Mononuclear Phagocytes in Health and Disease

1. Mononuclear phagocytes, including monocytes, macrophages, and dendritic cells, are pivotal in both immune defense and physiological homeostasis.
2. Functions range from phagocytosis and antigen presentation to inflammation and tissue repair.
3. Their roles and behaviors vary in health and disease, with implications for therapeutic targeting.

Have you ever squeezed a spot and wondered what the white pus is? Or have you ever questioned the science behind tattoos?

Breaking out in spots is an inflammatory reaction where immune cells travel to the site of infection or injury performing immune function to restore homeostasis. Similarly, in 1882 a Russian scientist, Elie Metchnikoff pierced a rose thorn into a starfish where he observed cells moving towards the rose thorn and attempting to engulf it. It was this experiment which first conceived the theory of phagocytosis. Phagocytosis is the process of engulfing foreign material which is primarily carried out by professional phagocytes, namely granulocytes and mononuclear phagocytes.

Following the identification of phagocytes, interest in the origin of these cells began to arise. Early studies demonstrated the ability of blood monocytes to differentiate into macrophages (Ebert and Florey, 1939). These studies allowed scientists at the time to conclude that circulating monocytes are precursor cells to the majority of tissue monocytes (van Furth et al., 1972).

During the 1970s, a new cell type was identified having ‘stellate’ morphology owed to dendrites and was termed the ‘dendritic cell’. Today, monocytes, macrophages and dendritic cells are collectively known as the mononuclear phagocytes of the immune system. This article will discuss the role these cells play under steady physiological conditions and inflammation.

During a typical inflammatory response, tissue macrophages are the first cells to respond and therefore sometime regarded as sentinel cells of the immune system. Activation of these cells, results in the release of inflammatory mediators such as chemokines and cytokines which results in a first wave of neutrophil recruitment that engulf foreign invaders. A second wave of cells, mostly monocytes is recruited to tissue which aid in clearing apoptotic neutrophils and remaining pathogens. Dendritic cells bridge the gap the between innate and adaptive immunity.

As mentioned above, macrophages are often the first responders to infection owed to their scattered location all over the body. Although they are found within all tissues they do not behave in the same way as one another, instead macrophages from one tissue are functionally and transcriptionally distinct from another (Lavin et al., 2014).

Whilst monocytes were regarded as precursor cells to tissue resident macrophages, studies from the early 1970s challenged this theory as primitive macrophages were observed within the yolk-sac prior to the development of monocytes (Cline and Moore, 1972; Takahashi, 1989). More recently, the advances in technology have allowed macrophage biologists to truly understand the origin of macrophages. It is now clear that the majority of macrophages are seeded during embryonic development (Ginhoux et al., 2010; Schulz et al., 2012; Hashimoto et al., 2013; Yona et al., 2013; Epelman et al., 2014) which are able to self-renew throughout adulthood (Soucie et al., 2016) independently of monocytes under steady state. It is believed that persistence of tattoos lies within the longevity of tissue-resident macrophages.

Haematopoiesis initially starts in the yolk sac known as primitive hematopoiesis, at later stages of development the fetal liver becomes the major site marking the onset of definitive hematopoiesis. Of note, the bone marrow becomes the primary site around the time of birth. As a consequence, hematopoietic cells can originate from any of these three sources. Macrophages are either yolk-sac or fetal-liver derived or a combination of both. The microglia of the brain are a prime example of yolk-sac derived macrophages (Ginhoux et al., 2010), whereas alveolar macrophages are of fetal liver origin (van de Laar et al., 2016) and Langerhans cells of dual origin (Hoeffel et al., 2012). This raises the question why macrophages of distinct origins dominate in one tissue but not the other. While the answer to this question remains unknown, preliminary studies on alveolar macrophages demonstrated fetal liver macrophages outcompete yolk-sac derived macrophages in the alveolar niche due to their increased response to proliferate via GM-CSF (van de Laar et al., 2016), a cytokine essential for alveolar macrophage development (Guilliams et al., 2013). This suggests competition between cells occur resulting in the more adapted cell to reside within the tissue niche which has recently been proposed by the Guilliams’ group (Guilliams and Scott, 2017).

While the general consensus is that tissue macrophages are of embryonic origin, as always with scientific research there are exceptions. Following development, macrophages in some tissues fail to self-renew, as a result circulating monocytes replenish the empty niche throughout adulthood (Bain et al., 2014; McGovern et al., 2014; Keller et al., 2017). Why embryonic macrophages populations fail to self-renew continues to be investigated.

