Abstract
Macrophages were first described over a hundred years ago. Throughout the years, they were shown to be essential players in their tissue-specific environment, performing various functions during homeostatic and disease conditions. Recent reports shed more light on their ontogeny as long-lived, self-maintained cells with embryonic origin in most tissues. They populate the different tissues early during development, where they help to establish and maintain homeostasis. In this chapter, the history of macrophages is discussed. Furthermore, macrophage ontogeny and core functions in the different tissues are described.
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References
Metschnikoff E (1891) Lecture on phagocytosis and immunity. BMJ 1:213–217
Metchnikov E (1883) Untersuchungen ueber die mesodermalen Phagocyten einiger Wirbeltiere. Biologisches Centralblatt 3:560–565
Arroyo Portilla C, Tomas J, Gorvel JP, Lelouard H (2021) From species to regional and local specialization of intestinal macrophages. Front Cell Dev Biol 8:1910
Kierdorf K, Prinz M, Geissmann F, Gomez Perdiguero E (2015) Development and function of tissue resident macrophages in mice. Semin Immunol 27:369–378
Saraiva Camara NO, Braga TT (2022) Macrophages in the human body: a tissue level approach. Elsevier
van Furth R, Cohn ZA, Hirsch JG et al (1972) The mononuclear phagocyte system: a new classification of macrophages, monocytes, and their precursor cells. Bull World Health Organ 46:845–852
Bain CC, Bravo-Blas A, Scott CL et al (2014) Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat Immunol 15:929–937. https://doi.org/10.1038/ni.2967
Epelman S, Lavine KJ, Beaudin AE et al (2014) Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40:91–104. https://doi.org/10.1016/j.immuni.2013.11.019
Calderon B, Carrero JA, Ferris ST et al (2015) The pancreas anatomy conditions the origin and properties of resident macrophages. J Exp Med 212:1497–1512. https://doi.org/10.1084/jem.20150496
Tamoutounour S, Guilliams M, MontananaSanchis F et al (2013) Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin. Immunity 39:925–938. https://doi.org/10.1016/j.immuni.2013.10.004
Ginhoux F, Guilliams M (2016) Tissue-resident macrophage ontogeny and homeostasis. Immunity 44:439–449. https://doi.org/10.1016/j.immuni.2016.02.024
Merad M, Manz MG, Karsunky H et al (2002) Langerhans cells renew in the skin throughout life under steady-state conditions. Nat Immunol 3:1135–1141. https://doi.org/10.1038/ni852
Jenkins SJ, Ruckerl D, Cook PC et al (2011) Local macrophage proliferation, rather than recruitment from the blood, is a signature of T H2 inflammation. Science (1979) 332:1284–1288. https://doi.org/10.1126/science.1204351
Jakubzick C, Gautier EL, Gibbings SL et al (2013) Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity 39:599–610. https://doi.org/10.1016/j.immuni.2013.08.007
Hashimoto D, Chow A, Noizat C et al (2013) Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38:792–804. https://doi.org/10.1016/j.immuni.2013.04.004
Ajami B, Bennett JL, Krieger C et al (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10:1538–1543. https://doi.org/10.1038/nn2014
Palis J, Robertson S, Kennedy M et al (1999) Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse. Development 126:5073–5084
Ji RP, Phoon CKL, Aristizábal O et al (2003) Onset of cardiac function during early mouse embryogenesis coincides with entry of primitive erythroblasts into the embryo proper. Circ Res 92:133–135
McGrath KE, Koniski AD, Malik J, Palis J (2003) Circulation is established in a stepwise pattern in the mammalian embryo. Blood 101:1669–1676. https://doi.org/10.1182/blood-2002-08-2531
Gomez Perdiguero E, Klapproth K, Schulz C et al (2015) Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518:547–551. https://doi.org/10.1038/nature13989
McGrath KE, Frame JM, Fegan KH et al (2015) Distinct sources of hematopoietic progenitors emerge before HSCs and provide functional blood cells in the mammalian embryo. Cell Rep 11:1892–1904. https://doi.org/10.1016/j.celrep.2015.05.036
