Abstract Macrophages are present in virtually almost all tissues, exhibiting highly heterogeneous phenotypes as a consequence of adaptation to local tissue environments. Tissue-resident macrophages perform specialized functions that are essential for the maintenance of tissue homeostasis, and abnormalities of their functions are linked to various pathologies. Recent advances have shown that tissue-specific transcriptional programs are responsible for functional specialization of macrophages in different tissues. Here, I discuss the molecular basis of tissue-resident macrophage specialization and how it is regulated by tissue environmental cues. differentiation, polarization, tissue homeostasis Introduction Macrophages are a key component of the innate immune system, first discovered by Eli Metchnikoff in the late 19th century (1). They are uniquely equipped with a broad array of sensing molecules, including phagocytic, scavenger and pattern-recognition receptors, with which macrophages function as sentinel cells for infection and tissue damage (2, 3). Macrophages exhibit a very high level of phagocytic activity, which is not only critical for host defense mechanisms against invading pathogens but also important for housekeeping mechanism of the body (e.g. clearance of dead cells and cellular debris) (4). Macrophages also play a central role in inflammation through the production of inflammatory cytokines. Additionally, they can be involved in the tissue repair response by secreting growth factors including platelet-derived growth factors (PDGFs), transforming growth factor β (TGF-β), fibroblast growth factors (FGFs) and vascular endothelial growth factors (VEGFs) as well as anti-inflammatory cytokines such as IL-4 and IL-10 (5). Recently, studies have shed light on multi-functionality and plasticity of the macrophages, and our view has expanded to include more of the non-immunological roles of macrophages in vertebrate biology (6). The accumulating evidence highlighted homeostatic roles of macrophages in organ development, in angiogenesis and in metabolism. Macrophages are present in virtually almost all tissues, where they are continuously exposed to the signals present in tissue microenvironments. Thus, tissue-resident macrophages respond to these tissue-derived signals and perform specialized functions as a result of adaptation to local tissue environments. Therefore, tissue-resident macrophages are highly heterogeneous populations in terms of their phenotypes and functions (7–9). In this Review, I discuss how tissue environmental cues shape macrophage identities in different tissues and transcriptional regulation controlling tissue-resident macrophage phenotypes. The origin of tissue-specific macrophages and their roles in physiology All tissue-resident macrophage populations are established by colonization of migratory cells that originate from common progenitor pools. Historically, the macrophage was classified as a part of the mononuclear phagocyte system (MPS), proposed by Ralph van Furth and Zanvil Cohn in 1968, which held that all tissue macrophages originate from hematopoietic stem cells in the bone marrow (10, 11). Although this concept is still applicable in certain settings and during inflammation, our view of the origin of macrophages has begun to dramatically change in the last few decades. The revised concept accommodates the existence of distinct origins of tissue macrophages (12, 13). Recent fate-mapping studies elucidated that tissue-resident macrophages in many adult tissues are derived from prenatal origins that are distinct from bone marrow hematopoietic stem cells (14). In tissues such as the brain, epidermis, lung, liver and peritoneum, macrophages from embryonic origins are maintained by local proliferation with a minimal contribution from adult bone marrow (15–17). For example, the origin of microglia, which are tissue-resident macrophages in the central nervous system (CNS), is exclusively from progenitors in the embryonic yolk sac prior to the formation of the blood–brain barrier and they appear to persist in adulthood by self-renewal (18). The long-term persistence of embryo-derived populations of tissue-resident macrophages is likely due to prolonged lifespans as well as the ability to self-renew, which in turn results in substantial influence of tissue environmental cues to macrophage phenotypes. However, the contribution of embryonic sources versus adult bone marrow sources to resident macrophage populations varies by tissue. For example, embryo-derived populations in the gut and dermis are replaced shortly after birth by macrophages that have differentiated from bone marrow-derived monocytes (12). The heterogeneity of tissue-resident macrophage phenotypes can be considered as macrophage specialization to fulfill distinct functional demands of different tissues (19). For example, resorption of old bone mineral by osteoclasts (bone macrophages) is essential for the remodeling of bone tissue (20). Adipose tissue macrophages, through the release of noradrenaline, control lipolysis in white adipose tissue (WAT) and adaptive thermogenesis in brown adipose tissue (BAT) (21). Subcapsular sinus macrophages in lymph nodes facilitate adaptive immune responses through capturing antigen-containing immune complexes and through displaying these complexes to B-cell follicles independently of their phagocytic activity (22). Microglia