This extra fluid and the chemicals released by infected cells can cause inflammation. This hurts, but actually helps your body fight infections better! Macrophages and neutrophils work to keep the body clean of debris and invaders, but they also call for backup when an infection is too big for the two of them to handle alone. Other immune system cells, like the T-Cells and B-Cells in our story, are alerted that their help is needed by chemicals the macrophages release.
Macrophages are also linked to the presence of other types of cells like basophils and eosinophils, which are most often involved in allergic reactions. These cells also help control the inflammation of tissues.
Think of macrophages as cell-eating machines. 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. Macrophages are innate immune cells present in every tissue and necessary for homeostasis.
Macrophages sense and respond to pathogens and other environmental challenges and participate in tissue repair after injury. Work from many groups in the last decade reveals macrophages as remarkably plastic cells that are epigenetically programmed in response to signals originating from the tissue environment 1 , 2.
Macrophages integrate endocrine or paracrine signals with signals originating from phagocytosed cells, microvesicles, and molecules in the extracellular matrix. In addition, macrophages can interact directly with surface receptors on other tissue-resident cell populations, immune cells recruited during injury, and extracellular proteins.
As a result, macrophages play diverse roles in development, the acute response to infection and tissue injury, and tissue repair. Because macrophages play tissue- and disease stage—specific roles, therapies that target them might be expected to have fewer of the off-target effects that limit the use of less selective therapies. Achieving this goal will require more precise molecular endotyping and targeting of macrophage subpopulations over the course of tissue injury and repair.
Here we describe recent advances in our understanding of the origin, subtype, and phenotype of tissue macrophages during homeostasis and repair. Developmental origins of tissue macrophages. In , based on labeling studies after whole-body irradiation, van Furth and colleagues proposed that bone marrow—derived circulating monocytes are the source of tissue macrophages 3. This paradigm was overturned within the last decade when several independent groups reported the results of genetic lineage tracing studies in mice 4 — They found that in many tissues, macrophages originate from precursor cells derived from the yolk sac or fetal liver and differentiate into macrophages as part of prenatal or antenatal development.
In other tissues, tissue-resident macrophage populations are replaced by monocyte-derived cells over different time scales. For example, in the intestine, locally maintained tissue-resident macrophages coexist with monocyte-derived populations with relatively short half-life, which have distinct roles in gut homeostasis and intestinal physiology 14 — Advances in flow cytometry, lineage tracing systems, and insights from single-cell transcriptomics have dramatically improved our ability to identify distinct macrophage populations For example, a recent study identified at least two unique tissue-resident interstitial macrophages in the steady-state lung that could be distinguished by unique transcriptional profiles and spatially localized to the interstitium of the bronchovascular bundles, but not alveolar walls Indeed, most tissues are now recognized to contain multiple macrophage populations localized to distinct microanatomical domains 18 — Each of these populations differs in its ontogeny, rate of replacement by monocyte-derived cells, and capacity for self-renewal, and each is likely to play a specialized role in tissue homeostasis, injury, and repair Figure 1 and refs.
The application of single-cell transcriptomics and high-throughput spatial transcriptomics in mice and humans combined with advanced lineage tracing studies in mice will allow a more complete understanding of the spectrum of macrophage phenotypes in different microdomains within healthy and diseased tissues. These same technologies can be used to generate and test hypotheses with respect to the molecular mechanisms by which macrophages contribute to tissue injury and repair and how they can be targeted for therapy Tissue-resident macrophages and monocyte-derived macrophages play distinct roles in tissue injury and repair.
Tissue-resident macrophages TRMs originate from the yolk sac and fetal liver during development and persist in many tissues via self-renewal. During homeostasis left panel , TRMs clear apoptotic cells, proteins, and phospholipids and either clear or respond to toxins, particulates, and pathogens within the local microenvironment.
Many TRMs are capable of maintaining themselves by local proliferation without the contribution of monocyte-derived macrophages MoMs. TRMs produce a variety of factors that stimulate the activation, proliferation, and differentiation of immune cells, epithelial cells, endothelial cells, fibroblasts, and stem cells that facilitate tissue homeostasis.
In response to tissue injury middle panel , bone marrow—derived monocytes are recruited to the injured tissue, where they differentiate into MoMs. During the resolution of injury right panel , TRMs may die or expand through self-renewal and repopulate the niche. MoMs either undergo apoptosis or persist, sometimes gaining the capacity for self-renewal.