Mass E, Ballesteros I, Farlik M et al (2016) Specification of tissue-resident macrophages during organogenesis. Science (1979) 353:aaf4238. https://doi.org/10.1126/science.aaf4238
Stremmel C, Schuchert R, Wagner F et al (2018) Yolk sac macrophage progenitors traffic to the embryo during defined stages of development. Nat Commun 9:75. https://doi.org/10.1038/s41467-017-02492-2
Bertrand JY, Jalil A, Klaine M et al (2005) Three pathways to mature macrophages in the early mouse yolk sac. Blood 106:3004–3011. https://doi.org/10.1182/blood-2005-02-0461
Mukouyama YS, Chiba N, Mucenski ML et al (1999) Hematopoietic cells in cultures of the murine embryonic aorta-gonad-mesonephros region are induced by c-Myb. Curr Biol 9:833–836. https://doi.org/10.1016/S0960-9822(99)80368-6
Dege C, Fegan KH, Creamer JP et al (2020) Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. Dev Cell 53:229–239.e7. https://doi.org/10.1016/j.devcel.2020.02.016
Guilliams M, De Kleer I, Henri S et al (2013) Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J Exp Med 210:1977–1992. https://doi.org/10.1084/jem.20131199
Hoeffel G, Chen J, Lavin Y et al (2015) C-Myb+ erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42:665–678. https://doi.org/10.1016/j.immuni.2015.03.011
Medvinsky A, Dzierzak E (1996) Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 86:897–906. https://doi.org/10.1016/S0092-8674(00)80165-8
Boisset JC, van Cappellen W, Andrieu-Soler C et al (2010) In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature 464:116–120. https://doi.org/10.1038/nature08764
Christensen JL, Wright DE, Wagers AJ, Weissman IL (2004) Circulation and chemotaxis of fetal hematopoietic stem cells. PLoS Biol 2:e75. https://doi.org/10.1371/journal.pbio.0020075
dos Cassado AA, D’Império Lima MR, Bortoluci KR (2015) Revisiting mouse peritoneal macrophages: heterogeneity, development, and function. Front Immunol 6:225. https://doi.org/10.3389/fimmu.2015.00225
Chakarov S, Lim HY, Tan L et al (2019) Two distinct interstitial macrophage populations coexist across tissues in specific subtissular niches. Science 363:eaau0964. https://doi.org/10.1126/science.aau0964
Cox N, Geissmann F (2020) Macrophage ontogeny in the control of adipose tissue biology. Curr Opin Immunol 62:1–8
Sierro F, Evrard M, Rizzetto S et al (2017) A liver capsular network of monocyte-derived macrophages restricts hepatic dissemination of intraperitoneal bacteria by neutrophil recruitment. Immunity 47:374–388.e6. https://doi.org/10.1016/j.immuni.2017.07.018
Ginhoux F, Jung S (2014) Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 14:392–404. https://doi.org/10.1038/nri3671
McGrath KE, Frame JM, Palis J (2015) Early hematopoiesis and macrophage development. Semin Immunol 27:379–387
Migliaccio G, Migliaccio AR Petti S et al Human embryonic hemopoiesis Kinetics of progenitors and precursors underlying the yolk sac-+ liver transition. J Clin Invest 78:51–60
Ivanovs A, Rybtsov S, Welch L et al (2011) Highly potent human hematopoietic stem cells first emerge in the intraembryonic aorta-gonad-mesonephros region. J Exp Med 208:2417–2427. https://doi.org/10.1084/jem.20111688
Aorta-associated CD34+ hematopoietic cells in the early human embryo - PubMed. https://pubmed.ncbi.nlm.nih.gov/8547678/. Accessed 6 Jan 2023
Bian Z, Gong Y, Huang T et al (2020) Deciphering human macrophage development at single-cell resolution. Nature 582:571–576. https://doi.org/10.1038/s41586-020-2316-7
Hoeksema MA, Glass CK (2019) Nature and nurture of tissue-specific macrophage phenotypes. Atherosclerosis 281:159–167
Gordon S, Plüddemann A (2017) Tissue macrophages: heterogeneity and functions. BMC Biol 15:53. https://doi.org/10.1186/s12915-017-0392-4
Mass E, Nimmerjahn F, Kierdorf K, Schlitzer A (2023) Tissue-specific macrophages: how they develop and choreograph tissue biology. Nat Rev Immunol 2023:1–17. https://doi.org/10.1038/s41577-023-00848-y
Gordon S (2007) The macrophage: past, present and future. Eur J Immunol 37:S9–S17. https://doi.org/10.1002/eji.200737638
Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis and disease. Nature 496:445–455. https://doi.org/10.1038/nature12034