contribute to the development and function of CNS through synaptic pruning, a process for eliminating excess, defective or immature neuronal synapses (23). Thus, the functions of tissue-resident macrophages are essential components for normal tissue physiologies. Accordingly, abnormalities of tissue-resident macrophage functions link to various pathologies including osteopetrosis, type 2 diabetes, immune deficiency and neurodevelopmental diseases (6). Therefore, understanding and manipulation of tissue-resident macrophage functions seems to provide a valid therapeutic approach for these diseases. ‘Universal’ and ‘tissue-specific’ macrophage signatures Recent whole genome transcriptional and epigenetic studies uncovered the existence of core macrophage-associated genes that are universally expressed in tissue-resident macrophages whereas there are also significant numbers of genes that are selectively expressed in particular types of tissue-resident macrophages (24–26). This leads to the proposal that, conceptionally, the properties of tissue-resident macrophages can be broken down into two aspects: the ‘universal’ macrophage signature and the ‘tissue-specific’ macrophage signature. The ‘universal’ macrophage signature is considered as the functional modules that uniformly equip all tissue macrophages such as enhancement of lysosomal biogenesis and the expression of pathogen recognition receptors (Table 1). This signature is regulated by core macrophage-associated genes and is likely to be coupled with differentiation of the macrophage lineage. In contrast, the ‘tissue-specific’ macrophage signature can be considered as the functional specialization of macrophages to particular tissue environments, which are exemplified by the ability of osteoclasts to resorb old bone minerals and axon pruning by microglia (Table 2). Table 1. The ‘universal’ macrophage signature and its effector genes Function Effector genes Lysosomal biogenesis LAMP1, LAMP2, Cathepsin D Phagocytosis MerTK, CD64 Pathogen recognition TLRs, CLRs, CD14 Differentiation and survival M-CSFR, Fert2 Function Effector genes Lysosomal biogenesis LAMP1, LAMP2, Cathepsin D Phagocytosis MerTK, CD64 Pathogen recognition TLRs, CLRs, CD14 Differentiation and survival M-CSFR, Fert2 This table is not comprehensive and has been simplified for clarity . View Large Table 1. The ‘universal’ macrophage signature and its effector genes Function Effector genes Lysosomal biogenesis LAMP1, LAMP2, Cathepsin D Phagocytosis MerTK, CD64 Pathogen recognition TLRs, CLRs, CD14 Differentiation and survival M-CSFR, Fert2 Function Effector genes Lysosomal biogenesis LAMP1, LAMP2, Cathepsin D Phagocytosis MerTK, CD64 Pathogen recognition TLRs, CLRs, CD14 Differentiation and survival M-CSFR, Fert2 This table is not comprehensive and has been simplified for clarity . View Large Table 2. The ‘tissue-specific’ macrophage signature and TSTFs Tissue Macrophage Function TSTF Peritoneum Peritoneal macrophage (LPM) Peritoneal immunity GATA6 Bone Osteoclast Bone resorption NFATc1 Spleen Red-pulp macrophage Iron recycling Spi-C Lung Alveolar macrophage Surfactant clearance PPARγ, Bach2 Brain Microglia Neuronal development Sall1 Tissue Macrophage Function TSTF Peritoneum Peritoneal macrophage (LPM) Peritoneal immunity GATA6 Bone Osteoclast Bone resorption NFATc1 Spleen Red-pulp macrophage Iron recycling Spi-C Lung Alveolar macrophage Surfactant clearance PPARγ, Bach2 Brain Microglia Neuronal development Sall1 This table is not comprehensive and has been simplified for clarity. View Large Table 2. The ‘tissue-specific’ macrophage signature and TSTFs Tissue Macrophage Function TSTF Peritoneum Peritoneal macrophage (LPM) Peritoneal immunity GATA6 Bone Osteoclast Bone resorption NFATc1 Spleen Red-pulp macrophage Iron recycling Spi-C Lung Alveolar macrophage Surfactant clearance PPARγ, Bach2 Brain Microglia Neuronal development Sall1 Tissue Macrophage Function TSTF Peritoneum Peritoneal macrophage (LPM) Peritoneal immunity GATA6 Bone Osteoclast Bone resorption NFATc1 Spleen Red-pulp macrophage Iron recycling Spi-C Lung Alveolar macrophage Surfactant clearance PPARγ, Bach2 Brain Microglia Neuronal development Sall1 This table is not comprehensive and has been simplified for clarity. View Large Signals and transcriptional regulation shaping the ‘universal’ macrophage signature Terminal differentiation of macrophages occurs in peripheral tissues, regulated by dedicated growth factors (27). Macrophage colony-stimulating factor (M-CSF; also known as CSF1), which signals through the M-CSF receptor (M-CSFR), is the most prominent growth factor for commitment to the macrophage lineage. This notion is supported by the evidence that osteopetrotic (Csf1op/op) mice that harbor a mutation in the M-CSF gene show severe macrophage defects in many tissues (e.g. bone, gut, kidney and peritoneum) (28). M-CSF is also involved in peripheral self-renewal of tissue-resident macrophages, which is demonstrated by the finding that administration of anti-M-CSFR antibody neutralizes the steady-state proliferation of macrophages (29). Thus, M-CSF has a broad range of actions (differentiation, survival and self-renewal) on the macrophage lineage. IL-34 is another ligand that binds to the M-CSFR and regulates macrophage differentiation; however, the expression patterns of M-CSF and IL-34 are spatially and temporally distinct so that they function in a complementary way rather