Arrows indicate interactions with other cell types. Epigenetic control of macrophage differentiation is tissue-specific. Relative to dendritic cells, tissue macrophages poorly present antigens to other immune cells and fail to migrate to regional lymph nodes Transcriptomic profiling of four tissue-resident macrophage populations by the ImmGen consortium revealed that macrophages from different tissues — brain microglia, splenic red pulp macrophages, large peritoneal macrophages, and Kupffer cells in the liver — had more differences in their transcriptional program than similarities In contrast, dendritic cells recovered from a variety of tissues had more similar transcriptomes.
These findings suggested that tissue-resident macrophages were uniquely defined by factors originating from their microenvironment.
In seminal studies, two groups of investigators used transcriptional and epigenomic profiling of tissue-resident macrophage populations to provide insights into the molecular events that allow monocytes to differentiate along widely divergent paths in a tissue-specific context 2 , They found that macrophage populations were distinguished from other myeloid cells and each other at the epigenetic level as measured by histone modifications in both promoters and enhancers.
These epigenetic modifications determined tissue macrophage transcriptomic identity. Enhancers are regions distal to the transcriptional start site of genes marked by the corresponding histone marks H3K4me1 for poised enhancers or H3K27ac for active enhancers.
Most macrophage-specific enhancers contain binding domains for the pioneering transcription factor PU. Importantly, these epigenetic enhancer landscapes are similar both in naive mice embryonically derived macrophages and in macrophages derived from monocytes after total-body irradiation and congenic bone marrow reconstitution, suggesting that fully developed tissues retain the ability to epigenetically program monocytes into tissue-resident macrophages.
Furthermore, these epigenetic changes are reversible, as mature macrophages adoptively transferred from one tissue to another take on the phenotype of the recipient tissue macrophages 2 , 25 , Together these findings support a model whereby the tissue microenvironment continuously provides signals that reversibly induce macrophage differentiation in a tissue-specific context through the hierarchical recruitment of transcription factors that alter the epigenetic landscape of the cell.
Given the dramatic changes in environmental signals associated with tissue injury, these results suggest important plasticity in macrophage responses as the microenvironment changes. Macrophages during tissue injury. For almost a century, investigators have focused on the role of monocytes and macrophages in the acute response to tissue injury, where they are known to produce cytotoxic and proinflammatory mediators, clear invading microorganisms, remove apoptotic and damaged cells, and promote tumor progression 27 , Chemokine receptor 2 CCR2 is required for the release of monocytes from the bone marrow and the recruitment of monocytes to tissues during injury.
Mice deficient in CCR2 are therefore monocytopenic and fail to recruit monocytes and monocyte-derived macrophages to tissues during injury. More recently, investigators have used selective deletion strategies to specifically demonstrate a contribution of monocyte-derived alveolar macrophages to tissue injury and fibrosis, in some cases excluding a role for tissue-resident macrophages reviewed below.
Comparisons of monocyte-derived and tissue-resident macrophages colocalized in the injured tissue using bulk or single-cell RNA-Seq reveal distinct transcriptional profiles during injury 29 , In general, both tissue-resident and monocyte-derived macrophages demonstrate qualitatively similar changes in gene expression in response to injury, but these responses are more robust in monocyte-derived cells 9 and disproportionately affect physiologic measures of injury. Collectively, these findings highlight the importance of macrophage ontogeny during acute injury with important consequences for the interpretation of both published and prospective studies.
Specifically, experimental strategies that target genes necessary for monocyte-to-tissue macrophage differentiation have to be interpreted with caution. For example, monocyte-to-alveolar macrophage differentiation has been reported to require several genes, including Torc1 , Pparg , and Tgfb1 34 — Deletion of these genes in monocytes or differentiating macrophages for example with a LysM-Cre or CD11c-Cre system will therefore prevent or slow accumulation of monocyte-derived macrophages in the tissues upon the injury As a result, it is impossible to distinguish effects on tissue injury or repair secondary to depletion of monocyte-derived cells from those related to the specific functions of the targeted gene unless the study is combined with lineage tagging to distinguish monocyte-derived and tissue-resident cells.
This was definitively shown by Xue et al. These macrophage responses can be remarkably selective. For example, Avraham et al. During repair, monocyte-derived macrophages increasingly mature and resemble tissue-resident macrophages, a process that can take weeks 2 , 13 , Macrophages have frequently been reported to play divergent roles in tissue injury and tissue repair Figure 1.