Macrophages are seeded around the same time as organogenesis (Mass et al., 2016) therefore questioning whether they play a role during embryonic development. Indeed it has been observed that mice lacking microglia exhibit reduced synaptic pruning which is thought to contribute to neurological disorders (Paolicelli et al., 2011; Parkhurst et al., 2013). Similarly, cardiac macrophages have been noted to be play a role in blood vessel development (Leid et al., 2016).

In addition to developmental roles macrophages continue to perform homeostatic role during adulthood, for example, alveolar macrophages are critical for the clearance of surfactant (van de Laar et al., 2016) while splenic macrophages are critical for iron homeostasis (Kohyama et al., 2009). Macrophages silently perform non-immune functions on a daily basis which we often take for granted as they are merely regarded as ‘immune’ cells.

The once thought monocyte-macrophage precursor relationship has since been revised and scientists within the field now visualise both cells are distinct cell types. In the context of inflammation, infiltrating monocyte-derived cells and resident macrophages are apparent at sites of injury/inflammation, however it can be difficult to dissect these two populations visually and phenotypically as they share several cell surface markers. Studies are beginning to distinguish between the two populations and started to investigate the role of bona fide resident macrophage population in response to inflammation.

Some studies suggest that resident macrophages do not play a role in inflammation. In a model of multiple sclerosis, monocyte-derived cells expressed pro-inflammatory genes whereas the profile of the microglia remains relatively unchanged (Yamasaki et al., 2014). Other studies have noticed a decrease in macrophage numbers following insult, referred to as the macrophage disappearance reaction (Barth et al., 1995). What happens to these macrophages remains unclear. On the other hand, resident macrophages response under certain inflammatory conditions, namely Th2 responses. In this setting, monocyte recruitment is not observed and rather macrophages have been shown to proliferate in response to helminth infections (Jenkins et al., 2011; Minutti et al., 2017).

Collectively, these studies highlight the role of macrophages under physiological conditions and inflammation.

Following the discovery of dendritic cells (DC) in the 1970s (Steinman and Cohn, 1973), it was soon show that these cells are specialised in presenting antigen and activating naïve T-cells (Nussenzweig et al., 1980). Like with macrophages, various flavours of DCs exist which can be essentially categorised as conventional/classical DCs (cDC) or plasmacytoid DCs (pDC), interestingly two types of cDC have been identified cDC1 and cDC2 in both mouse and humans. Recently, single-cell sequencing has allowed a deeper explorations of these cells where a further novel subsets and circulating precursors have been described (See et al., 2017; Villani et al., 2017), which will not be further discussed here. Like macrophages, DC are also maintained independently of monocytes with their own distinct lineage.

pDC are best known for their production of type 1 interferons in response to viral stimuli which are necessary for the activation of lymphocytes. Mice deficient for pDC exhibit increased viral loads and low levels of type 1 interferons. The importance of pDC has been demonstrated in human patients with Pitt-Hopkins syndrome who are deficient for these cells and unable to elicit a response to viral stimuli due to a mutation in the transcription factor (E2-2) necessary for pDC development (Cisse et al., 2008).

As the name suggests, classical DC are involved in antigen presentation. These cells are necessary for T cell stimulation as demonstrated by mice lacking cDC (Jung et al., 2002). Both exogenous and endogenous antigen can be presented, however cDC1 subset is more efficient at cross-presentation than the cDC2 (den Haan, Lehar and Bevan, 2000; Bedoui et al., 2009).

Monocytes were once viewed as circulating precursors that populate tissue macrophage and dendritic cells. However, it is now clear that the majority macrophages and dendritic cells are maintained independently of monocytes under steady state. Consequently this raises the question – what is the true function of monocytes?

Monocytes are heterogeneous population composed of multiple subsets across several species (Ziegler-Heitbrock, 2014). In humans, three subsets of monocytes exist with classical monocytes making up approximately 80-90% of the circulating monocyte pool and the remainder by intermediate and non-classical monocytes. Recently, the three subsets were shown to be developmentally related where classical monocytes mature into non-classical monocytes using humanised mice (Patel et al., 2017), which mirrored similar findings in mice (Varol et al., 2007; Yona et al., 2013; Gamrekelashvili et al., 2016; Mildner et al., 2017).

