What do monocytes become

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. 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. Leukocytes and white blood cells are the same thing.

Leukocyte is just the scientific term. Lymphocytes and monocytes are both white blood cells but they are different in many ways, including morphology, development and function. 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 CD 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. You might take a look at that work. Hi Anne lodge, pls I difference between recruited Macrophages and resident Macrophages.. 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.

Data from in vitro studies demonstrate that human monocytes can acquire the phenotype of polarized M1 macrophages and then mature into M2 repair macrophages upon exposure in culture to sequential changes in the microenvironmental conditions We have described above that tissue macrophages have basically an M2-like phenotype, whereas infiltrating recruited monocytes differentiate in M1 or M2 depending on the tissue conditions. For instance, it has been shown that tissue-resident macrophages, rather than recruited monocytes, are alternatively activated in the tissue during infection with Litomosoides sigmodondis Also, recruited monocytes can be directly polarized into an anti-inflammatory M2 phenotype by basophil-derived IL-4, in order to alleviate allergic inflammation in the skin Although it is not possible discriminating between tissue-resident and monocyte-derived macrophages in steady-state conditions, it seems that alternatively activated tissue macrophages have a transcriptional profile and phenotype different from that of alternatively activated monocyte-derived macrophages, with the latter having immunoregulatory properties It should be considered that in vitro studies do not fully recapitulate in vivo differentiation for two main reasons:.

While M2 macrophages can convert to the M1 phenotype, the reverse generally does not occur, or it may only occur in particular conditions e. In fact, M1 is probably an end-stage killer cell that dies during the inflammatory response, possibly succumbing to its own NO production, as it was demonstrated in vitro So, their selective death may give the impression that they convert in M2 cells, which in fact proportionally increase It seems that M1 vs. There are cases in which a phenotypic switch in the macrophage population occurs over time, often associated with pathology 91 , Three specific examples of this phenotypic switch are the following:.

These are metabolic syndromes that can lead to a switch in the phenotype of adipose tissue macrophages from wound healing as in healthy non-obese human beings to classically activated macrophages , ;. In the past few years, gene expression profiling techniques and genetic approaches have been used to cast some light on the plasticity of macrophage activation.

The commonly held view is that macrophage polarization is driven by cues in the tissue microenvironment, which can include cytokines, growth factors, and microorganism-associated molecular patterns. These signals are thought to dictate a transcriptional response that shapes the phenotype and function of macrophages based on the physiological or pathological context.

Progress has been made in defining the molecular mechanism underlying macrophage polarization, including signaling pathways, miRNA, epigenetic modification, post-transcriptional regulators, and transcriptional factors , — However, the data are still incomplete and far from being systematic, and our knowledge of the mechanistic basis of macrophage diversity in different tissues or in response to changing environment is to a large extent unknown.

The capacity of taking up and presenting antigen i. 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.

Based on what described above, the cell populations present in the tissue during the acute phase of an inflammatory reaction are the following:. 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. These cells induce the inflammatory response by differentiating in the M1 functional phenotype.

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.

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.

They may also become memory macrophages. Their life span in the tissue is presently unknown. In general, tissue-resident macrophages are maintained locally by proliferative self-renewal , , and retain an M2-like phenotype, for example, in the peritoneal cavity, brain, and lung 86 , , 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. 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 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 , 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. Eigenbrod T, Dalpke AH. Bacterial RNA: An underestimated stimulus for innate immune responses.

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Thanks for your feedback! Sign Up. What are your concerns? Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy. Related Articles. Understanding the Purpose of Lymph Nodes in the Body. Do Macrophages Impact Your Asthma? What Is Neutropenia? Building on this, another study confirmed the relationship between CD33 and risk allele rsC, further suggesting that it can result in higher surface expression of TREM2, another biomarker of AD pathology in the cortex Recently, there has been a renewed interest in the link between TREM2 expression and AD pathology, in particular where the late onset forms are concerned The characterization of AD in the brain has recently been advanced by emerging single-cell technologies which allow an in-depth look at changes in aging transcriptomes.

One study assessed age-related microglia changes by examining gene expression profiles of purified parietal cortex microglia leading to the identification of human-specific signatures. More recently, a dataset consisting of 80, single nuclei transcriptomes from AD patients' human prefrontal cortexes at different stages of the disease indicated the existence of heterogeneity in six identified cell types.

In addition, these subpopulation profiles uncover new AD-associated genes, including the complement component C1QB and CD14 , which have not been reported before. Interestingly, transcriptional changes in response to the earlier disease stages were more cell type-specific in comparison with more ubiquitous late stage variations where the genes being upregulated represented a more general stress response In none of these single-cell sequencing studies on AD presented above have researchers been able to identify bone marrow-derived monocytes.

The reason for this could be monocyte exclusion in sorting panels, such as in Galatro et al. In contrast, single-cell studies on pre-clinical models of other neuroinflammatory diseases, such as multiple sclerosis, the numbers of microglia and circulating monocytes in the brain have been shown to be increased in comparison with homeostasis Consequently, the way monocytes are involved in neurodegenerative diseases depends on both the condition itself and the severity stage.

Human monocytes are still widely studied in context of peripheral blood and the advent of novel single-cell technologies, including sequencing-based methods have fueled new interest in these cells. While higher heterogeneity has been suggested, we still propose classical, intermediate, and non-classical monocytes as the three major subsets within the monocyte cell space.

We would suggest further heterogeneity being explained by functional states of these important immune cells. However, this requires a community effort with guidelines on how to define such newly defined cell states in the monocyte compartment.

Of particular interest are current and future studies on spatio-temporal behaviors of monocyte-derived cells within diseased tissues and organs. We are convinced that the new single-cell technologies can help to decipher the role of these important cells during the major chronic, but also acute inflammatory diseases. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

JS has received funding from the European Union's Horizon research and innovation program under grant agreement No. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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