A better understanding of these roles might be obtained by considering unique factors associated with the environmental stimulus that induces the injury, the resident tissue microenvironment in which the injury occurs, and the ontogeny of the macrophages.
In addition, the role of any given macrophage population in tissue injury and repair can change dramatically with time, which might explain occasionally divergent results in the same model system. The molecular events that orchestrate the changing roles for different macrophage populations over the course of tissue injury and repair are beginning to be understood.
Some of these common mechanisms are discussed below. Macrophages as active or passive participants in tissue repair. During tissue injury, pathogens, infected cells, and cells dying from necroptosis or pyroptosis release pathogen- or damage-associated molecular patterns PAMPs or DAMPS , which activate inflammatory signaling pathways in macrophages and other resident cell populations that recruit neutrophils, monocytes, and other inflammatory cells to the tissue.
Once the acute injury has been controlled, macrophages play a role in suppressing inflammation and initiating wound repair by clearing debris and producing growth factors and mediators that provide trophic support to the tissue in which they reside We suggest two nonexclusive pathways by which tissue macrophages might contribute to repair Figure 2.
As this process of differentiation occurs, the macrophages take on phenotype and function increasingly similar to those of homeostatic tissue-resident macrophages.
This suggests that AMPK is important for anti-inflammatory M2-type activation and that AMPK-dependent changes in cellular metabolism contribute to phenotypic switching in macrophages. Consistent with that idea, myeloid Ampka1 deletion in a cardiotoxin injury model leads to delayed muscle regeneration with decreased numbers of Ly6C lo macrophages In addition, although cellular metabolism responds to the microenvironment, it is also controlled in a cell autonomous manner via lipid metabolism, which affects macrophage activation states Taken together, these findings highlight the close interlinkage between macrophage metabolism and function in inflammation and repair.
In a model of fatty degeneration, however, FAPs also gave rise to ectopic adipocytes within degenerating muscle as well as fibroblasts that mediated fibrosis in mdx dystrophic mice Interestingly, muscle damage results in rapid recruitment of eosinophils, which secrete IL-4 to activate FAP proliferation and inhibit their differentiation into adipocytes Notably, in the same study, IL-4 signaling was dispensable for macrophage proliferation and muscle regeneration.
The number of FAPs peaks 96 h after notexin-induced injury and then declines to pre-damage levels within 9 days As discussed in the previous sections, macrophages greatly influence the behavior of SCs. SCs and MPCs also interact with endothelial cells and fibroblasts T reg cells also contribute to muscle regeneration, in part by producing amphiregulin, which promotes MPC differentiation 43 , In mdx dystrophic mice, T reg cell depletion exacerbates muscle inflammation and affects CD expression in Ly6C lo macrophages 90 , suggesting that their regulatory effects on macrophages in muscle are similar to those seen in other tissues.
Angiogenesis and vascular remodeling and maturation are essential for tissue regeneration Inhibiting macrophage accumulation reduces angiogenesis , , demonstrating that macrophages contribute to the proper vascularization of regenerating muscle tissue. After acute muscle injury, there is a transient increase in collagen deposition during the inflammatory phase, which is resolved later, during the resolution phase In fact, efficient muscle repair requires the migration and proliferation of fibroblasts that produce new temporary ECM components.
ECM is important for stabilization of the tissue, and acts as a scaffold for the new muscle fibers. SCs also utilize the basement membranes of pre-existing necrotic muscle fibers to ensure that new myofibers maintain similar positions. Accordingly, proper ECM production and remodeling are important for regeneration. Macrophages promote fibrosis and its resolution.
They also crucially contribute to ECM remodeling. They may also promote fibrosis by influencing local immune cell activation toward type 2 inflammation. By contrast, macrophages may also produce matrix metalloproteinases MMPs and other degradative enzymes that affect ECM.
Some MMP activity contributes to resolving fibrosis, while other activity appears to drive fibrosis 7 , This suggests macrophages stimulate ECM production after acute muscle injury. Although these findings indicate macrophages are important for ECM production and remodeling during muscle regeneration, their precise roles are not yet well characterized.
Inflammation and regeneration processes are tightly orchestrated, and interactions between MPCs, macrophages and other cells are spatiotemporally coordinated. The fact that exercise can trigger inflammation suggests that the adaptive response to acute injury has been under strong selective pressure, resulting in the evolution of an elaborate mechanism In sharp contrast, the response to chronic damage is often insufficient to mediate structural or functional recovery.
Under such conditions, spatiotemporal control of the activities of immune cells and other cells, such as fibroblasts, becomes disorganized. One example is muscular dystrophy, which is characterized by persistent inflammation and muscle wasting in which progressive fibrosis and tissue remodeling impair muscle function. In this pathological condition, chronic inflammation is responsible for secondary damage promoting muscle degeneration and fibrosis.
Although tightly regulated sequential macrophage activation is essential for muscle regeneration after acute muscle damage, the activity of macrophages may become detrimental under chronic inflammatory conditions.
For instance, genetic deletion of Ccr2 and pharmacologic inhibition of CCR2 in mdx dystrophic mice reduces recruitment of monocyte-derived Ly6C hi macrophages, which is associated with suppression of inflammation and improvement of muscle function This is indicative of the contribution made by macrophages to the persistent inflammation and pathology in this model.
Interestingly, a large subset of macrophages in mdx muscle express both Tnf and Tgfb1 , indicating that when damage is chronic, macrophages adopt transcriptomes different from those observed after acute injury. IL-6 appears to contribute to proper muscle repair by controlling inflammation and regeneration Low levels of IL-6 promote SC activation and myotube regeneration. However, chronically elevated production of IL-6 promotes skeletal muscle wasting, which again points to the pathological impact of persistent inflammation.
These findings demonstrate that in muscular diseases, dysregulated activation of macrophages and their altered functionality contribute to persistent inflammation, fibrosis, tissue remodeling and failed regeneration. The liver has a remarkable capacity to regenerate in response to injury. Liver injury induces mature liver cells to proliferate to replace the damaged tissue , However, under conditions in which hepatocyte proliferation is prevented or insufficient, such as chronic liver injury, a population of bipotent hepatic progenitor cells HPCs is activated to regenerate both cholangiocytes and hepatocytes.
Macrophages promote both hepatocyte proliferation and HPC differentiation. Indeed, macrophage depletion greatly compromises liver regeneration. In a mouse biliary injury model, macrophages that have engulfed hepatocyte debris express Wnt3a, which activates Wnt signaling in HPCs and promotes their hepatocytic differentiation In a mouse model of CCl 4 -induced liver injury fibrosis is transient and spontaneously resolved after cessation of CCl 4 treatment In that model, comparison of the effects of macrophage depletion during the period of CCl 4 treatment i.
Early macrophage depletion during liver injury ameliorates fibrosis. By contrast, late macrophage depletion, during the repair period, results in a failure of resolution with persistent activation of the fibrotic response During the injury phase, monocyte-derived Ly6C hi macrophages predominate in the liver and promote fibrosis by supporting stellate cell activation 54 , , Kupffer cells may also exert profibrotic effects in certain contexts During the recovery phase, Ly6C lo macrophages become predominant and play a key role in resolution of fibrosis and repair through MMP production and phagocytotic clearance of debris 54 , Phagocytosis of hepatocyte debris induces a matrix-degrading phenotype with expression of MMPs in monocyte-derived macrophages Moreover, stimulating phagocytosis in vivo reduces numbers of Ly6C hi macrophages and increases those of Ly6C lo macrophages, which is consistent with the idea that phagocytosis is important for phenotypic switching in monocyte-derived macrophages after liver injury.
Unlike with liver, resection of a kidney does not elicit organ regrowth, which is indicative of its limited regeneration capacity However, the kidney does recover from various types of damage in part through regeneration of renal tubules Differentiated tubular epithelial cells are thought to proliferate and repair damaged renal tubules, though the possibility that there is a progenitor population has not been excluded.
This is followed by predominant accumulation of M2-type macrophages, which proliferate in situ within the injured kidney By contrast, inhibition of the later increase in M2-type macrophages impairs tubular epithelial cell proliferation and delays recovery , M2-type macrophages are also important for recovery in a mouse model of selective proximal tubule injury, which does not recruit monocyte-derived M1-type macrophages Similarly, in a mouse unilateral ureteral obstruction UUO model, early accumulation of Ly6C hi pro-inflammatory macrophages is followed by a predominant increase of Ly6C lo M2-type macrophages , Indeed, while isolated Ly6C hi macrophages promote tubular cell apoptosis, Ly6C lo macrophages activate fibroblasts into myofibroblasts, which is suggestive of their role in fibrosis Inhibition of early pro-inflammatory macrophages improves renal function in these models, though it may be that the pro-inflammatory macrophages also contribute to processes leading to recovery, as was seen after skeletal muscle injury.
Consequently, dysregulated activation of macrophages likely leads to pathological tissue remodeling in chronic kidney disease. Although proliferation of existing adult cardiomyocytes has been observed in mice and humans, the renewal rate is very limited so that meaningful regeneration of cardiomyocytes is unlikely to occur after pathological cardiomyocyte death, such as that induced by myocardial infarction MI As discussed, in tissues with high regenerative capacity, such as skeletal muscle and liver, inflammation induced by tissue injury leads to repair through tissue regeneration.
By contrast, because of the very limited regenerative capacity of the heart, MI inevitably results in tissue remodeling through a series of structural and functional changes, including scar formation in the infarct area, reactive hypertrophy of the remaining cardiomyocytes in the non-infarcted area and ventricular chamber dilation Moreover, inflammation may be chronically activated in the non-infarcted area, leading to adverse cardiac remodeling and heart failure.
As such, the inflammation and repair processes triggered by MI have potentially adverse consequences. On the other hand, the rapid replacement of dead tissue with scar tissue is critical for survival of the individual because of the continuous contraction of the heart and the lack of regenerative capacity. Accordingly, repair through scar formation is essentially adaptive in the heart.
Previous studies have shown that macrophages can be both protective and harmful after MI, and that the functions of macrophages differ during the different phases of the tissue response to myocardial injury as well as to the different types of cardiac injury.
Moreover, the developmental origins differ among cardiac macrophages. In young mice, cardiac-resident macrophages derive from embryonic cells and are maintained through self-renewal 66 , Cardiac injury induces rapid accumulation of monocyte-derived macrophages.
Aging also increases replacement of embryo-derived resident macrophages with monocyte-derived cells Following MI, monocytes abundantly infiltrate the injured tissue and differentiate into macrophages By contrast, resident Ly6C lo macrophages within infarcted tissues disappear within 1 day via local death or exit from the infarct , The recruited monocytes are also the major source of Ly6C lo macrophages during the first 2 weeks after MI Thereafter, local proliferation of macrophages appears to predominate.
MI also increases macrophages within non-ischemic tissues through both accumulation of monocyte-derived macrophages and local proliferation The early accumulation of Ly6C hi monocyte-derived cells is thus important for clearance of debris By contrast, depletion of macrophages after day 3 results in decreased fibrosis and angiogenesis, indicating that Ly6C lo macrophages have profibrotic and pro-angiogenic functions.
Serial administration of clodronate liposome increases mortality after MI, presumably because of embolism formation from left ventricular thrombi This serial macrophage depletion impairs debris clearance and scar formation.
Left ventricular thrombi are formed presumably due to delayed re-endothelialization of the damaged left ventricular cavity, which highlights the importance of macrophages for repair of infarcted tissue.
In this model, the number of neutrophils expressing MMP-9 is increased, leading to left ventricular wall instability and rupture. Clearance of neutrophils by macrophages thus appears to be important for repair after MI.
These observations demonstrate that macrophages are indispensable for clearance of necrotic debris as well as repair following MI. As with macrophages in injured skeletal muscle, phagocytosis of dying cardiomyocytes appears to be important for the functional transition from pro-inflammatory to pro-resolution macrophages in the heart.
A scavenger receptor, CD36, is important for phagocytosis of dying cells by monocyte-derived Ly6C hi cells, and bone marrow-specific Cd36 deletion increases both infarct size and the likelihood of cardiac rupture After MI, Ly6C lo macrophages that have engulfed dying cardiomyocytes express higher levels of MerTK and a transcription factor Nr4a1, which transactivates Mertk expression MerTK is important for engulfment of dying cardiomyocytes and is predominantly expressed in Ly6C lo macrophages beginning 3 days after MI Deletion of Mertk severely impairs clearance of dead cardiomyocytes on days 5 and 7 after MI, which is associated with augmented tissue remodeling and functional deterioration by day Mertk deletion also impairs clearance of dead cells and worsens cardiac injury in this model.