Classical monocytes are known to repopulate tissue pools where embryonic macrophages do not persist throughout adulthood as mentioned above (Bain et al., 2014; Epelman et al., 2014; McGovern et al., 2014; Keller et al., 2017). They have also been shown to enter tissues keeping their blood monocyte signature where they survey and carry antigen from tissues to lymph nodes (Jakubzick et al., 2013). On the other hand, non-classical monocytes are restricted to circulation under steady state where they patrol the endothelium acting as ‘housekeepers’ monitoring for any damage (Auffray et al., 2007; Carlin et al., 2013; Collison et al., 2015). Evidence for the role of intermediate monocytes under steady state remains scarce however these cells express the highest level of HLA-DR in comparison to the other subsets (Patel et al., 2017) suggesting a potential role in antigen presentation. Recently, intermediate monocytes have been suggested to consist of two heterogeneous populations (Villani et al., 2017), however further experiments are needed to confirm their roles.

In response to infection or injury, classical monocytes are recruited to sites of inflammation (Geissmann, Jung and Littman, 2003; Nahrendorf et al., 2007; Tsou et al., 2007). The chemokine receptor, CCR2 is necessary for bone marrow extravasation, therefore studies have used CCR2-\- mice which lack circulating classical monocytes to study their contribution to tissue injury/infection. While classical monocytes have been referred to as inflammatory monocytes, non-classical monocytes have also been implicated in some pathologies for example in a murine model of rheumatoid arthritis (Misharin et al., 2014).

In a human model of acute local inflammation, classical monocytes were observed at early time points and an intermediate monocyte phenotype at later events (Motwani et al., 2016), however it is unclear whether the intermediate monocytes were derived from the circulating pool or whether they matured from the classical monocytes at the site. Monocyte-derived cells can exhibit macrophage-like functions or behave more like a dendritic cell. Recently it was shown that specific transcription factors and ligation of aryl hydrocarbon receptor were involved in determining the fate of monocyte-derived cells (Goudot et al., 2017).

Whether recruited monocytes contribute to the long term tissue macrophages is also an area of investigation. While some studies have reported that monocytes persist in the tissues following challenge (Yona et al., 2013; Machiels et al., 2017), in other conditions it was shown that monocyte-derived cells were cleared during resolution by apoptosis. (Janssen et al., 2011).

Summary

In summary, mononuclear phagocytes are key players not only of the immune system but also in maintaining physiological homeostasis. The importance of these cells can be emphasised by patients who have a deficiency in circulating mononuclear phagocytes due to mutations in transcription factors necessary for their development (Bigley et al., 2011; Dickinson et al., 2011; Hambleton et al., 2011; Frankenberger et al., 2013). Ongoing studies continue to evaluate the role and relationship between mononuclear phagocytes in both health and disease. With a clearer understanding it is hoped that these cells can be targeted to increase their beneficial functions when needed or reduce their functional capacity in detrimental settings.

