Molecular control of the identity of tissue-resident macrophages

Molecular control of the identity of tissue-resident macrophages 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 [24]. 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 [24]. 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. 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All rights reserved. For permissions, please e-mail: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Immunology Oxford University Press

Molecular control of the identity of tissue-resident macrophages

International Immunology , Volume Advance Article – Feb 23, 2018

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Abstract

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 [24]. 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 [24]. 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. 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International ImmunologyOxford University Press

Published: Feb 23, 2018

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