Li Q, Barres BA (2018) Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol 18:225–242. https://doi.org/10.1038/nri.2017.125
Kierdorf K, Erny D, Goldmann T et al (2013) Microglia emerge from erythromyeloid precursors via Pu.1-and Irf8-dependent pathways. Nat Neurosci 16:273–280. https://doi.org/10.1038/nn.3318
Cunningham CL, Martínez-Cerdeño V, Noctor SC (2013) Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J Neurosci 33:4216–4233. https://doi.org/10.1523/JNEUROSCI.3441-12.2013
Checchin D, Sennlaub F, Levavasseur E et al (2006) Potential role of microglia in retinal blood vessel formation. Invest Ophthalmol Vis Sci 47:3595–3602. https://doi.org/10.1167/iovs.05-1522
Fantin A, Vieira JM, Gestri G et al (2010) Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116:829–840. https://doi.org/10.1182/blood-2009-12-257832
Squarzoni P, Oller G, Hoeffel G et al (2014) Microglia modulate wiring of the embryonic forebrain. Cell Rep 8:1271–1279. https://doi.org/10.1016/j.celrep.2014.07.042
Ueno M, Fujita Y, Tanaka T et al (2013) Layer v cortical neurons require microglial support for survival during postnatal development. Nat Neurosci 16:543–551. https://doi.org/10.1038/nn.3358
Stevens B, Allen NJ, Vazquez LE et al (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–1178. https://doi.org/10.1016/j.cell.2007.10.036
Schafer DP, Lehrman EK, Kautzman AG et al (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691–705. https://doi.org/10.1016/j.neuron.2012.03.026
Stephan AH, Barres BA, Stevens B (2012) The complement system: an unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci 35:369–389
Hoshiko M, Arnoux I, Avignone E et al (2012) Deficiency of the microglial receptor CX3CR1 impairs postnatal functional development of thalamocortical synapses in the barrel cortex. J Neurosci 32:15106–15111. https://doi.org/10.1523/JNEUROSCI.1167-12.2012
Li Y, Du XF, Liu CS et al (2012) Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo. Dev Cell 23:1189–1202. https://doi.org/10.1016/j.devcel.2012.10.027
Safaiyan S, Kannaiyan N, Snaidero N et al (2016) Age-related myelin degradation burdens the clearance function of microglia during aging. Nat Neurosci 19:995–998. https://doi.org/10.1038/nn.4325
Ho MS (2019) Microglia in Parkinson’s disease. In: Advances in experimental medicine and biology. Springer, New York LLC, pp 335–353
Hansen DV, Hanson JE, Sheng M (2018) Microglia in Alzheimer’s disease. J Cell Biol 217:459–472
Sekar A, Bialas AR, de Rivera H et al (2016) Schizophrenia risk from complex variation of complement component 4. Nature 530:177–183. https://doi.org/10.1038/nature16549
Clarke BE, Patani R (2020) The microglial component of amyotrophic lateral sclerosis. Brain 143:3526–3539
Rademakers R, Baker M, Nicholson AM et al (2012) Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet 44:200–205. https://doi.org/10.1038/ng.1027
Oosterhof N, Chang IJ, Karimiani EG et al (2019) Homozygous mutations in CSF1R cause a pediatric-onset leukoencephalopathy and can result in congenital absence of microglia. Am J Hum Genet 104:936–947. https://doi.org/10.1016/j.ajhg.2019.03.010
Mass E, Jacome-Galarza CE, Blank T et al (2017) A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease. Nature 549:389–393. https://doi.org/10.1038/nature23672
Palis J (2014) Primitive and definitive erythropoiesis in mammals. Front Physiol 5 JAN
Willekens FLA, Werre JM, Kruijt JK et al (2005) Liver Kupffer cells rapidly remove red blood cell-derived vesicles from the circulation by scavenger receptors. Blood 105:2141–2145. https://doi.org/10.1182/blood-2004-04-1578
Guilliams M, Scott CL (2022) Liver macrophages in health and disease. Immunity 55:1515–1529. https://doi.org/10.1016/j.immuni.2022.08.002
Wang Y, van der Tuin S, Tjeerdema N et al (2015) Plasma cholesteryl ester transfer protein is predominantly derived from Kupffer cells. Hepatology 62:1710–1722. https://doi.org/10.1002/hep.27985
Krenkel O, Tacke F (2017) Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol 17:306–321. https://doi.org/10.1038/nri.2017.11
Westphalen K, Gusarova GA, Islam MN et al (2014) Sessile alveolar macrophages communicate with alveolar epithelium to modulate immunity. Nature 506:503–506. https://doi.org/10.1038/nature12902
MacLean JA, Xia W, Pinto CE et al (1996) Sequestration of inhaled particulate antigens by lung phagocytes: a mechanism for the effective inhibition of pulmonary cell-mediated immunity. Am J Pathol 148:657–666
Goritzka M, Makris S, Kausar F et al (2015) Alveolar macrophage-derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes. J Exp Med 212:699–714. https://doi.org/10.1084/jem.20140825
Mould KJ, Jackson ND, Henson PM et al (2019) Single cell RNA sequencing identifies unique inflammatory airspace macrophage subsets. JCI Insight 4. https://doi.org/10.1172/jci.insight.126556
Suzuki T, Trapnell BC (2016) Pulmonary alveolar Proteinosis syndrome. Clin Chest Med 37:431–440
Chiaranunt P, Tai SL, Ngai L, Mortha A (2021) Beyond immunity: underappreciated functions of intestinal macrophages. Front Immunol 12:3866
de Schepper S, Verheijden S, Aguilera-Lizarraga J et al (2018) Self-maintaining gut macrophages are essential for intestinal homeostasis. Cell 175:400–415.e13. https://doi.org/10.1016/j.cell.2018.07.048
Viola MF, Boeckxstaens G (2020) Intestinal resident macrophages: multitaskers of the gut. Neurogastroenterol Motil 32:e13843. https://doi.org/10.1111/nmo.13843
Bain CC, Schridde A (2018) Origin, differentiation, and function of intestinal macrophages. Front Immunol 9. https://doi.org/10.3389/fimmu.2018.02733
Morhardt TL, Hayashi A, Ochi T et al (2019) IL-10 produced by macrophages regulates epithelial integrity in the small intestine. Sci Rep 9:1223. https://doi.org/10.1038/s41598-018-38125-x
Ye Z, Hu W, Wu B et al (2021) Predictive prenatal diagnosis for infantile-onset inflammatory bowel disease because of Interleukin-10 signalling defects. J Pediatr Gastroenterol Nutr 72:276–281. https://doi.org/10.1097/MPG.0000000000002937
Hoffmann D, Sens J, Brennig S et al (2021) Genetic correction of IL-10RB deficiency reconstitutes anti-inflammatory regulation in iPSC-derived macrophages. J Pers Med 11:221. https://doi.org/10.3390/jpm11030221
Redhu NS, Bakthavatchalu V, Conaway EA et al (2017) Macrophage dysfunction initiates colitis during weaning of infant mice lacking the interleukin-10 receptor. elife 6. https://doi.org/10.7554/eLife.27652
Delfini M, Stakenborg N, Viola MF, Boeckxstaens G (2022) Macrophages in the gut: masters in multitasking. Immunity 55:1530–1548
Cox N, Crozet L, Holtman IR et al (2021) Diet-regulated production of PDGFcc by macrophages controls energy storage. Science (1979) 373:eabe9383. https://doi.org/10.1126/science.abe9383, 373
Pridans C, Raper A, Davis GM et al (2018) Pleiotropic impacts of macrophage and microglial deficiency on development in rats with targeted mutation of the Csf1r locus. J Immunol 201:2683–2699. https://doi.org/10.4049/jimmunol.1701783
Wei S, Lightwood D, Ladyman H et al (2005) Modulation of CSF-1-regulated post-natal development with anti-CSF-1 antibody. Immunobiology 210:109–119. https://doi.org/10.1016/j.imbio.2005.05.005
Chawla A, Boisvert WA, Lee CH et al (2001) A PPARγ-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell 7:161–171. https://doi.org/10.1016/S1097-2765(01)00164-2
Weisberg SP, McCann D, Desai M et al (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Investig 112:1796–1808. https://doi.org/10.1172/jci19246
Cinti S, Mitchell G, Barbatelli G et al (2005) Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 46:2347–2355. https://doi.org/10.1194/jlr.M500294-JLR200
Kanda H, Tateya S, Tamori Y et al (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Investig 116:1494–1505. https://doi.org/10.1172/JCI26498
Weisberg SP, Hunter D, Huber R et al (2006) CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Investig 116:115–124. https://doi.org/10.1172/JCI24335
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Makdissi, N. (2024). Macrophage Development and Function. In: Mass, E. (eds) Tissue-Resident Macrophages. Methods in Molecular Biology, vol 2713. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-3437-0_1
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