References

1. Auffray, C., Fogg, D., Garfa, M., Elain, G., Join-Lambert, O., Kayal, S., Sarnacki, S., Cumano, A., Lauvau, G. and Geissmann, F. (2007) ‘Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior.’, Science (New York, N.Y.), 317(5838), pp. 666–70. doi: 10.1126/science.1142883.
2. Bain, C. C., Bravo-Blas, A., Scott, C. L., Perdiguero, E. G., Geissmann, F., Henri, S., Malissen, B., Osborne, L. C., Artis, D. and Mowat, A. M. (2014) ‘Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice.’, Nature immunology, (August). doi: 10.1038/ni.2967.
3. Barth, M. W., Hendrzak, J. A., Melnicoff, M. J. and Morahan, P. S. (1995) ‘Review of the macrophage disappearance reaction.’, Journal of leukocyte biology, 57(3), pp. 361–7. Available at: http://www.jleukbio.org/content/57/3/361.abstract...
4. Bedoui, S., Whitney, P. G., Waithman, J., Eidsmo, L., Wakim, L., Caminschi, I., Allan, R. S., Wojtasiak, M., Shortman, K., Carbone, F. R., Brooks, A. G. and Heath, W. R. (2009) ‘Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells.’, Nature Immunology, 10(5), pp. 488–495. doi: 10.1038/ni.1724.
5. Bigley, V., Haniffa, M., Doulatov, S., Wang, X.-N., Dickinson, R., McGovern, N., Jardine, L., Pagan, S., Dimmick, I., Chua, I., Wallis, J., Lordan, J., Morgan, C., Kumararatne, D. S., Doffinger, R., van der Burg, M., van Dongen, J., Cant, A., Dick, J. E., Hambleton, S. and Collin, M. (2011) ‘The human syndrome of dendritic cell, monocyte, B and NK lymphoid deficiency.’, The Journal of experimental medicine, 208(2), pp. 227–234. doi: 10.1084/jem.20101459.
6. Carlin, L. M., Stamatiades, E. G., Auffray, C., Hanna, R. N., Glover, L., Vizcay-Barrena, G., Hedrick, C. C., Cook, H. T., Diebold, S. and Geissmann, F. (2013) ‘Nr4a1-dependent Ly6Clow monocytes monitor endothelial cells and orchestrate their disposal’, Cell, 153(2), pp. 362–375. doi: 10.1016/j.cell.2013.03.010.
7. Cisse, B., Caton, M. L., Lehner, M., Maeda, T., Scheu, S., Locksley, R., Holmberg, D., Zweier, C., den Hollander, N. S., Kant, S. G., Holter, W., Rauch, A., Zhuang, Y. and Reizis, B. (2008) ‘Transcription Factor E2-2 Is an Essential and Specific Regulator of Plasmacytoid Dendritic Cell Development’, Cell, 135(1), pp. 37–48. doi: 10.1016/j.cell.2008.09.016.
8. Cline, M. J. and Moore, M. A. (1972) ‘Embryonic origin of the mouse macrophage.’, Blood, 39(6), pp. 842–9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/5028525.
9. Collison, J. L., Carlin, L. M., Eichmann, M., Geissmann, F. and Peakman, M. (2015) ‘Heterogeneity in the Locomotory Behavior of Human Monocyte Subsets over Human Vascular Endothelium In Vitro.’, Journal of immunology (Baltimore, Md. : 1950), 195(3), pp. 1162–70. doi: 10.4049/jimmunol.1401806.
10. Dickinson, R. E., Griffin, H., Bigley, V., Reynard, L. N., Hussain, R., Haniffa, M., Lakey, J. H., Rahman, T., Wang, X. N., McGovern, N., Pagan, S., Cookson, S., McDonald, D., Chua, I., Wallis, J., Cant, A., Wright, M., Keavney, B., Chinnery, P. F., Loughlin, J., Hambleton, S., Santibanez-Koref, M. and Collin, M. (2011) ‘Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency’, Blood, 118(10), pp. 2656–2658. doi: 10.1182/blood-2011-06-360313.
11. Ebert, R. H. and Florey, H. W. (1939) ‘The Extravascular Development of the Monocyte Observed In vivo’, British Journal of Experimental Pathology, 20(1), p. 342. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2065374%5Cnhtt...
12. Epelman, S., Lavine, K. J., Beaudin, A. E., Sojka, D. K., Carrero, J. A., Calderon, B., Brija, T., Gautier, E. L., Ivanov, S., Satpathy, A. T., Schilling, J. D., Schwendener, R., Sergin, I., Razani, B., Forsberg, E. C., Yokoyama, W. M., Unanue, E. R., Colonna, M., Randolph, G. J. and Mann, D. L. (2014) ‘Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation.’, Immunity. Elsevier Inc., 40(1), pp. 91–104. doi: 10.1016/j.immuni.2013.11.019.
