Abstract
Embryo-derived tissue-resident macrophages are the first representatives of the haematopoietic lineage to emerge in metazoans. In mammals, resident macrophages originate from early yolk sac progenitors and are specified into tissue-specific subsets during organogenesis—establishing stable spatial and functional relationships with specialized tissue cells—and persist in adults. Resident macrophages are an integral part of tissues together with specialized cells: for instance, microglia reside with neurons in brain, osteoclasts reside with osteoblasts in bone, and fat-associated macrophages reside with white adipocytes in adipose tissue. This ancillary cell type, which is developmentally and functionally distinct from haematopoietic stem cell and monocyte-derived macrophages, senses and integrates local and systemic information to provide specialized tissue cells with the growth factors, nutrient recycling and waste removal that are critical for tissue growth, homeostasis and repair. Resident macrophages contribute to organogenesis, promote tissue regeneration following damage and contribute to tissue metabolism and defence against infectious disease. A correlate is that genetic or environment-driven resident macrophage dysfunction is a cause of degenerative, metabolic and possibly inflammatory and tumoural diseases. In this Review, we aim to provide a conceptual outline of our current understanding of macrophage physiology and its importance in human diseases, which may inform and serve the design of future studies.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Change history
03 July 2023
A Correction to this paper has been published: https://doi.org/10.1038/s41586-023-06386-w
References
Metchnikoff, E. Lecture on phagocytosis and immunity. Br. Med. J. 1, 213–217 (1891).
Alliot, F., Godin, I. & Pessac, B. Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res. Dev. Brain Res. 117, 145–152 (1999).
Herbomel, P., Thisse, B. & Thisse, C. Ontogeny and behaviour of early macrophages in the zebrafish embryo. Development 126, 3735–3745 (1999).
Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).
Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).
Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).
Hassnain Waqas, S. F. et al. Adipose tissue macrophages develop from bone marrow-independent progenitors in Xenopus laevis and mouse. J. Leukoc. Biol. 102, 845–855 (2017). References 7,14 describe the embryo-derived macrophage lineage in metazoans and its independence from the HSC lineage.
Mase, A., Augsburger, J. & Bruckner, K. Macrophages and their organ locations shape each other in development and homeostasis—a Drosophila perspective. Front. Cell Dev. Biol. 9, 630272 (2021).
Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).
Gomez Perdiguero, E. & Geissmann, F. Myb-independent macrophages: a family of cells that develops with their tissue of residence and is involved in its homeostasis. Cold Spring Harb. Symp. Quant. Biol. 78, 91–100 (2013).
Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W. & Rossi, F. M. V. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10, 1538–1543 (2007).
Merad, M. et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nat. Immunol. 3, 1135–1141 (2002).
Ajami, B., Bennett, J. L., Krieger, C., McNagny, K. M. & Rossi, F. M. V. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat. Neurosci. 14, 1142–1149 (2011).
Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015).
Mass, E. et al. Specification of tissue-resident macrophages during organogenesis. Science 353, aaf4238 (2016). This study, along with refs. 17,21,77, describes tissue specification of resident macrophages.
Perdiguero, E. G. & Geissmann, F. The development and maintenance of resident macrophages. Nat. Immunol. 17, 2–8 (2016).
Sakai, M. et al. Liver-derived signals sequentially reprogram myeloid enhancers to initiate and maintain Kupffer cell identity. Immunity 51, 655–670.e658 (2019).
Moore, K. J., Sheedy, F. J. & Fisher, E. A. Macrophages in atherosclerosis: a dynamic balance. Nat. Rev. Immunol. 13, 709–721 (2013).
Heldin, C. H., Lu, B., Evans, R. & Gutkind, J. S. Signals and receptors. Cold Spring Harb. Perspect. Biol. 8, a005900 (2016).
Haldar, M. et al. Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages. Cell 156, 1223–1234 (2014).
Okabe, Y. & Medzhitov, R. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157, 832–844 (2014).
Sun, L., Wu, J., Du, F., Chen, X. & Chen, Z. J. Cyclic GMP–AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791 (2013).
Santiago-Garcia, J., Kodama, T. & Pitas, R. E. The class A scavenger receptor binds to proteoglycans and mediates adhesion of macrophages to the extracellular matrix. J. Biol. Chem. 278, 6942–6946 (2003).
Leitinger, B. Transmembrane collagen receptors. Annu. Rev. Cell Dev. Biol. 27, 265–290 (2011).