Macrophages also potentially mitigate MI injury by regulating fibrosis and angiogenesis Deletion of Trib1 , which encodes an adaptor protein involved in protein degradation, severely reduces M2-like macrophages in bone marrow, spleen, lung and adipose tissue Ly6C lo macrophages also promote angiogenesis which is important for healing after MI In addition, macrophages support cardiomyocyte survival by producing and secreting myeloid-derived growth factor, which also has the potential to activate angiogenesis In addition to showing that macrophages are integral to healing after MI, clodronate liposome studies showed that inhibiting monocyte accumulation starting 1 week after MI improves left ventricular contractility and suppresses fibrosis in non-infarct tissues, which is indicative of the detrimental pro-remodeling function of macrophages In a model of cardiomyocyte ablation wherein diphtheria toxin induces cell death among cardiomyocytes expressing DTR, the cardiac injury leads to recruitment of monocytes and monocyte-derived macrophages that have a robust pro-inflammatory phenotype In this model, inhibition of monocyte influx into the injured heart decreases inflammation and enhances coronary angiogenesis, indicating monocyte-derived macrophages promote cardiac injury.
In addition, while the initial replacement fibrosis i. These studies highlight the pathological activities of macrophages after MI. In particular, macrophages appear to crucially contribute to persistent inflammation and tissue remodeling in non-infarcted areas during the chronic phase after MI, which may lead to heart failure.
In sharp contrast to the adult heart, neonatal mouse heart can fully regenerate after apical resection or MI , but this robust regeneration capacity is lost by postnatal day 7 P7.
The reduced expression of several angiogenic genes in P14 macrophages may indicate that the function of macrophages in hearts change between P1 and P In the diphtheria toxin-induced cardiomyocyte death model, cardiac injury increases only resident macrophages that exhibit reparative functionality in P1 to P7 mice, but it begins recruiting monocyte-derived macrophages on P14 In this model, inhibition of monocyte recruitment to the injured heart preserves an embryonically derived macrophage subset, reduces inflammation, and enhances coronary angiogenesis in adult mice Thus embryonically derived, resident macrophages have a reparative function, while monocyte-derived macrophages do not.
Through their diverse and changing functions, macrophages lead the complex tissue response to injury throughout the course from inflammation to healing. They also play key pathological roles during chronic inflammation, which causes pathological remodeling and tissue dysfunction. Given the varied characteristics of different tissues e. Nonetheless, it appears that acute injury triggers similar processes e.
In the early inflammatory phase triggered by tissue injury, monocytes and macrophages lead inflammation by expressing pro-inflammatory cytokines and interact with other pro-inflammatory immune cells. Macrophages are activated by various DAMPs, fibrin and pro-inflammatory cytokines 91— Hypoxic conditions may also affect macrophage activity In addition to monocyte-derived macrophages, resident macrophages may contribute to the recruitment and activation of circulating immune cells.
Macrophages and monocytes are central players involved in the clearing of cell and tissue debris, which is prerequisite for successful healing. Clearance of neutrophils is also important to limit inflammation.
Consequently, repair and regeneration processes are tightly linked to initial inflammatory processes. In other words, acute inflammation not only paves the way to healing through clearing and preparing the damaged tissue for repair and regeneration, it also guides the initial cellular response toward regeneration. The observation that perturbation of that sequence, either by forced prolongation of inflammation or its premature resolution, is detrimental to skeletal muscle regeneration 61 , 62 emphasizes the importance of temporal coordination of inflammation resolution with other ongoing cellular processes.
This transition may also be recorded as a shift from M1 to M2 macrophages. These phenotypic changes are associated with dynamic changes in transcriptomes, which may occur regardless of the macrophage subtypes determined based on their surface markers e. The functional and phenotypic changes in macrophages appear to be driven by multiple factors, including both microenvironmental and endogenous cues Table 1.
Cytokines and other mediators also likely promote functional changes. Our knowledge is still limited to a relatively small number of mediators, and many additional active molecules are likely involved.
In addition, in the later phase of the injury response, both monocyte-derived and resident macrophages may proliferate. This in situ proliferation may promote macrophage functional transition, though the mechanism linking cell proliferation to epigenetic regulation of macrophages remains poorly understood The functional transition of macrophages also associates with changes in cellular metabolism, which can be affected by environmental cues as well as cell-autonomous mechanisms.
For instance, they may suppress inflammation through expression of anti-inflammatory cytokines, such as IL Or they may promote proliferation of existing parenchymal cells, as is seen in the liver and kidney. In addition, they may indirectly support repair by parenchymal cells by promoting proliferation and activation of stromal cells, such as endothelial cells and fibroblasts, which build the microenvironment needed for repair and healing.