13. Frankenberger, M., Ekici, A. B., Angstwurm, M. W., Hoffmann, H., Hofer, T. P. J., Heimbeck, I., Meyer, P., Lohse, P., Wjst, M., Häussinger, K., Reis, A. and Ziegler-Heitbrock, L. (2013) ‘A defect of CD16-positive monocytes can occur without disease’, Immunobiology. Elsevier GmbH., 218(2), pp. 169–174. doi: 10.1016/j.imbio.2012.02.013.
14. van Furth, R., Cohn, Z. A., Hirsch, J. G., Humphrey, J. H., Spector, W. G. and Langevoort, H. L. (1972) ‘The mononuclear phagocyte system: a new classification of macrophages, monocytes, and their precursor cells.’, Bulletin of the World Health Organization, 46, pp. 845–852.
15. Gamrekelashvili, J., Giagnorio, R., Jussofie, J., Soehnlein, O., Duchene, J., Briseño, C. G., Ramasamy, S. K., Krishnasamy, K., Limbourg, A., Kapanadze, T., Ishifune, C., Hinkel, R., Radtke, F., Strobl, L. J., Zimber-Strobl, U., Napp, L. C., Bauersachs, J., Haller, H., Yasutomo, K., Kupatt, C., Murphy, K. M., Adams, R. H., Weber, C. and Limbourg, F. P. (2016) ‘Regulation of monocyte cell fate by blood vessels mediated by Notch signalling.’, Nature communications, 7, p. 12597. doi: 10.1038/ncomms12597.
16. Geissmann, F., Jung, S. and Littman, D. R. (2003) ‘Blood monocytes consist of two principal subsets with distinct migratory properties’, Immunity, 19(1), pp. 71–82. doi: 10.1016/S1074-7613(03)00174-2.
17. Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., Mehler, M. F., Conway, S. J., Ng, L. G., Stanley, E. R., Samokhvalov, I. M. and Merad, M. (2010) ‘Fate mapping analysis reveals that adult microglia derive from primitive macrophages.’, Science (New York, N.Y.), 330(6005), pp. 841–5. doi: 10.1126/science.1194637.
18. Goudot, C., Coillard, A., Villani, A.-C., Gueguen, P., Cros, A., Sarkizova, S., Tang-Huau, T.-L., Bohec, M., Baulande, S., Hacohen, N., Amigorena, S. and Segura, E. (2017) ‘Aryl Hydrocarbon Receptor Controls Monocyte Differentiation into Dendritic Cells versus Macrophages’, Immunity, 47(3), p. 582–596.e6. doi: 10.1016/j.immuni.2017.08.016.
19. Guilliams, M., De Kleer, I., Henri, S., Post, S., Vanhoutte, L., De Prijck, S., Deswarte, K., Malissen, B., Hammad, H. and Lambrecht, B. N. (2013) ‘Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF.’, The Journal of experimental medicine, 210(10), pp. 1977–92. doi: 10.1084/jem.20131199.
20. Guilliams, M. and Scott, C. L. (2017) ‘Does niche competition determine the origin of tissue-resident macrophages?’, Nature Reviews Immunology, 17(7), pp. 451–460. doi: 10.1038/nri.2017.42.
21. den Haan, J. M., Lehar, S. M. and Bevan, M. J. (2000) ‘CD8(+) but not CD8(-) dendritic cells cross-prime cytotoxic T cells in vivo.’, The Journal of experimental medicine, 192(12), pp. 1685–96. doi: 10.1084/jem.192.12.1685.
22. Hambleton, S., Salem, S., Bustamante, J., Bigley, V., Boisson-Dupuis, S., Azevedo, J., Fortin, A., Haniffa, M., Ceron-Gutierrez, L., Bacon, C. M., Menon, G., Trouillet, C., McDonald, D., Carey, P., Ginhoux, F., Alsina, L., Zumwalt, T. J., Kong, X.-F., Kumararatne, D., Butler, K., Hubeau, M., Feinberg, J., Al-Muhsen, S., Cant, A., Abel, L., Chaussabel, D., Doffinger, R., Talesnik, E., Grumach, A., Duarte, A., Abarca, K., Moraes-Vasconcelos, D., Burk, D., Berghuis, A., Geissmann, F., Collin, M., Casanova, J.-L. and Gros, P. (2011) ‘IRF8 Mutations and Human Dendritic-Cell Immunodeficiency’, New England Journal of Medicine, 365(2), pp. 127–138. doi: 10.1056/NEJMoa1100066.
23. Hashimoto, D., Chow, A., Noizat, C., Teo, P., Beasley, M. B., Leboeuf, M., Becker, C. D., See, P., Price, J., Lucas, D., Greter, M., Mortha, A., Boyer, S. W., Forsberg, E. C., Tanaka, M., van Rooijen, N., García-Sastre, A., Stanley, E. R., Ginhoux, F., Frenette, P. S. and Merad, M. (2013) ‘Tissue-Resident Macrophages Self-Maintain Locally throughout Adult Life with Minimal Contribution from Circulating Monocytes’, Immunity, 38(4), pp. 792–804. doi: 10.1016/j.immuni.2013.04.004.