Woo, H. J., Shaw, L. M., Messier, J. M. & Mercurio, A. M. The major non-integrin laminin binding protein of macrophages is identical to carbohydrate binding protein 35 (Mac-2). J. Biol. Chem. 265, 7097–7099 (1990).
Ley, K., Pramod, A. B., Croft, M., Ravichandran, K. S. & Ting, J. P. How mouse macrophages sense what is going on. Front. Immunol. 7, 204 (2016).
Solis, A. G. et al. Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity. Nature 573, 69–74 (2019).
Kashio, M. et al. Redox signal-mediated sensitization of transient receptor potential melastatin 2 (TRPM2) to temperature affects macrophage functions. Proc. Natl Acad. Sci. USA 109, 6745–6750 (2012).
Link, T. M. et al. TRPV2 has a pivotal role in macrophage particle binding and phagocytosis. Nat. Immunol. 11, 232–239 (2010).
Machnik, A. et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat. Med. 15, 545–552 (2009). A study the homeostatic functions of macrophages.
Tcymbarevich, I. et al. Lack of the pH-sensing receptor TDAG8 (GPR65) in macrophages plays a detrimental role in murine models of inflammatory bowel disease. J. Crohns Colitis 13, 245–258 (2019).
Fang, H. Y. et al. Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia. Blood 114, 844–859 (2009).
Cox, N., Pokrovskii, M., Vicario, R. & Geissmann, F. Origins, biology, and diseases of tissue macrophages. Annu. Rev. Immunol. 39, 313–344 (2021).
Fantin, A. et al. Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116, 829–840 (2010). The studies in refs. 34,45,151,157 examine the roles of macrophages in tissue growth and repair.
Lobov, I. B. et al. WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature. Nature 437, 417–421 (2005).
Ip, W. K. E. & Medzhitov, R. Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation. Nat. Commun. 6, 6931 (2015).
Zhou, X. et al. Circuit design features of a stable two-cell system. Cell 172, 744–757.e717 (2018).
Jacome-Galarza, C. E. et al. Developmental origin, functional maintenance and genetic rescue of osteoclasts. Nature 568, 541–545 (2019). An investigation into the origin and maintenance of bone osteoclasts.
Boyle, W. J., Simonet, W. S. & Lacey, D. L. Osteoclast differentiation and activation. Nature 423, 337–342 (2003).
Saftig, P. et al. Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc. Natl Acad. Sci. USA 95, 13453–13458 (1998).
Meijer, C. et al. Kupffer cell depletion by CI2MDP-liposomes alters hepatic cytokine expression and delays liver regeneration after partial hepatectomy. Liver 20, 66–77 (2000).
Duffield, J. S. et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56–65 (2005).
Aurora, A. B. et al. Macrophages are required for neonatal heart regeneration. J. Clin. Invest. 124, 1382–1392 (2014).
Lin, S. L. et al. Macrophage Wnt7b is critical for kidney repair and regeneration. Proc. Natl Acad. Sci. USA 107, 4194–4199 (2010).
Shang, M. et al. Macrophage-derived glutamine boosts satellite cells and muscle regeneration. Nature 587, 626–631 (2020).
Pollard, J. W. Trophic macrophages in development and disease. Nat. Rev. Immunol. 9, 259–270 (2009).
Ueno, M. et al. Layer V cortical neurons require microglial support for survival during postnatal development. Nat. Neurosci. 16, 543–551 (2013).
Squarzoni, P. et al. Microglia modulate wiring of the embryonic forebrain. Cell Rep. 8, 1271–1279 (2014).
Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011).
Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007). References 50,55,73,78,143 describe tissue-specific functions of resident macrophages.
Wake, H., Moorhouse, A. J., Jinno, S., Kohsaka, S. & Nabekura, J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29, 3974–3980 (2009).
Tremblay, M. E., Lowery, R. L. & Majewska, A. K. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 8, e1000527 (2010).
Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013).
Coull, J. A. M. et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017–1021 (2005).
Cox, N. et al. Diet-regulated production of PDGFcc by macrophages controls energy storage. Science 373, eabe9383 (2021).
Nguyen, K. D. et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480, 104–108 (2011).
Rajbhandari, P. et al. IL-10 signaling remodels adipose chromatin architecture to limit thermogenesis and energy expenditure. Cell 172, 218–233.e217 (2018).