than redundantly for macrophage generation and maintenance. Indeed, deficiency of the IL-34 gene results in a defect of specific subsets of tissue-resident macrophages (microglia in the CNS and Langerhans cells in skin) but other macrophages remain unaffected (30). The above-described differentiation signals induce the expression of lineage-determining transcription factors (LDTFs) that play key roles in macrophage differentiation and the establishment of ‘universal’ macrophage signature (Fig. 1). In particular, the transcription factor PU.1 is one of the most important LDTFs for the macrophage lineage. PU.1 binds to and activates the M-CSFR promoter, leading to higher levels of expression of M-CSFR and increased sensitivity to its ligands, which in turn induce more PU.1 (31). This feed-forward loop is likely a key mechanism to consolidate and stabilize the macrophage lineage choice. Another role of PU.1 is to function as a ‘pioneer’ transcription factor that can occupy and engage macrophage-specific gene enhancers, by recruiting chromatin-remodeling complexes to make the loci accessible to the other transcriptional regulators (32). Fig. 1. View largeDownload slide Transcriptional control for ‘universal’ and ‘tissue-specific’ macrophage signatures. Differentiation signals (M-CSF or IL-34) induce the expression of LDTFs (e.g. PU.1) that control genes commonly expressed in all macrophage subsets. TSTFs (e.g. GATA6, NFATc1 or Spi-C) that are induced by tissue-specific signals (e.g. retinoic acid, RANKL or heme) regulate tissue-specific transcriptional programs in combination with LDTFs. Fig. 1. View largeDownload slide Transcriptional control for ‘universal’ and ‘tissue-specific’ macrophage signatures. Differentiation signals (M-CSF or IL-34) induce the expression of LDTFs (e.g. PU.1) that control genes commonly expressed in all macrophage subsets. TSTFs (e.g. GATA6, NFATc1 or Spi-C) that are induced by tissue-specific signals (e.g. retinoic acid, RANKL or heme) regulate tissue-specific transcriptional programs in combination with LDTFs. Given the fact that PU.1 is expressed in many cell types, including macrophages, B cells and granulocytes, and that it contributes to a broad spectrum of cell lineage choices, macrophage-specific enhancer selection is achieved by collaborative interaction with additional transcription factors. CCAAT/enhancer-binding protein (C/EBP) is a family of transcription factors composed of six members: C/EBP-α, -β, -γ, -δ, -ε and -ζ (33). The crucial roles of C/EBP proteins in macrophage differentiation are illustrated by the evidence that transduction of C/EBP-α or C/EBP-β triggers trans-differentiation of macrophages from mature B cells, and the impairment of development of the myeloid lineage in C/EBP/-β-deficient mice (34–36). MafB/cMaf are members of the musculoaponeurotic fibrosarcoma family and regulate terminal differentiation of macrophages, which is generally linked to cell cycle exit. Macrophages that lack MafB/cMaf were shown to undergo continuous proliferation, and transient down-regulation of these transcription factors is likely to be a key step for the progression of self-renewal of tissue-resident macrophages (37, 38). Transcriptional programs regulating the ‘tissue-specific’ macrophage signature Generation of the ‘tissue-specific’ macrophage signature is regulated by tissue-specific transcription factors (TSTFs) that are induced by tissue environmental signals (Fig. 1). However, TSTFs need to coordinate with LDTFs for the commitment of the resident macrophages to a tissue specificity; combinations of TSTFs and LDTFs define the epigenetic and transcriptomic states of tissue-resident macrophages (26, 32, 39). For example, PU.1 is known to work in combination with transcription factor GATA6, which is one of the TSTFs for peritoneal macrophages, for the induction of the peritoneum-specific gene expression program (40). Various types of signals that are present in different tissue environments are likely to induce multiple TSTFs for the establishment of a full picture of a tissue-specific macrophage signature, although most of these tissue-derived signals and TSTFs remain to be determined (Table 2). In the following sections, I briefly discuss some selected examples of molecular controls for the tissue specialization of resident macrophages. Peritoneal macrophages The peritoneal cavity is a large body cavity surrounded by mesothelial layers that cover the parietal wall and visceral tissues. It is filled with fluid that functions as a lubricant for the surface of the mesothelium, and harbors large numbers of macrophages. Because of their ease of isolation, peritoneal macrophages are among the best-studied tissue-resident macrophages, and therefore they have significantly contributed to our understanding about the development and tissue specification of macrophages (41, 42). In the steady state, two distinct macrophage populations in terms of origin, cell surface markers and gene expression are present in peritoneal cavity. Ghosn et al. identified the majority of macrophages, which are termed as large peritoneal macrophages (LPMs) as those expressing high levels of F4/80 and having low or absent MHC class II (MHC-II) (43). The other population is characterized as having lower F4/80 levels but having high levels of MHC-II and they are called small peritoneal macrophages (SPMs). Later studies identified that CD102 [intracellular