Macrophages have important regulatory functions in angiogenesis and ECM production. The stroma is where immune cells, vascular cells, and fibroblasts interact, and cellular processes occurring within the stroma are central to inflammation, repair and regeneration.
For instance, formation of new blood vessels via angiogenesis is indispensable to tissue regeneration and repair 6. ECM synthesis and remodeling are also essential for formation of the scaffolding that supports regeneration. Moreover, ECM controls various aspects of growth, proliferation, movement, differentiation, and activation of the cells living within it 1.
Indeed, damage to the ECM framework hinders regeneration and leads to scar formation. Properly organized ECM is thus essential for regeneration 1.
During inflammation and healing after tissue injury, the ECM is remodeled through dynamic synthesis and degradation. After skeletal muscle injury, for example, transient ECM deposition occurs This temporary ECM, which stabilizes the tissue and acts as a scaffold for new muscle fibers, is resolved during the progression of regeneration and disappears from regenerated tissue.
Conversely, ECM components may alter macrophage function and phenotype , which underscores the complex reciprocal interactions between macrophages and ECM, though the details of these interactions during repair and regeneration are not well understood. Many of the inflammatory and reparative processes led by macrophages are commonly observed after injury in the different tissues discussed in this article. While it may appear that macrophages play a few variations on a common theme, there are also many significant differences.
For instance, because of the very limited regenerative capacity of the adult heart, macrophages appear to have adjusted for rapid repair through scar formation Similarly, neurons in the adult central nervous system have limited regenerative capacity.
On the other hand, remyelination, the formation of myelin sheaths by myelin-forming oligodendrocytes newly differentiated from oligodendrocyte precursor cells, can robustly repair demyelination injury in young animals.
Macrophages and microglia crucially contribute to remyelination, in part by controlling the proliferation and differentiation of oligodendrocyte precursor cells , It is thus very likely that macrophages are highly tuned to the tasks necessary for repair throughout the array of different tissue structures found in complex organisms.
How then is macrophage tissue- and injury-specificity conferred? Recent studies have revealed the dynamic and flexible nature of the macrophage epigenome, which can be dynamically modulated by the microenvironment , Each tissue macrophage has a distinct epigenome that appears to confer distinct functional properties and, upon injury, these macrophage epigenomes are dynamically modulated.
Following acute injury, monocyte-derived macrophages enter the affected tissue and become predominant. Their epigenomes differ from those of tissue-resident macrophages when they initially enter. It is likely that a combination of epigenomic status and microenvironmental cues shapes their function.
As discussed in this article, macrophages markedly change their function over the course of injury and repair. Such temporal dynamics are also likely driven by environmental cues as well as by cell-autonomous mechanisms. For instance, pro-angiogenic macrophages are located in close proximity to blood vessels Accordingly, it is clear that the functional characteristics of macrophages are much more diverse than can be defined by small numbers of surface markers.
To better understand this diversity, we will need to analyze the gene expression and localization of macrophages at the single cell level The lineages of macrophages may also influence their function. In that regard, Satoh et al. In this review we mainly focused on acute injury, which heals through well-coordinated cellular responses wherein macrophages with programs spatiotemporally tuned to repair are the central player.
However, it is often the case that continued unresolved inflammation and repair progressively remodel tissue structure such that tissue function is impaired. This is particularly relevant to chronic non-communicable diseases, such as cardiovascular disease. In those settings, the actions of macrophages are often pathogenic. This review does not address those actions of macrophages in detail. However, by comparing the adaptive and reparative functions of macrophages in this review, we raise several related questions about the pathogenicity of macrophages.
For instance, why does the behavior of macrophages become pathogenic? What drives the pathogenic activities and are they merely programmed responses? Clear answers to these questions are elusive. Given that macrophages are highly responsive to environmental cues, one might think that even within a pathogenic process, macrophages are just playing out their programs, which are essentially adaptive. Within a setting of disorganized interactions among many cells and ECM, it is conceivable that environmental cues given to macrophages are spatiotemporally more complex than those in coordinated repair processes.
That said, many of the fundamental programs controlling macrophage activity may be shared in both physiological and pathological responses to tissue injury.
There is clearly much to learn about the endogenous and exogenous regulatory programs of macrophage dynamics in response to injury, but such studies are opening up opportunities to therapeutically modulate macrophage function to promote regeneration and repair, to limit pathological remodeling, or to reverse tissue remodeling in chronic diseases.
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