Lee, Y. H., Kim, S. N., Kwon, H. J., Maddipati, K. R. & Granneman, J. G. Adipogenic role of alternatively activated macrophages in beta-adrenergic remodeling of white adipose tissue. Am. J. Physiol. 310, R55–R65 (2016).
Guo, L. et al. Bi-allelic CSF1R mutations cause skeletal dysplasia of dysosteosclerosis–Pyle disease spectrum and degenerative encephalopathy with brain malformation. Am. J. Hum. Genet. 104, 925–935 (2019).
Oosterhof, N. et al. Homozygous mutations in CSF1R cause a pediatric-onset leukoencephalopathy and can result in congenital absence of microglia. Am. J. Hum. Genet. 104, 936–947 (2019).
Erblich, B., Zhu, L. Y., Etgen, A. M., Dobrenis, K. & Pollard, J. W. Absence of colony stimulation factor-1 receptor results in loss of microglia, disrupted brain development and olfactory deficits. PLoS ONE 6, e26317 (2011).
Dai, X. M. et al. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood 99, 111–120 (2002).
Platt, F. M., d’Azzo, A., Davidson, B. L., Neufeld, E. F. & Tifft, C. J. Lysosomal storage diseases. Nat. Rev. Dis. Primers 4, 27 (2018).
Rademakers, R. et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat. Genet. 44, 200–205 (2012).
Nicholson, A. M. et al. CSF1R mutations link POLD and HDLS as a single disease entity. Neurology 80, 1033–1040 (2013).
Nott, A. et al. Brain cell type-specific enhancer–promoter interactome maps and disease-risk association. Science 366, 1134–1139 (2019).
Frattini, A. et al. Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat. Genet. 25, 343–346 (2000).
Sobacchi, C. et al. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat. Genet. 39, 960–962 (2007).
Mirza, R., DiPietro, L. A. & Koh, T. J. Selective and specific macrophage ablation is detrimental to wound healing in mice. Am. J. Pathol. 175, 2454–2462 (2009).
Wynn, T. A. & Vannella, K. M. Macrophages in tissue repair, regeneration, and fibrosis. Immunity 44, 450–462 (2016).
Zhang, M. Z. et al. CSF-1 signaling mediates recovery from acute kidney injury. J. Clin. Invest. 122, 4519–4532 (2012).
Kohyama, M. et al. Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 457, 318–321 (2009).
Cohen, P. E., Hardy, M. P. & Pollard, J. W. Colony-stimulating factor-1 plays a major role in the development of reproductive function in male mice. Mol. Endocrinol. 11, 1636–1650 (1997).
Nishinakamura, R. et al. The pulmonary alveolar proteinosis in granulocyte macrophage colony-stimulating factor/interleukins 3/5 beta c receptor-deficient mice is reversed by bone marrow transplantation. J. Exp. Med. 183, 2657–2662 (1996).
Baker, A. D. et al. Targeted PPARγ deficiency in alveolar macrophages disrupts surfactant catabolism. J. Lipid Res. 51, 1325–1331 (2010).
Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).
Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).
Werner, Y. et al. Cxcr4 distinguishes HSC-derived monocytes from microglia and reveals monocyte immune responses to experimental stroke. Nat. Neurosci. 23, 351–362 (2020).
Guilliams, M. et al. Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches. Cell 185, 379–396.e338 (2022).
Dick, S. A. et al. Three tissue resident macrophage subsets coexist across organs with conserved origins and life cycles. Sci. Immunol. 7, eabf7777 (2022).
Masuda, T. et al. Specification of CNS macrophage subsets occurs postnatally in defined niches. Nature 604, 740–748 (2022).
Bertrand, J. Y. et al. Definitive hematopoiesis initiates through a committed erythromyeloid progenitor in the zebrafish embryo. Development 134, 4147–4156 (2007).
Okuda, T., van Deursen, J., Hiebert, S. W., Grosveld, G. & Downing, J. R. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84, 321–330 (1996).
Le Guyader, D. et al. Origins and unconventional behavior of neutrophils in developing zebrafish. Blood 111, 132–141 (2008).
Tober, J., McGrath, K. E. & Palis, J. Primitive erythropoiesis and megakaryopoiesis in the yolk sac are independent of c-myb. Blood 111, 2636–2639 (2008).
Palis, J., Robertson, S., Kennedy, M., Wall, C. & Keller, G. Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse. Development 126, 5073–5084 (1999).