adhesion molecule 2 (ICAM2)], CD49f (integrin-α6) and CD93 are useful cell surface markers for LPMs (24, 25). SPMs are, on the other hand, positive for the chemokine receptor CCR2 and for CD226 (DNAM-1) (44). Recent fate-mapping studies support the idea that LPMs are derived from cells of prenatal origin that display longevity and a self-renewal capacity (15). SPMs are, in contrast, thought to originate from bone marrow-derived monocytes, as demonstrated by a significant decrease of the number of SPMs, but not of LPMs, in mice deficient in CCR2, which plays a critical role in monocyte egress from the bone marrow and recruitment (25, 44). Additionally, SPMs were shown to be dependent on the transcription factor IRF4 for their development (44). Recently, three groups independently reported that the zinc-finger transcription factor GATA6 is specifically expressed in LPMs and acts as the master regulator for their tissue specialization (25, 45, 46). Whereas GATA6 is not required for the development of LPMs, it controls the expression of a large number of peritoneal-macrophage-specific genes (PMSGs). In particular, GATA6 is essential for peritoneum-specific expression of TGF-β2 and genes that are associated with TGF-β functions like as thrombospondin 1(Thbs1) and latent TGF-β binding protein 1 (Ltbp1). This TGF-β signature controls the production of IgA by peritoneal B1 lymphocytes (25). GATA6 also regulates the expression of cell adhesion molecules such as CD49f, CD73 (ecto-5′-nucleotidase), CD62P (P-selectin) and CD93, that are required for the localization of LPMs in their proper tissue compartment (25). In addition, GATA6 controls the expression of genes associated with cell proliferation, and a deficiency of the GATA6 gene causes increased cell proliferation and decreased cell survival in LPMs (45, 46). Regarding GATA6 gene induction in LPMs, the vitamin A metabolite retinoic acid directly activates the GATA6 gene promoter through retinoic acid nuclear receptors (RARs) (25). Notably, LPMs have bimodal expression of GATA6 protein and its expression is modulated by the local availability of retinoic acid. This supports the notion that GATA6 controls a reversible program for macrophage specialization, rather than a hardwired and irreversible fixation of macrophage phenotype. Indeed, transplantation of resident peritoneal macrophages into the alveolar cavity induces a phenotypic switch to an alveolar macrophage signature, which includes the down-regulation of the GATA6 gene (26). Therefore, the GATA6-dependent program is analogous to M1/M2 macrophage polarization, which can be reversibly regulated by the withdrawal of extracellular signals (47). Whereas tissue-resident macrophages are in general stationary, peritoneal macrophages are uniquely motile. Peritoneal macrophages are reported to develop in the visceral adipose tissue omentum and migrate into the peritoneal cavity after maturation (48). Although the omentum is primarily an adipose tissue, it contains lymphoid aggregates, called milky spots, at regular intervals; they are considered to have characteristics of secondary lymphoid tissue (49). Milky spots are rich sources of M-CSF, and local proliferation of macrophages was observed around milky spots (50). Additionally, omental stromal cells produce retinoic acid which is required for GATA6 gene induction (25). Taken together, the milky spot is likely to provide a niche for differentiation of peritoneal macrophages and their tissue specialization. Although the exact mechanism for LPM translocation to the peritoneal cavity remains unclear, GATA6 is involved in macrophage egress from the omentum, demonstrated by the finding that GATA6 deficient LPMs fail to translocate into the peritoneal cavity and instead accumulate around milky spots (25). The omentum may also contribute to the self-renewal of peritoneal macrophages that are of prenatal origin, supported by the notion that omentectomy in adult rats results in a reduction in the number of peritoneal macrophages (51). If this is the case, an inverse direction of macrophage migration (from the peritoneal cavity to the omentum) must take place during macrophage self-renewal. This possibility is actually supported by the phenomenon called the macrophage disappearance reaction (MDR), which is a rapid peritoneal macrophage migration to the omentum in response to intraperitoneal challenge by bacterial components (25, 52). In addition to translocation between the omentum and the peritoneal cavity, Wang and Kubes reported that LPMs rapidly migrate into damaged liver, where they contribute to the tissue repair response in a CD44-dependent and ATP-dependent manner (53). In summary, these findings clearly illustrate a migratory property of peritoneal macrophages although its mechanism remains to be determined. Osteoclasts Bone is a rigid organ designed to provide structure and support for the body. Bone formation is regulated by the balance of two activities: bone matrix formation by mesenchymal-lineage osteoblasts and bone resorption by osteoclasts that are specialized bone-resident macrophages. Osteoclasts exhibit a unique capacity to resorb bone mineral through the release of cathepsin K, matrix metalloproteinase-9 (MMP-9) and tartrate-resistant acid phosphatase (TRAP) into the resorption lacunae (20). Tissue specialization of osteoclasts is one of the examples of irreversible macrophage specification, accompanied