency, the rhythmic release of CCL2 was ablated along with monocyte pools.
Thus, myeloid cells produce low diurnal levels of CCL2 in a circadian fashion, and CCL2 in turn stimulates the release of CCR2-expressing monocytes from the bone marrow into the blood. As previously mentioned 45 , it has been observed that the two subsets of monocytes differentiate into two distinct cells types. However, in other systems, this double recruitment of different monocyte subsets has not been observed.
Generally, classical monocytes infiltrate inflamed tissues more robustly than their non-classical counterparts, and their number is significantly increased in the circulation during systemic or chronic infection Yet, another situation is that of myocardial infarction, during which both monocyte subsets appear to home to the same tissue at different stages of inflammation However, it was recently demonstrated that the maintenance and accumulation of monocyte-derived macrophages in atherosclerotic plaques mainly depend on local proliferation of bone marrow-derived macrophages rather than on the influx of circulating monocytes , In an atopic dermatitis model and in experimental autoimmune encephalomyelitis, a massive proliferation of LC and microglia cells has been observed , , despite a significant monocyte influx In the peritoneal cavity and in the lung, where the macrophage disappearance phenomenon occurs upon bacterial and virus insults, the few remaining macrophages are responsible for repopulating the tissue 86 , , Similarly, in the context of Th2-mediated immunity against nematode infection, IL-4 drives tissue-resident macrophage expansion in the pleural cavity in the absence of peripheral monocyte recruitment Proliferation of macrophages is observed in a variety of human diseases [see Ref.
In this context, a question is still open. Having established that monocytes are recruited into tissues during an inflammatory event, to what extent are they capable to differentiate in tissue macrophages and to proliferate?
As proposed by Jenkins and Hume, the negligible contribution of monocytes to the pool of resident macrophages could be due to the fact that monocyte recruitment is specifically aiming at providing a population of functionally differentiated cells needed for resolving an acute inflammatory event, rather than being triggered by the homeostatic need of maintaining the autonomous pool of resident macrophages 9. This view is supported by another interesting hypothesis, i. The gastrointestinal tract provides evidence in favor of this hypothesis.
In the gut, blood monocytes are constantly recruited to the tissue where they contribute to maintaining the resident macrophage population, but during an inflammatory event they re-program their differentiation plan toward adopting an inflammatory phenotype 57 , Thus, we should consider that monocyte-derived macrophages adopt different and opposing phenotypes based on microenvironmental signals.
In this context, it is conceivable that monocytes entering the tissue at later times could find conditions favorable to adopting an M2-like phenotype see above , thereby becoming tissue macrophages over time. Inflammatory monocyte-derived macrophages 12 , 86 and tissue monocytes 64 can be phenotypically and functionally distinguished from resident macrophages in many tissues. In the central nervous system, inflammatory monocyte-derived macrophages do not contribute to the resident population In contrast, fate-mapping experiments revealed that monocyte-derived macrophages recruited to the peritoneal cavity upon thioglycollate injection differentiate into resident macrophages and persist over time The fraction of monocyte-derived macrophages that do not die upon inflammation and become tissue-resident macrophages share gene profiling with resident macrophages 45 , 64 , , but there is no information as to whether they are functionally different or not.
The accumulation of inflammatory monocytes in an inflamed tissue is due to their influx from blood rather than by their proliferative ability, and in fact inflammatory signals of microbial origin generally prevent their proliferation. An exception to this general paradigm comes from a recent study that has demonstrated that also inflammatory monocyte-derived macrophages can proliferate at certain stages during the resolution of zymosan-induced peritonitis Figure 3.
Schematic representation of monocyte and macrophage populations in homeostasis and inflammation. Some tissue macrophages derive directly from yolk sac during the embryogenesis e. The large majority of these cells gives rise to the inflammatory monocyte-derived macrophages, while some of them do not differentiate into macrophages and remain monocyte-like cells, are able to take up antigens, and to migrate to the draining lymph nodes tissue monocytes.
These are the antigen-uptaking and -presenting cells of the tissue. These cells produce a series of cytokines and other inflammatory factors. Tissue-resident macrophages increase their capacity of proliferation to compensate the loss of macrophages caused by the inflammatory reaction. Recent evidence demonstrates that also inflammatory monocyte-derived macrophages are able to proliferate in a late phase of the inflammatory reaction.
Memory macrophages are important players in the inflammatory reaction, as they can react to inflammatory stimuli with a faster and stronger inflammatory cytokine production. They probably remain in the blood vessels as sentinels, and in some cases they could enter in the tissue, as it has been reported in the case of myocardial infarction, to take up a repair function. The precise nature and extent of the contribution of monocyte-derived macrophages to tissue macrophages could depend on how, and to which extent, inflammation or its cause has affected the tissue-resident macrophages.
In this view, as proposed by Ginhoux and Jung 90 , tissue-resident macrophages are more involved in tissue macrophage repopulation after mild injury, while monocyte-derived macrophages are more involved in severe inflammatory injuries.
In the mouse it seems that non-classical monocytes contribute to the resident macrophage population. It is possible although there is little evidence in this respect that when non-classical monocytes are recruited in the inflamed tissue, they may differentiate into alternatively activated macrophages, while classical monocytes would give rise to classically activated macrophages.
In this context, the developmental relationship between the different monocyte subsets and the different macrophage functional phenotypes has yet to be fully and formally proven. No evidence in this sense has been generated yet in human being see below. Macrophage polarization occurs through different activation programs by which macrophages carry out their defensive functions.
In this way, macrophages become able to respond with appropriate functions in distinct contexts, functional diversity becoming the key feature of these cells. The main difference between these cells is that in M2 macrophages the arginine metabolism is shifted to ornithine and polyamines, while in M1 cells it is shifted to NO and citrulline M2-produced ornithine can promote cell proliferation and repair through polyamine and collagen synthesis, fibrosis and other tissue remodeling functions , while M1-produced NO is an important effector molecule with microbicidal activity and cell proliferation inhibitory capacity Moreover, M1 and M2 macrophages have distinct features in terms of chemokine production profiles , and iron and glucose metabolism , The description of macrophages polarization is leading immunologists to take a step back and revise their concept on how the immune system works 14 , Thus, considering that macrophages recognize pathogens directly , , while T-cell do not, and considering that T-cells proliferate through interaction with macrophages , it is logical to think that macrophages are the cells that initiate and direct T-cell response, and that the adaptive immune response needs the triggering and guidance of innate immunity Notably, M1 and M2 macrophage activities do not need the presence of lymphocytes In vitro , macrophages are activated toward an M1 functional program by infectious microorganism-related molecules e.
In general, these macrophages take part in polarized Th2 responses, allergy, parasites clearance, dampening of inflammation, tissue remodeling, angiogenesis, immunoregulation, and tumor promotion Macrophage taxonomy is an attempt to rationally categorize an extended variety of cell functions.
In vivo , macrophages can adopt a variety of functional phenotypes depending on subtle and continuous changes in the tissue microenvironment.
In this regard, Mosser and Edwards have suggested a macrophage classification that takes into account the three functions of these cells in maintaining homeostasis: host defense, wound healing, and immune regulation. Classifying macrophages according to these functions provides three basic macrophage populations: classically activated macrophages, wound-healing macrophages, and regulatory macrophages , The authors believe that this classification also helps to illustrate how macrophages can evolve to exhibit characteristics that are shared by more than one macrophage population Thus, as already mentioned above, it is logical to hypothesize that the subsets are varying mixtures of M1- and M2-type macrophages, as observed in the lung and in the peritoneal cavity, where tissue-specific variations in the balance of M1- and M2-type responses have been revealed 74 , This situation has also been observed in pathological conditions, where macrophages can develop mixed M1 and M2 phenotypes , Moreover, it has also been proposed to consider the heterogeneity of macrophage functions as a consequence of interaction with different immunological pathways e.
In summary, the initial inflammatory response is carried out by activated macrophages in classical or alternative modality depending on the triggering events , aiming at eliminating invading microbes by promoting the inflammatory response.
Then, the resolution phase is carried out by macrophages in deactivated modality, unresponsive to inflammatory stimuli, and active in the elimination of the injured cells and tissue components, in promoting angiogenesis, cell proliferation, matrix deposition, and in general in tissue remodeling.
The mechanisms that account for macrophage deactivation play a key role in maintaining homeostasis and keeping the immune response under control Both innate and adaptive signals can influence the macrophage functional phenotype, which can have potentially dangerous consequences if not appropriately regulated.
For example, classically activated M1 macrophages can cause damage to host tissues, predispose surrounding tissue to neoplastic transformation and influence glucose metabolism by promoting insulin resistance. Macrophages that are normally involved in wound healing can promote fibrosis, exacerbate allergic responses, and be exploited by pathogens for intracellular survival. These M2-type macrophages can contribute to the progression of neoplasia by promoting tumor survival see Table 3.
Plasticity and flexibility are key features of macrophages and of their activation states. A controversial issue is whether a phenotypic and functional evolution of macrophages occurs in vivo , and how it happens. As mentioned above, it has been observed in mice that the M1 to M2 switch during the progression of the inflammatory response enables macrophages to perform different activities in the different phases of the reaction.
The controversy refers to the mechanisms underlying this switch, i. Several hypotheses are attempting to explain the issue. A first hypothesis is that different subsets of monocytes or macrophages can adopt a different functional phenotype. It is possible that resident macrophages maintain cytoprotective and reparative functions, whereas macrophages derived from circulating inflammatory monocytes perform mainly M1 type functions.
A second hypothesis is that there are sequential waves of monocyte recruitment into a tissue throughout the course of an inflammatory reaction. Therefore, monocytes recruited into the tissue at different times encounter different microenvironments with different signals that can polarize them in M1 during early phases and in M2 in late phases In this case, cytokines and other microenvironmental signals in the tissue play a key role in determining the different functional phenotypes of macrophages.
Although the role of cytokines in steering the macrophage functional phenotypes has been proven in vitro , the situation could be very different in vivo , where M2 activity is strongly increased in sterile wounds or injured kidney in absence of Th2-like cytokines IL-4 or IL which in any case do not induce the typical M2 phenotype, i.
In these cases, M2 macrophages derive largely from M1 macrophages, with monocytes recruited from the circulation first acquiring an inflammatory phenotype, and then persisting in the tissue and maturing into repair macrophages. Based on the latter data, a third hypothesis is that polarized macrophage populations can switch one to the other in response to different conditions. Your email address will not be published.
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Lost your password? Please enter your email address. You will receive mail with link to set new password. Skip to content. My Account. You are here:. November 16, Author: Anne Lodge, Ph. Stock Up on Cryopreserved Cells for Thank you in advance for your response. Kind regards, Simona. Leave a Reply Cancel reply Your email address will not be published. Sign in New account. Remember me. Log in. By registering, you're agreeing to our Terms and Conditions.
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