Palis, J. et al. Spatial and temporal emergence of high proliferative potential hematopoietic precursors during murine embryogenesis. Proc. Natl Acad. Sci. USA 98, 4528–4533 (2001).
Li, Z. et al. Adult connective tissue-resident mast cells originate from late erythro-myeloid progenitors. Immunity 49, 640–653 e645 (2018).
Gentek, R. et al. Hemogenic endothelial fate mapping reveals dual developmental origin of mast cells. Immunity 48, 1160–1171.e1165 (2018).
McGrath, K. E. et al. Distinct sources of hematopoietic progenitors emerge before HSCs and provide functional blood cells in the mammalian embryo. Cell Rep. 11, 1892–1904 (2015).
Chen, M. J., Yokomizo, T., Zeigler, B. M., Dzierzak, E. & Speck, N. A. Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter. Nature 457, 887–891 (2009).
Sumner, R., Crawford, A., Mucenski, M. & Frampton, J. Initiation of adult myelopoiesis can occur in the absence of c-Myb whereas subsequent development is strictly dependent on the transcription factor. Oncogene 19, 3335–3342 (2000).
Chorro, L. et al. Langerhans cell (LC) proliferation mediates neonatal development, homeostasis, and inflammation-associated expansion of the epidermal LC network. J. Exp. Med. 206, 3089–3100 (2009).
Bertrand, J. Y. et al. Haematopoietic stem cells derive directly from aortic endothelium during development. Nature 464, 108–111 (2010).
Boisset, J. C. et al. In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature 464, 116–120 (2010).
Kissa, K. & Herbomel, P. Blood stem cells emerge from aortic endothelium by a novel type of cell transition. Nature 464, 112–115 (2010).
Bain, C. C. et al. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat. Immunol. 15, 929–U236 (2014).
Sheng, J., Ruedl, C. & Karjalainen, K. Most tissue-resident macrophages except microglia are derived from fetal hematopoietic stem cells. Immunity 43, 382–393 (2015).
Pei, W. et al. Polylox barcoding reveals haematopoietic stem cell fates realized in vivo. Nature 548, 456–460 (2017).
Tsou, C. L. et al. Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. J. Clin. Invest. 117, 902–909 (2007).
Serbina, N. V. & Pamer, E. G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat. Immunol. 7, 311–317 (2006).
Hoyer, F. F. et al. Tissue-specific macrophage responses to remote injury impact the outcome of subsequent local immune challenge. Immunity 51, 899–914.e897 (2019).
De Schepper, S. et al. Self-maintaining gut macrophages are essential for intestinal homeostasis. Cell 175, 400–415.e413 (2018).
Petraki, S., Alexander, B. & Bruckner, K. Assaying blood cell populations of the Drosophila melanogaster larva. J. Vis. Exp. https://doi.org/10.3791/52733 (2015).
Sampson, C. J., Amin, U. & Couso, J. P. Activation of Drosophila hemocyte motility by the ecdysone hormone. Biol. Open 2, 1412–1420 (2013).
Grigorian, M., Mandal, L., Hakimi, M., Ortiz, I. & Hartenstein, V. The convergence of Notch and MAPK signaling specifies the blood progenitor fate in the Drosophila mesoderm. Dev. Biol. 353, 105–118 (2011).
Lanot, R., Zachary, D., Holder, F. & Meister, M. Postembryonic hematopoiesis in Drosophila. Dev. Biol. 230, 243–257 (2001).
Rizki, T. M. & Rizki, R. M. Lamellocyte differentiation in Drosophila larvae parasitized by Leptopilina. Dev. Comp. Immunol. 16, 103–110 (1992).
Geissmann, F. & Mass, E. A stratified myeloid system, the challenge of understanding macrophage diversity. Semin. Immunol. 27, 353–356 (2015).
Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).
Buttgereit, A. et al. Sall1 is a transcriptional regulator defining microglia identity and function. Nat. Immunol. 17, 1397–1406 (2016).
Rosas, M. et al. The transcription factor Gata6 links tissue macrophage phenotype and proliferative renewal. Science 344, 645–648 (2014).
Yu, X. Y. et al. The cytokine TGF-β promotes the development and homeostasis of alveolar macrophages. Immunity 47, 903–912.e4 (2017).
Butovsky, O. et al. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).
Wang, Y. M. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol. 13, 753–760 (2012).