with cell–cell fusion of mononuclear pre-osteoclasts followed by the formation of multi-nuclear mature osteoclasts, in sharp contrast to the reversible polarization program of LPMs mediated by the retinoic acid—GATA6 axis in the peritoneal cavity (20). The pre- and post-natal ontogeny of osteoclast is controversial. Especially, it remains unclear whether osteoclasts are derived from circulating monocytes or from bone tissue-resident precursors (54). Differentiation of osteoclast is induced by M-CSF and receptor activator of nuclear factor κB ligand (RANKL), which is a member of the TNF superfamily (55). These external signals regulate several transcription factors for osteoclast development. In particular, NFATc1 has been described as a master regulator for osteoclast differentiation and controls the expression of a number of osteoclast-specific genes including cathepsin K and TRAP (56). Mice deficient in RANKL or NFATc1 exhibit abnormal osteoclast differentiation, followed by the development of osteopetrosis in which the bones become sclerotic and thick. Splenic macrophages The red pulp of the spleen is characterized by sinus cavities awash with blood and the presence of a large number of macrophages and it functions to remove senescent or damaged red blood cells. Macrophages that reside in the red pulp are derived from fetal progenitor cells and locally maintained by self-renewal (16, 57). Red-pulp macrophages are specialized in the removal of senescent red blood cells (erythrophagocytosis), degrading hemoglobin and transport of the iron back into the circulation (58). These specialized functions require the selective expression of genes such as the hemoglobin scavenger receptor (CD163), the iron transporter ferroportin and heme oxygenase-1 (HO-1). Differentiation and tissue specification of red-pulp macrophages require the transcription factor Spi-C; ablation of Spi-C leads to a failure to induce differentiation of red-pulp macrophages, resulting in impaired clearance of erythrocytes and the development of selective iron overload in the spleen (58). Interestingly, the expression of Spi-C is induced by heme, with which the majority of iron in the body binds (59). This illustrates that functional needs derived from tissues control macrophage phenotypes: conditions leading to increased heme levels are sensed by macrophages and their progenitor cells to induce the expression of Spi-C for degradation of hemoglobin and for recycling iron. Alveolar macrophages The lung is the primary respiratory system where microorganisms and dust are constantly inhaled from the airway. Alveolar macrophages, residing in the pulmonary alveoli, develop from prenatal origin and differentiate into long-lived macrophages (17, 60). They provide the first line of defense against pathogens and particles that have invaded the lower airways. In addition to being a part of the host defense mechanism, alveolar macrophages have a homeostatic role by controlling the amount of pulmonary surfactant in alveoli (61). Pulmonary surfactant is a complex of lipids and proteins that contributes to reduce the surface tension caused by inflation and deflation during breathing. However, too much surfactant causes hindered gas-exchange, which results in the symptoms of alveolar proteinosis and alveolar macrophages are specialized in the removal of excess surfactant (62). Although M-CSFR signaling has a dominant role in macrophage differentiation, alveolar macrophages are exceptionally dependent on GM-CSF (also known as CSF2) for their terminal differentiation (61). GM-CSF- or GM-CSFR-deficient mice do not develop fully differentiated alveolar macrophages but other tissue macrophage populations remain intact. Either M-CSF or GM-CSF can induce the differentiation of macrophages from bone marrow or fetal liver monocytes in vitro. However, these factors provoke distinct types of macrophage phenotypes that are known as M1/M2 macrophages (63–65). M-CSF induces M2-type macrophage polarization, which is generally associated with the secretion of low levels of pro-inflammatory cytokines and tissue repair. GM-CSF, in contrast, induces M1-type macrophage polarization, which is characterized by high production of pro-inflammatory cytokines upon challenge by microbes. In this regard, intracellular signals through either M-CSFR or GM-CSFR are likely to determine the first phase of tissue specialization of macrophages in vivo (64). Indeed, GM-CSF induces selective expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), a nuclear receptor activated by lipid-derived substrates, in alveolar macrophages (66). Additionally, the transcriptional repressor BTB and CNC homology 2 (Bach2) is also involved in alveolar macrophage functions although its expression is independent of GM-CSF (67). TGF-β was recently shown to control functional maturation of alveolar macrophages, although whether TGF-β controls Bach2 expression remains to be determined (68). In summary, functional specialization of alveolar macrophages exemplifies how the combination of multiple signals (GM-CSF, PPAR-γ ligands and TGF-β) integrates the full spectrum of tissue-specific macrophage identity. Microglia The CNS is a complex organ of neurons and other cell types. Accumulating evidence indicates that reciprocal microglia–neuron interactions play critical roles in CNS development and homeostasis (69). Microglia arise early during development from