24. Hoeffel, G., Wang, Y., Greter, M., See, P., Teo, P., Malleret, B., Leboeuf, M., Low, D., Oller, G., Almeida, F., Choy, S. H. Y., Grisotto, M., Renia, L., Conway, S. J., Stanley, E. R., Chan, J. K. Y., Ng, L. G., Samokhvalov, I. M., Merad, M. and Ginhoux, F. (2012) ‘Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages.’, The Journal of experimental medicine, 209(6), pp. 1167–81. doi: 10.1084/jem.20120340.
25. Jakubzick, C., Gautier, E. L., Gibbings, S. L., Sojka, D. K., Schlitzer, A., Johnson, T. E., Ivanov, S., Duan, Q., Bala, S., Condon, T., van Rooijen, N., Grainger, J. R., Belkaid, Y., Ma’ayan, A., Riches, D. W. H., Yokoyama, W. M., Ginhoux, F., Henson, P. M. and Randolph, G. J. (2013) ‘Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes.’, Immunity. Elsevier Inc., 39(3), pp. 599–610. doi: 10.1016/j.immuni.2013.08.007.
26. Janssen, W. J., Barthel, L., Muldrow, A., Oberley-Deegan, R. E., Kearns, M. T., Jakubzick, C. and Henson, P. M. (2011) ‘Fas determines differential fates of resident and recruited macrophages during resolution of acute lung injury’, American Journal of Respiratory and Critical Care Medicine, 184(5), pp. 547–560. doi: 10.1164/rccm.201011-1891OC.
27. Jenkins, S. J., Ruckerl, D., Cook, P. C., Jones, L. H., Finkelman, F. D., van Rooijen, N., MacDonald, A. S. and Allen, J. E. (2011) ‘Local Macrophage Proliferation, Rather than Recruitment from the Blood, Is a Signature of TH2 Inflammation’, Science, 332(6035), pp. 1284–1288. doi: 10.1126/science.1204351.
28. Jung, S., Unutmaz, D., Wong, P., Sano, G. I., De Los Santos, K., Sparwasser, T., Wu, S., Vuthoori, S., Ko, K., Zavala, F., Pamer, E. G., Littman, D. R. and Lang, R. A. (2002) ‘In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens’, Immunity, 17(2), pp. 211–220. doi: 10.1016/S1074-7613(02)00365-5.
29. Keller, N. M., Gentek, R., Gimenez, G., Bigot, S., Mailfert, S. and Sieweke, M. H. (2017) ‘Developmental origin and maintenance of distinct testicular macrophage populations’, Jem, 214(10), pp. 1–14. doi: 10.1084/jem.20170829.
30. Kohyama, M., Ise, W., Edelson, B. T., Wilker, P. R., Hildner, K., Mejia, C., Frazier, W. a, Murphy, T. L. and Murphy, K. M. (2009) ‘Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis.’, Nature. Nature Publishing Group, 457(7227), pp. 318–21. doi: 10.1038/nature07472.
31. Lavin, Y., Winter, D., Blecher-Gonen, R., David, E., Keren-Shaul, H., Merad, M., Jung, S. and Amit, I. (2014) ‘Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment’, Cell. Elsevier Inc., 159(6), pp. 1312–1326. doi: 10.1016/j.cell.2014.11.018.
32. Leid, J., Carrelha, J., Boukarabila, H., Epelman, S., Jacobsen, S. E. W. and Lavine, K. J. (2016) ‘Primitive Embryonic Macrophages are Required for Coronary Development and Maturation’, Circulation Research, 118(10), pp. 1498–1511. doi: 10.1161/CIRCRESAHA.115.308270.
33. Machiels, B., Dourcy, M., Xiao, X., Javaux, J., Mesnil, C., Sabatel, C., Desmecht, D., Lallemand, F., Martinive, P., Hammad, H., Guilliams, M., Dewals, B., Vanderplasschen, A., Lambrecht, B. N., Bureau, F. and Gillet, L. (2017) ‘A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes’, Nature Immunology. Nature Publishing Group, (October). doi: 10.1038/ni.3857.
34. Mass, E., Ballesteros, I., Farlik, M., Halbritter, F., Günther, P., Crozet, L., Jacome-Galarza, C. E., Händler, K., Klughammer, J., Kobayashi, Y., Gomez-Perdiguero, E., Schultze, J. L., Beyer, M., Bock, C. and Geissmann, F. (2016) ‘Specification of tissue-resident macrophages during organogenesis.’, Science (New York, N.Y.), 353(6304). doi: 10.1126/science.aaf4238.