Makhijani, K. & Bruckner, K. Of blood cells and the nervous system: hematopoiesis in the Drosophila larva. Fly 6, 254–260 (2012).
Weinberger, T. et al. Ontogeny of arterial macrophages defines their functions in homeostasis and inflammation. Nat. Commun. 11, 4549 (2020).
Molawi, K. et al. Progressive replacement of embryo-derived cardiac macrophages with age. J. Exp. Med. 211, 2151–2158 (2014).
Calderon, B. et al. The pancreas anatomy conditions the origin and properties of resident macrophages. J. Exp. Med. 212, 1497–1512 (2015).
Serbina, N. V., Jia, T., Hohl, T. M. & Pamer, E. G. Monocyte-mediated defense against microbial pathogens. Annu. Rev. Immunol. 26, 421–452 (2008).
Auffray, C., Sieweke, M. H. & Geissmann, F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu. Rev. Immunol. 27, 669–692 (2009).
Shemer, A. et al. Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge. Nat. Commun. 9, 5206 (2018).
Bouwens, L., Baekeland, M., De Zanger, R. & Wisse, E. Quantitation, tissue distribution and proliferation kinetics of Kupffer cells in normal rat liver. Hepatology 6, 718–722 (1986).
Kanitakis, J., Petruzzo, P. & Dubernard, J. M. Turnover of epidermal Langerhans’ cells. N. Engl. J. Med. 351, 2661–2662 (2004).
Bajpai, G. et al. The human heart contains distinct macrophage subsets with divergent origins and functions. Nat. Med. 24, 1234–1245 (2018).
Bittmann, I. et al. Cellular chimerism of the lung after transplantation. An interphase cytogenetic study. Am. J. Clin. Pathol. 115, 525–533 (2001).
Bittmann, I. et al. The role of graft-resident Kupffer cells and lymphocytes of donor type during the time course after liver transplantation—a clinico-pathological study. Virchows Arch. 443, 541–548 (2003).
Dai, X. M., Zong, X. H., Sylvestre, V. & Stanley, E. R. Incomplete restoration of colony-stimulating factor 1 (CSF-1) function in CSF-1-deficient Csf1op/Csf1op mice by transgenic expression of cell surface CSF-1. Blood 103, 1114–1123 (2004).
Pridans, C. et al. Macrophage colony-stimulating factor increases hepatic macrophage content, liver growth, and lipid accumulation in neonatal rats. Am. J. Physiol. Gastrointest. Liver Physiol. 314, G388–G398 (2018).
Lin, H. et al. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science 320, 807–811 (2008).
Huffman, J. A., Hull, W. M., Dranoff, G., Mulligan, R. C. & Whitsett, J. A. Pulmonary epithelial cell expression of GM-CSF corrects the alveolar proteinosis in GM-CSF-deficient mice. J. Clin. Invest. 97, 649–655 (1996).
Nagata, S. & Segawa, K. Sensing and clearance of apoptotic cells. Curr. Opin. Immunol. https://doi.org/10.1016/j.coi.2020.07.007 (2021).
Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).
Kimura, Y. et al. The innate immune receptor Dectin-2 mediates the phagocytosis of cancer cells by Kupffer cells for the suppression of liver metastasis. Proc. Natl Acad. Sci. USA 113, 14097–14102 (2016).
Chao, M. P. et al. Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci. Transl. Med. 2, 63ra94 (2010).
Gardai, S. J. et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123, 321–334 (2005).
Goodridge, H. S. et al. Activation of the innate immune receptor Dectin-1 upon formation of a ‘phagocytic synapse’. Nature 472, 471–475 (2011).
Okabe, Y. & Medzhitov, R. Tissue biology perspective on macrophages. Nat. Immunol. 17, 9–17 (2016).
Kristiansen, M. et al. Identification of the haemoglobin scavenger receptor. Nature 409, 198–201 (2001).
Terpstra, V. & van Berkel, T. J. Scavenger receptors on liver Kupffer cells mediate the in vivo uptake of oxidatively damaged red blood cells in mice. Blood 95, 2157–2163 (2000).
Theurl, I. et al. On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver. Nat. Med. 22, 945–951 (2016).
Trapnell, B. C., Whitsett, J. A. & Nakata, K. Pulmonary alveolar proteinosis. New Engl. J. Med. 349, 2527–2539 (2003).
Stamatiades, E. G. et al. Immune monitoring of trans-endothelial transport by kidney-resident macrophages. Cell 166, 991–1003 (2016).
Miyagawa, K. et al. Osteoclast-derived IGF1 is required for formation of pagetic bone lesions in vivo. JCI Insight 5, e133113 (2020).
Xian, L. et al. Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nat. Med. 18, 1095–1101 (2012).
Rodan, G. A. & Martin, T. J. Therapeutic approaches to bone diseases. Science 289, 1508–1514 (2000).
Takeshita, S. et al. SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts. Nat. Med. 8, 943–949 (2002).
Shook, B. A. et al. Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. Science 362, eaar2971 (2018).
Tonkin, J. et al. Monocyte/macrophage-derived IGF-1 orchestrates murine skeletal muscle regeneration and modulates autocrine polarization. Mol. Ther. 23, 1189–1200 (2015).
Du, H. et al. Macrophage-released ADAMTS1 promotes muscle stem cell activation. Nat. Commun. 8, 669 (2017).
Simkin, J. et al. Macrophages are required to coordinate mouse digit tip regeneration. Development 144, 3907–3916 (2017).
Vi, L. et al. Macrophage cells secrete factors including LRP1 that orchestrate the rejuvenation of bone repair in mice. Nat. Commun. 9, 5191 (2018).
Schlundt, C. et al. Macrophages in bone fracture healing: Their essential role in endochondral ossification. Bone 106, 78–89 (2018).
Cattin, A. L. et al. Macrophage-induced blood vessels guide schwann cell-mediated regeneration of peripheral nerves. Cell 162, 1127–1139 (2015).
Kigerl, K. A. et al. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J. Neurosci. 29, 13435–13444 (2009).
Godwin, J. W., Pinto, A. R. & Rosenthal, N. A. Macrophages are required for adult salamander limb regeneration. Proc. Natl Acad. Sci. USA 110, 9415–9420 (2013).
Petrie, T. A., Strand, N. S., Yang, C. T., Rabinowitz, J. S. & Moon, R. T. Macrophages modulate adult zebrafish tail fin regeneration. Development 141, 2581–2591 (2014).
Liu, C. et al. Macrophages mediate the repair of brain vascular rupture through direct physical adhesion and mechanical traction. Immunity 44, 1162–1176 (2016).
Coates, J. A. et al. Identification of functionally distinct macrophage subpopulations in Drosophila. eLife 10, e58686 (2021).
Karlmark, K. R. et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50, 261–274 (2009).
Dick, S. A. et al. Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction. Nat. Immunol. 20, 29–39 (2019).
Kitagawa, K. et al. Blockade of CCR2 ameliorates progressive fibrosis in kidney. Am. J. Pathol. 165, 237–246 (2004).
Misharin, A. V. et al. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J. Exp. Med. 214, 2387–2404 (2017).
Kondo, T. et al. Heterogeneity of presenile dementia with bone cysts (Nasu–Hakola disease): three genetic forms. Neurology 59, 1105–1107 (2002).
Paloneva, J. et al. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am. J. Hum. Genet. 71, 656–662 (2002).
Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013).
Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107–116 (2013).
Pridans, C. et al. Pleiotropic impacts of macrophage and microglial deficiency on development in rats with targeted mutation of the Csf1r locus. J. Immunol. 201, 2683–2699 (2018).
Satoh, T. et al. Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages. Nature 495, 524–528 (2013).
Pirzgalska, R. M. et al. Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat. Med. 23, 1309–1318 (2017).
Igarashi, Y. et al. Partial depletion of CD206-positive M2-like macrophages induces proliferation of beige progenitors and enhances browning after cold stimulation. Sci. Rep. 8, 14567 (2018).
Hotamisligil, G. S., Arner, P., Caro, J. F., Atkinson, R. L. & Spiegelman, B. M. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J. Clin. Invest. 95, 2409–2415 (1995).
Hotamisligil, G. S., Shargill, N. S. & Spiegelman, B. M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).
Jaitin, D. A. et al. Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner. Cell 178, 686–698.e614 (2019).
Wolf, Y. et al. Brown-adipose-tissue macrophages control tissue innervation and homeostatic energy expenditure. Nat. Immunol. 18, 665–674 (2017).
Barreda, D. R., Neely, H. R. & Flajnik, M. F. Evolution of myeloid cells. Microbiol. Spectr. 4, 0007-2015 (2016).