progenitors in the yolk sac, and are crucial for the differentiation and functions of neurons through synaptic pruning and provision of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), which contributes to shape the functional organization of neural circuits (70). Conversely, neurons are important for the regulation of microglial differentiation and functions, through the release of soluble factors and/or cell–cell interactions. For examples, neuron-derived IL-34 has a central role for differentiation and maintenance of microglia, and ablation of IL-34 results in defective microglial development (30). Additionally, neuron-derived fractalkine (CX3CL1), which acts on CX3CR1 expressed on microglia, is critical for proper neurodevelopment, demonstrated by abnormal brain connectivity in the absence of this pathway (71). Thus, microglia–neuron interaction illustrates a functional network consisting of bi-directional inputs between tissue-resident macrophages and a tissue parenchymal cell type. In addition, TGF-β and the transcription factor Sall1 are reported to be involved in a microglia-specific transcriptional profile, although its source and inducer remain to be determined, respectively (72, 73). Taken together, a combination of signals derived from neurons and other sources defines the microglia-specific signature. Conclusion Macrophages are present in virtually all tissues. They monitor and sense signals derived from tissue microenvironments and adapt to distinct tissue environments through polarization or/and differentiation programs. Consequently, their functions are highly specialized depending on their anatomical locations and macrophages contribute to the physiology of normal tissues. Emerging evidence indicates that functional specialization of tissue-resident macrophages is regulated by tissue-specific transcriptional programs and chromatin landscapes achieved by the coordination of LDTFs, TSTFs and co-activators. Further investigation will be needed to define more tissue-derived signals and transcriptional programs, and how they are affected during disease states. Funding This work was supported by a Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 15K21773, Kibou Projects Startup Support for Young Researchers in Immunology, the Smoking Research Foundation, the Mitsubishi Foundation, the Astellas Foundation for Research on Metabolic Disorders and the Takeda Science Foundation. Conflicts of interest statement The author declares no competing financial interests. References 1 Tauber, A. I. 2003. Metchnikoff and the phagocytosis theory. Nat. Rev. Mol. Cell Biol . 4: 897. Google Scholar CrossRef Search ADS PubMed 2 Greaves, D. R. and Gordon, S. 2005. Thematic review series: the immune system and atherogenesis. Recent insights into the biology of macrophage scavenger receptors. J. Lipid Res . 46: 11. Google Scholar CrossRef Search ADS PubMed 3 Takeuchi, O. and Akira, S. 2010. Pattern recognition receptors and inflammation. Cell 140: 805. Google Scholar CrossRef Search ADS PubMed 4 Aderem, A. and Underhill, D. M. 1999. Mechanisms of phagocytosis in macrophages. Annu. Rev. Immunol . 17: 593. Google Scholar CrossRef Search ADS PubMed 5 Wynn, T. A. and Vannella, K. M. 2016. Macrophages in tissue repair, regeneration, and fibrosis. Immunity 44: 450. Google Scholar CrossRef Search ADS PubMed 6 Wynn, T. A., Chawla, A. and Pollard, J. W. 2013. Macrophage biology in development, homeostasis and disease. Nature 496: 445. Google Scholar CrossRef Search ADS PubMed 7 Varol, C., Mildner, A. and Jung, S. 2015. Macrophages: development and tissue specialization. Annu. Rev. Immunol . 33: 643. Google Scholar CrossRef Search ADS PubMed 8 Davies, L. C., Jenkins, S. J., Allen, J. E. and Taylor, P. R. 2013. Tissue-resident macrophages. Nat. Immunol . 14: 986. Google Scholar CrossRef Search ADS PubMed 9 Gordon, S., Plüddemann, A. and Martinez Estrada, F. 2014. Macrophage heterogeneity in tissues: phenotypic diversity and functions. Immunol. Rev . 262: 36. Google Scholar CrossRef Search ADS PubMed 10 van Furth, R. and Cohn, Z. A. 1968. The origin and kinetics of mononuclear phagocytes. J. Exp. Med . 128: 415. Google Scholar CrossRef Search ADS PubMed 11 Jenkins, S. J. and Hume, D. A. 2014. Homeostasis in the mononuclear phagocyte system. Trends Immunol . 35: 358. Google Scholar CrossRef Search ADS PubMed 12 Ginhoux, F. and Guilliams, M. 2016. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44: 439. Google Scholar CrossRef Search ADS PubMed 13 Perdiguero, E. G. and Geissmann, F. 2016. The development and maintenance of resident macrophages. Nat. Immunol . 17: 2. Google Scholar CrossRef Search ADS PubMed 14 Sieweke, M. H. and Allen, J. E. 2013. Beyond stem cells: self-renewal of differentiated macrophages. Science 342: 1242974. Google Scholar CrossRef Search ADS PubMed 15 Yona, S., Kim, K. W., Wolf, Y.et al. 2013. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38: 79. Google Scholar CrossRef Search ADS PubMed 16 Schulz, C., Gomez Perdiguero, E., Chorro, L.et al. 2012. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336: 86. Google Scholar CrossRef Search ADS PubMed 17 Hashimoto, D., Chow, A., Noizat, C.et al. 2013. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38: 792. Google Scholar CrossRef Search ADS PubMed 18 Ginhoux, F., Greter, M., Leboeuf, M.et al. 2010. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330: 841. Google Scholar CrossRef Search ADS PubMed 19 Okabe, Y. and Medzhitov, R. 2016. Tissue biology perspective on macrophages. Nat. Immunol . 17: 9. Google Scholar CrossRef Search ADS PubMed 20 Boyle, W. J., Simonet, W. S. and Lacey, D. L. 2003. Osteoclast differentiation and activation. Nature 423: 337. Google Scholar CrossRef Search ADS PubMed 21 Odegaard, J. I. and Chawla, A. 2013. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science 339: 172. Google Scholar CrossRef Search ADS PubMed 22 Phan, T. G., Green, J. A., Gray, E. E., Xu, Y. and Cyster, J. G. 2009. Immune complex relay by subcapsular sinus macrophages and noncognate B cells drives antibody affinity maturation. Nat. Immunol . 10: 786. Google Scholar CrossRef Search ADS PubMed 23 Paolicelli, R. C., Bolasco, G., Pagani, F.et al. 2011. Synaptic pruning by microglia is necessary for normal brain development. Science 333: 1456. Google Scholar CrossRef Search ADS PubMed 24 Gautier, E. L., Shay, T., Miller, J.et al. ; Immunological Genome Consortium. 2012. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol . 13: 1118. Google Scholar CrossRef Search ADS PubMed 25 Okabe, Y. and Medzhitov, R. 2014. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157: 832. Google Scholar CrossRef Search ADS PubMed 26 Lavin, Y., Winter, D., Blecher-Gonen, R.et al. 2014. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159: 1312. Google Scholar CrossRef Search ADS PubMed 27 Stanley, E. R. and Chitu, V. 2014. CSF-1 receptor signaling in myeloid cells. Cold Spring Harb. Perspect. Biol . 6:pii: a021857. 28 Pollard, J. W. 2009. Trophic macrophages in development and disease. Nat. Rev. Immunol . 9: 259. Google Scholar CrossRef Search ADS PubMed 29 Davies, L. C., Rosas, M., Jenkins, S. J.et al. 2013. Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation. Nat. Commun . 4: 1886. Google Scholar CrossRef Search ADS PubMed 30 Wang, Y., Szretter, K. J., Vermi, W.et al. 2012. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol . 13: 753. Google Scholar CrossRef Search ADS PubMed 31 Zhang, D. E., Hetherington, C. J., Chen, H. M. and Tenen, D. G. 1994. The macrophage transcription factor PU.1 directs tissue-specific expression of the macrophage colony-stimulating factor receptor. Mol. Cell. Biol . 14: 373. Google Scholar CrossRef Search ADS PubMed 32 Glass, C. K. and Natoli, G. 2016. Molecular control of activation and priming in macrophages. Nat. Immunol . 17: 26. Google Scholar CrossRef Search ADS PubMed 33 Ramji, D. P. and Foka, P. 2002. CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem. J . 365( Pt 3): 561. Google Scholar CrossRef Search ADS PubMed 34 Xie, H., Ye, M., Feng, R. and Graf, T. 2004. Stepwise reprogramming of B cells into macrophages. Cell 117: 663. Google Scholar CrossRef Search ADS PubMed 35 Cain, D. W., O’Koren, E. G., Kan, M. J.et al. 2013. Identification of a tissue-specific, C/EBPβ-dependent pathway of differentiation for murine peritoneal macrophages. J. Immunol . 191: 4665. Google Scholar CrossRef Search ADS PubMed 36 Satoh, T., Nakagawa, K., Sugihara, F.et al. 2017. Identification of an atypical monocyte and committed progenitor involved in fibrosis. Nature 541: 96. Google Scholar CrossRef Search ADS PubMed 37 Aziz, A., Soucie, E., Sarrazin, S. and Sieweke, M. H. 2009. MafB/c-Maf deficiency enables self-renewal of differentiated functional macrophages. Science 326: 867. Google Scholar CrossRef Search ADS PubMed 38 Soucie, E. L., Weng, Z., Geirsdóttir, L.et al. 2016. Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells. Science 351: aad5510. Google Scholar CrossRef Search ADS PubMed 39 Amit, I., Winter, D. R. and Jung, S. 2016. The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis. Nat. Immunol . 17: 18. Google Scholar CrossRef Search ADS PubMed 40 Gosselin, D., Link, V. M., Romanoski, C. E.et al. 2014. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159: 1327. Google Scholar CrossRef Search ADS PubMed 41 Newton, J., Lima, S., Maceyka, M. and Spiegel, S. 2015. Revisiting the sphingolipid rheostat: evolving concepts in cancer therapy. Exp. Cell Res . 333: 195. Google Scholar CrossRef Search ADS PubMed 42 Davies, L. C. and Taylor, P. R. 2015. Tissue-resident macrophages: then and now. Immunology 144: 541. Google Scholar CrossRef Search ADS PubMed 43 Ghosn, E. E., Cassado, A. A., Govoni, G. R.et al. 2010. Two physically, functionally, and developmentally distinct peritoneal macrophage subsets. Proc. Natl Acad. Sci. USA 107: 2568. Google Scholar CrossRef Search ADS 44 Kim, K. W., Williams, J. W., Wang, Y. T.et al. 2016. MHC II+ resident peritoneal and pleural macrophages rely on IRF4 for development from circulating monocytes. J. Exp. Med . 213: 1951. Google Scholar CrossRef Search ADS PubMed 45 Rosas, M., Davies, L. C., Giles, P. J.et al. 2014. The transcription factor Gata6 links tissue macrophage phenotype and proliferative renewal. Science 344: 645. Google Scholar CrossRef Search ADS PubMed 46 Gautier, E. L., Ivanov, S., Williams, J. W.et al. 2014. Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival. J. Exp. Med . 211: 1525. Google Scholar CrossRef Search ADS PubMed 47 Ishii, M., Wen, H., Corsa, C. A.et al. 2009. Epigenetic regulation of the alternatively activated macrophage phenotype. Blood 114: 3244. Google Scholar CrossRef Search ADS PubMed 48 Wijffels, J. F., Hendrickx, R. J., Steenbergen, J. J., Eestermans, I. L. and Beelen, R. H. 1992. Milky spots in the mouse omentum may play an important role in the origin of peritoneal macrophages. Res. Immunol . 