35. McGovern, N., Schlitzer, A., Gunawan, M., Jardine, L., Shin, A., Poyner, E., Green, K., Dickinson, R., Wang, X.-N., Low, D., Best, K., Covins, S., Milne, P., Pagan, S., Aljefri, K., Windebank, M., Miranda-Saavedra, D., Saavedra, D. M., Larbi, A., Wasan, P. S., Duan, K., Poidinger, M., Bigley, V., Ginhoux, F., Collin, M. and Haniffa, M. (2014) ‘Human dermal CD14+ cells are a transient population of monocyte-derived macrophages.’, Immunity. The Authors, 41(3), pp. 465–77. doi: 10.1016/j.immuni.2014.08.006.
36. Mildner, A., Schönheit, J., Giladi, A., David, E., Lara-Astiaso, D., Lorenzo-Vivas, E., Paul, F., Chappell-Maor, L., Priller, J., Leutz, A., Amit, I. and Jung, S. (2017) ‘Genomic Characterization of Murine Monocytes Reveals C/EBPβ Transcription Factor Dependence of Ly6C − Cells’, Immunity, 46(5), p. 849–862.e7. doi: 10.1016/j.immuni.2017.04.018.
37. Minutti, C. M., Jackson-Jones, L. H., García-Fojeda, B., Knipper, J. A., Sutherland, T. E., Logan, N., Rinqvist, E., Guillamat-Prats, R., Ferenbach, D. A., Artigas, A., Stamme, C., Chroneos, Z. C., Zaiss, D. M., Casals, C. and Allen, J. E. (2017) ‘Local amplifiers of IL-4Rα-mediated macrophage activation promote repair in lung and liver.’, Science (New York, N.Y.), 356(6342), pp. 1076–1080. doi: 10.1126/science.aaj2067.
38. Misharin, A. V., Cuda, C. M., Saber, R., Turner, J. D., Gierut, A. K., Kenneth Haines, G. K., Berdnikovs, S., Filer, A., Clark, A. R., Buckley, C. D., Mutlu, G. M., Scott Budinger, G. R. and Perlman, H. (2014) ‘Nonclassical Ly6C- monocytes drive the development of inflammatory arthritis in mice’, Cell Reports, 9(2), pp. 591–604. doi: 10.1016/j.celrep.2014.09.032.
39. Motwani, M. P., Flint, J. D., Ph, R., Maeyer, D., Fullerton, J. N., Smith, A. M., Marks, D. J. and Gilroy, D. W. (2016) ‘Novel translational model of resolving inflammation triggered by UV-killed E. coli’, Journal of Pathology: Clinical Research, 2(July), pp. 154–165. doi: 10.1002/cjp2.43.
40. Nahrendorf, M., Swirski, F. K., Aikawa, E., Stangenberg, L., Wurdinger, T., Figueiredo, J.-L., Libby, P., Weissleder, R. and Pittet, M. J. (2007) ‘The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions.’, The Journal of experimental medicine, 204(12), pp. 3037–47. doi: 10.1084/jem.20070885.
41. Nussenzweig, M. C., Steinman, R. M., Gutchinov, B. and Cohn, Z. A. (1980) ‘Dendritic cells are accessory cells for the development of anti-trinitrophenyl cytotoxic T lymphocytes.’, The Journal of experimental medicine, 152(4), pp. 1070–84. Available at: http://www.ncbi.nlm.nih.gov/pubmed/6968335%5Cnhtt...
42. Paolicelli, R. C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P., Giustetto, M., Ferreira, T. A., Guiducci, E., Dumas, L., Ragozzino, D. and Gross, C. T. (2011) ‘Synaptic pruning by microglia is necessary for normal brain development.’, Science (New York, N.Y.), 333(6048), pp. 1456–8. doi: 10.1126/science.1202529.
43. Parkhurst, C. N., Yang, G., Ninan, I., Savas, J. N., Yates, J. R., Lafaille, J. J., Hempstead, B. L., Littman, D. R. and Gan, W. B. (2013) ‘Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor’, Cell, 155(7), pp. 1596–1609. doi: 10.1016/j.cell.2013.11.030.
44. Patel, A. A., Zhang, Y., Fullerton, J. N., Boelen, L., Rongvaux, A., Maini, A. A., Bigley, V., Flavell, R. A., Gilroy, D. W., Asquith, B., Macallan, D. and Yona, S. (2017) ‘The fate and lifespan of human monocyte subsets in steady state and systemic inflammation’, The Journal of Experimental Medicine, 214(7), pp. 1913–1923. doi: 10.1084/jem.20170355.
45. Schulz, C., Gomez Perdiguero, E., Chorro, L., Szabo-Rogers, H., Cagnard, N., Kierdorf, K., Prinz, M., Wu, B., Jacobsen, S. E. W., Pollard, J. W., Frampton, J., Liu, K. J. and Geissmann, F. (2012) ‘A lineage of myeloid cells independent of Myb and hematopoietic stem cells.’, Science (New York, N.Y.), 336, pp. 86–90. doi: 10.1126/science.1219179.
46. See, P., Dutertre, C.-A., Chen, J., Günther, P., McGovern, N., Irac, S. E., Gunawan, M., Beyer, M., Händler, K., Duan, K., Sumatoh, H. R. Bin, Ruffin, N., Jouve, M., Gea-Mallorquí, E., Hennekam, R. C. M., Lim, T., Yip, C. C., Wen, M., Malleret, B., Low, I., Shadan, N. B., Fen, C. F. S., Tay, A., Lum, J., Zolezzi, F., Larbi, A., Poidinger, M., Chan, J. K. Y., Chen, Q., Rénia, L., Haniffa, M., Benaroch, P., Schlitzer, A., Schultze, J. L., Newell, E. W. and Ginhoux, F. (2017) ‘Mapping the human DC lineage through the integration of high-dimensional techniques’, Science, 356(6342), p. eaag3009. doi: 10.1126/science.aag3009.
47. Soucie, E. L., Soucie, E. L., Weng, Z., Geirsdóttir, L., Molawi, K., Maurizio, J., Fenouil, R., Mossadegh-keller, N., Gimenez, G., Vanhille, L., Favret, J., Berruyer, C., Perrin, P., Hacohen, N., Andrau, J., Dubreuil, P., Sidow, A. and Sieweke, M. H. (2016) ‘Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells’, 5510, pp. 1–20. doi: 10.1126/science.aad5510.
48. Steinman, R. M. and Cohn, Z. a (1973) ‘Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution.’, The Journal of experimental medicine, 137(5), pp. 1142–1162. doi: 10.1084/jem.137.5.1142.
49. Takahashi, K. (1989) ‘Differentiation , Maturation , and Proliferation Macrophages in the Mouse Yolk Sac : of and Ultrastructural Study’, Journal of Leukocyte Biology, 96(2), pp. 87–96.
50. Tsou, C. L., Peters, W., Si, Y., Slaymaker, S., Aslanian, A. M., Weisberg, S. P., Mack, M. and Charo, I. F. (2007) ‘Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites’, Journal of Clinical Investigation, 117(4), pp. 902–909. doi: 10.1172/JCI29919.
51. van de Laar, L., Saelens, W., De Prijck, S., Martens, L., Scott, C. L., Van Isterdael, G., Hoffmann, E., Beyaert, R., Saeys, Y., Lambrecht, B. N. and Guilliams, M. (2016) ‘Yolk Sac Macrophages, Fetal Liver, and Adult Monocytes Can Colonize an Empty Niche and Develop into Functional Tissue-Resident Macrophages’, Immunity. Elsevier Inc., pp. 1–14. doi: 10.1016/j.immuni.2016.02.017.
52. Varol, C., Landsman, L., Fogg, D. K., Greenshtein, L., Gildor, B., Margalit, R., Kalchenko, V., Geissmann, F. and Jung, S. (2007) ‘Monocytes give rise to mucosal, but not splenic, conventional dendritic cells.’, The Journal of experimental medicine, 204(1), pp. 171–80. doi: 10.1084/jem.20061011.
53. Villani, A.-C., Satija, R., Reynolds, G., Sarkizova, S., Shekhar, K., Fletcher, J., Griesbeck, M., Butler, A., Zheng, S., Lazo, S., Jardine, L., Dixon, D., Stephenson, E., Nilsson, E., Grundberg, I., McDonald, D., Filby, A., Li, W., De Jager, P. L., Rozenblatt-Rosen, O., Lane, A. A., Haniffa, M., Regev, A. and Hacohen, N. (2017) ‘Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors’, Science, 356(6335), p. eaah4573. doi: 10.1126/science.aah4573.
54. Yamasaki, R., Lu, H., Butovsky, O., Ohno, N., Rietsch, A. M., Cialic, R., Wu, P. M., Doykan, C. E., Lin, J., Cotleur, A. C., Kidd, G., Zorlu, M. M., Sun, N., Hu, W., Liu, L., Lee, J.-C., Taylor, S. E., Uehlein, L., Dixon, D., Gu, J., Floruta, C. M., Zhu, M., Charo, I. F., Weiner, H. L. and Ransohoff, R. M. (2014) ‘Differential roles of microglia and monocytes in the inflamed central nervous system’, The Journal of Experimental Medicine, 211(8), pp. 1533–1549. doi: 10.1084/jem.20132477.
55. Yona, S., Kim, K. W., Wolf, Y., Mildner, A., Varol, D., Breker, M., Strauss-Ayali, D., Viukov, S., Guilliams, M., Misharin, A., Hume, D. A., Perlman, H., Malissen, B., Zelzer, E. and Jung, S. (2013) ‘Fate Mapping Reveals Origins and Dynamics of Monocytes and Tissue Macrophages under Homeostasis’, Immunity, 38, pp. 79–91. doi: 10.1016/j.immuni.2012.12.001.
56. Ziegler-Heitbrock, L. (2014) ‘Monocyte subsets in man and other species’, Cellular Immunology. Elsevier Inc., 289(1–2), pp. 135–139. doi: 10.1016/j.cellimm.2014.03.019.