Geissmann, F., Jung, S. & Littman, D. R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003).
Nagata, S. Apoptosis and Clearance of Apoptotic Cells. Annu. Rev. Immunol. 36, 489–517 (2018).
Morioka, S., Maueroder, C. & Ravichandran, K. S. Living on the edge: efferocytosis at the interface of homeostasis and pathology. Immunity 50, 1149–1162 (2019).
Bian, Z. et al. Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells. Proc. Natl Acad. Sci. USA 113, E5434–E5443 (2016).
Scott, R. S. et al. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411, 207–211 (2001).
Cohen, P. L. et al. Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J. Exp. Med. 196, 135–140 (2002).
Hanayama, R. et al. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304, 1147–1150 (2004).
Miyanishi, M., Segawa, K. & Nagata, S. Synergistic effect of Tim4 and MFG-E8 null mutations on the development of autoimmunity. Int Immunol 24, 551–559 (2012).
Colonna, L., Parry, G. C., Panicker, S. & Elkon, K. B. Uncoupling complement C1s activation from C1q binding in apoptotic cell phagocytosis and immunosuppressive capacity. Clin. Immunol. 163, 84–90 (2016).
Botto, M. et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat. Genet. 19, 56–59 (1998).
Pickering, M. C., Botto, M., Taylor, P. R., Lachmann, P. J. & Walport, M. J. Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol 76, 227–324 (2000).
Baumann, I. et al. Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus. Arthritis Rheum. 46, 191–201 (2002).
Schrijvers, D. M., De Meyer, G. R. Y., Kockx, M. M., Herman, A. G. & Martinet, W. Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis. Arterioscl. Throm. Vas. 25, 1256–1261 (2005).
Bayon, L. G. et al. Role of Kupffer cells in arresting circulating tumor cells and controlling metastatic growth in the liver. Hepatology 23, 1224–1231 (1996).
DeNardo, D. G. & Ruffell, B. Macrophages as regulators of tumour immunity and immunotherapy. Nat. Rev. Immunol. 19, 369–382 (2019).
Zhu, Y. et al. Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47, 323–338.e326 (2017).
Matlung, H. L., Szilagyi, K., Barclay, N. A. & van den Berg, T. K. The CD47–SIRPα signaling axis as an innate immune checkpoint in cancer. Immunol. Rev. 276, 145–164 (2017).
Liu, J. et al. Targeting macrophage checkpoint inhibitor SIRPα for anticancer therapy. JCI Insight 5, e134728 (2020).
Barkal, A. A. et al. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature 572, 392–396 (2019).
Acknowledgements
The authors acknowledge present and past members of the Geissmann laboratory, researchers at Memorial Sloan Kettering Cancer Center (MSKCC), and the scientific community at large for scientific discussions. This work was supported by NIH/NCI P30CA008748 to MSKCC and by NIH/NIAID 1R01AI130345, NIH/NHLBI R01HL138090, NIH R01 NS115715-03, Leducq transatlantic network of excellence and Ludwig institute for Cancer research basic immunology grant to F.G. and NIH/NIDDK K99 DK131280 to N.C. S.J.-C. is a CRI Irvington postdoctoral fellow.
Author information
Authors and Affiliations
Contributions
T.L. and F.G. wrote the draft manuscript. T.L., S.J.-C., N.C. and F.G. prepared the final manuscript and figures.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature thanks Elvira Mass and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Lazarov, T., Juarez-Carreño, S., Cox, N. et al. Physiology and diseases of tissue-resident macrophages. Nature 618, 698–707 (2023). https://doi.org/10.1038/s41586-023-06002-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41586-023-06002-x
This article is cited by
-
The roles of tissue resident macrophages in health and cancer
Experimental Hematology & Oncology (2024)
-
Mineralocorticoid receptor promotes cardiac macrophage inflammaging
Basic Research in Cardiology (2024)
-
Unraveling the complex roles of macrophages in obese adipose tissue: an overview
Frontiers of Medicine (2024)
-
Proteomic studies of VEGFR2 in human placentas reveal protein associations with preeclampsia, diabetes, gravidity, and labor
Cell Communication and Signaling (2024)
-
Lysosomes, caspase-mediated apoptosis, and cytoplasmic activation of P21, but not cell senescence, participate in a redundant fashion in embryonic morphogenetic cell death
Cell Death & Disease (2023)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.