143: 401. Google Scholar CrossRef Search ADS PubMed 49 Meza-Perez, S. and Randall, T. D. 2017. Immunological functions of the omentum. Trends Immunol . 38: 526. Google Scholar CrossRef Search ADS PubMed 50 Ratajczak, M. Z., Jaskulski, D., Pojda, Z. and Wiktor-Jedrzejczak, W. 1987. Omental lymphoid organ as a source of macrophage colony stimulating activity in peritoneal cavity. Clin. Exp. Immunol . 69: 198. Google Scholar PubMed 51 Agalar, F., Sayek, I., Cakmakçi, M., Hasçelik, G. and Abbasoglu, O. 1997. Effect of omentectomy on peritoneal defence mechanisms in rats. Eur. J. Surg . 163: 605. Google Scholar PubMed 52 Barth, M. W., Hendrzak, J. A., Melnicoff, M. J. and Morahan, P. S. 1995. Review of the macrophage disappearance reaction. J. Leukoc. Biol . 57: 361. Google Scholar CrossRef Search ADS PubMed 53 Wang, J. and Kubes, P. 2016. A reservoir of mature cavity macrophages that can rapidly invade visceral organs to affect tissue repair. Cell 165: 668. Google Scholar CrossRef Search ADS PubMed 54 Kotani, M., Kikuta, J., Klauschen, F.et al. 2013. Systemic circulation and bone recruitment of osteoclast precursors tracked by using fluorescent imaging techniques. J. Immunol . 190: 605. Google Scholar CrossRef Search ADS PubMed 55 Wada, T., Nakashima, T., Hiroshi, N. and Penninger, J. M. 2006. RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol. Med . 12: 17. Google Scholar CrossRef Search ADS PubMed 56 Takayanagi, H., Kim, S., Koga, T.et al. 2002. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev. Cell 3: 889. Google Scholar CrossRef Search ADS PubMed 57 Epelman, S., Lavine, K. J., Beaudin, A. E.et al. 2014. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40: 91. Google Scholar CrossRef Search ADS PubMed 58 Kohyama, M., Ise, W., Edelson, B. T.et al. 2009. Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 457: 318. Google Scholar CrossRef Search ADS PubMed 59 Haldar, M., Kohyama, M., So, A. Y.et al. 2014. Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages. Cell 156: 1223. Google Scholar CrossRef Search ADS PubMed 60 Guilliams, M., De Kleer, I., Henri, S.et al. 2013. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J. Exp. Med . 210: 1977. Google Scholar CrossRef Search ADS PubMed 61 Hussell, T. and Bell, T. J. 2014. Alveolar macrophages: plasticity in a tissue-specific context. Nat. Rev. Immunol . 14: 81. Google Scholar CrossRef Search ADS PubMed 62 Dranoff, G., Crawford, A. D., Sadelain, M.et al. 1994. Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Science 264: 713. Google Scholar CrossRef Search ADS PubMed 63 Martinez, F. O. and Gordon, S. 2014. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep . 6: 13. Google Scholar CrossRef Search ADS PubMed 64 Gordon, S. and Martinez, F. O. 2010. Alternative activation of macrophages: mechanism and functions. Immunity 32: 593. Google Scholar CrossRef Search ADS PubMed 65 Sica, A. and Mantovani, A. 2012. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest . 122: 787. Google Scholar CrossRef Search ADS PubMed 66 Schneider, C., Nobs, S. P., Kurrer, M., Rehrauer, H., Thiele, C. and Kopf, M. 2014. Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages. Nat. Immunol . 15: 1026. Google Scholar CrossRef Search ADS PubMed 67 Nakamura, A., Ebina-Shibuya, R., Itoh-Nakadai, A.et al. 2013. Transcription repressor Bach2 is required for pulmonary surfactant homeostasis and alveolar macrophage function. J. Exp. Med . 210: 2191. Google Scholar CrossRef Search ADS PubMed 68 Yu, X., Buttgereit, A., Lelios, I.et al. 2017. The cytokine TGF-β promotes the development and homeostasis of alveolar macrophages. Immunity 47: 903. Google Scholar CrossRef Search ADS PubMed 69 Wohleb, E. S. 2016. Neuron-microglia interactions in mental health disorders: ‘for better, and for worse’. Front. Immunol . 7: 544. Google Scholar CrossRef Search ADS PubMed 70 Ginhoux, F., Lim, S., Hoeffel, G., Low, D. and Huber, T. 2013. Origin and differentiation of microglia. Front. Cell. Neurosci . 7: 45. Google Scholar CrossRef Search ADS PubMed 71 Cardona, A. E., Pioro, E. P., Sasse, M. E.et al. 2006. Control of microglial neurotoxicity by the fractalkine receptor. Nat. Neurosci . 9: 917. Google Scholar CrossRef Search ADS PubMed 72 Butovsky, O., Jedrychowski, M. P., Moore, C. S.et al. 2014. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat. Neurosci . 17: 131. Google Scholar CrossRef Search ADS PubMed 73 Buttgereit, A., Lelios, I., Yu, X.et al. 2016. Sall1 is a transcriptional regulator defining microglia identity and function. Nat. Immunol . 17: 1397. Google Scholar CrossRef Search ADS PubMed © The Japanese Society for Immunology. 2018. All rights reserved. For permissions, please e-mail: email@example.com
International Immunology – Oxford University Press
Published: Feb 23, 2018
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.
Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.
All the latest content is available, no embargo periods.
“Hi guys, I cannot tell you how much I love this resource. Incredible. I really believe you've hit the nail on the head with this site in regards to solving the research-purchase issue.”Daniel C.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud
“I must say, @deepdyve is a fabulous solution to the independent researcher's problem of #access to #information.”@deepthiw
“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera