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  • Review Article
  • Published:

Monocyte recruitment during infection and inflammation

Nature Reviews Immunology volume 11, pages 762–774 (2011)Cite this article

Subjects

Key Points

  • Monocytes are a heterogeneous population of myeloid cells that originate from progenitors in the bone marrow and traffic via the bloodstream to peripheral tissues.

  • Monocyte recruitment is guided by chemokines that bind to receptors expressed on the monocyte cell surface. The process is believed to follow a general paradigm of leukocyte adhesion and trafficking, and thus depends on the interactions of various adhesion molecules.

  • Circulating monocytes traffic into tissues during both homeostasis and inflammation. When conditioned by local growth factors, pro-inflammatory cytokines and microbial products, monocytes can differentiate into macrophage or dendritic cell populations.

  • The recruitment of monocytes is essential for effective control and clearance of bacterial, protozoal, fungal and viral infections, but recruited monocytes can also be deleterious and cause immunopathology during certain infections.

  • Monocyte recruitment contributes to the pathogenesis of aseptic inflammatory diseases. Different subsets of monocytes are recruited to the aorta during atherosclerosis and possibly have distinct roles at this site.

  • Monocyte egress from the bone marrow depends on CC-chemokine receptor 2 (CCR2), a chemokine receptor that binds to CC-chemokine ligand 2 (CCL2) and CCL7. Sensitive detection of circulating microbial molecules or pro-inflammatory cytokines by bone marrow-resident cells (such as mesenchymal stem cells and CXCL12-abundant reticular cells), with commensurate induction of CCL2, provides a mechanism to modulate the frequency of circulating inflammatory monocytes. This suggests that microorganisms may drive inflammatory disease in an otherwise 'sterile' tissue environment.

Abstract

Monocytes originate from progenitors in the bone marrow and traffic via the bloodstream to peripheral tissues. During both homeostasis and inflammation, circulating monocytes leave the bloodstream and migrate into tissues where, following conditioning by local growth factors, pro-inflammatory cytokines and microbial products, they differentiate into macrophage or dendritic cell populations. Recruitment of monocytes is essential for effective control and clearance of viral, bacterial, fungal and protozoal infections, but recruited monocytes also contribute to the pathogenesis of inflammatory and degenerative diseases. The mechanisms that control monocyte trafficking under homeostatic, infectious and inflammatory conditions are being unravelled and are the focus of this Review.

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Figure 1: Trafficking of circulating monocyte subsets.
Figure 2: Monocyte recruitment is crucial for defence against a broad range of pathogenic microorganisms.
Figure 3: Pro-inflammatory cytokines and TLR ligands promote the emigration of LY6Chi monocytes from the bone marrow.
Figure 4: Models of CCL2-mediated emigration of LY6Chi monocytes from the bone marrow.

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References

  1. Auffray, C., Sieweke, M. H. & Geissmann, F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu. Rev. Immunol. 27, 669–692 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. van Furth, R. & Cohn, Z. A. The origin and kinetics of mononuclear phagocytes. J. Exp. Med. 128, 415–435 (1968).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Serbina, N. V., Jia, T., Hohl, T. M. & Pamer, E. G. Monocyte-mediated defense against microbial pathogens. Annu. Rev. Immunol. 26, 421–452 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Woollard, K. J. & Geissmann, F. Monocytes in atherosclerosis: subsets and functions. Nature Rev. Cardiol. 7, 77–86 (2010).

    Article  Google Scholar 

  5. Peranzoni, E. et al. Myeloid-derived suppressor cell heterogeneity and subset definition. Curr. Opin. Immunol. 22, 238–244 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Palframan, R. T. et al. Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues. J. Exp. Med. 194, 1361–1373 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Geissmann, F., Jung, S. & Littman, D. R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003). A seminal study that formally defined two main subsets of mouse monocytes.

    Article  CAS  PubMed  Google Scholar 

  8. Kurihara, T., Warr, G., Loy, J. & Bravo, R. Defects in macrophage recruitment and host defense in mice lacking the CCR2 chemokine receptor. J. Exp. Med. 186, 1757–1762 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kuziel, W. A. et al. Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2. Proc. Natl Acad. Sci. USA 94, 12053–12058 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Si, Y., Tsou, C. L., Croft, K. & Charo, I. F. CCR2 mediates hematopoietic stem and progenitor cell trafficking to sites of inflammation in mice. J. Clin. Invest. 120, 1192–1203 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Auffray, C. et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317, 666–670 (2007). The patrolling behaviour of monocytes was first demonstrated using an intravital imaging technique in this study.

    Article  CAS  PubMed  Google Scholar 

  12. Ziegler-Heitbrock, L. The CD14+ CD16+ blood monocytes: their role in infection and inflammation. J. Leukoc. Biol. 81, 584–592 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Ziegler-Heitbrock, L. et al. Nomenclature of monocytes and dendritic cells in blood. Blood 116, e74–e80 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Cros, J. et al. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 33, 375–386 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Belge, K. U. et al. The proinflammatory CD14+CD16+DR++ monocytes are a major source of TNF. J. Immunol. 168, 3536–3542 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Grage-Griebenow, E., Flad, H. D. & Ernst, M. Heterogeneity of human peripheral blood monocyte subsets. J. Leukoc. Biol. 69, 11–20 (2001).

    CAS  PubMed  Google Scholar 

  17. Ingersoll, M. A. et al. Comparison of gene expression profiles between human and mouse monocyte subsets. Blood 115, e10–e19 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Struyf, S. et al. Synergistic induction of MCP-1 and -2 by IL-1β and interferons in fibroblasts and epithelial cells. J. Leukoc. Biol. 63, 364–372 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Tsuboi, N. et al. Roles of Toll-like receptors in C-C chemokine production by renal tubular epithelial cells. J. Immunol. 169, 2026–2033 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Rollins, B. J. & Pober, J. S. Interleukin-4 induces the synthesis and secretion of MCP-1/JE by human endothelial cells. Am. J. Pathol. 138, 1315–1319 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Brown, Z. et al. Chemokine gene expression and secretion by cytokine-activated human microvascular endothelial cells. Differential regulation of monocyte chemoattractant protein-1 and interleukin-8 in response to interferon-γ. Am. J. Pathol. 145, 913–921 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Proudfoot, A. E. et al. Glycosaminoglycan binding and oligomerization are essential for the in vivo activity of certain chemokines. Proc. Natl Acad. Sci. USA 100, 1885–1890 (2003). This study identified a regulatory mechanism for chemokine activity in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Allen, S. J., Crown, S. E. & Handel, T. M. Chemokine: receptor structure, interactions, and antagonism. Annu. Rev. Immunol. 25, 787–820 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Pruenster, M. et al. The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity. Nature Immunol. 10, 101–108 (2009).

    Article  CAS  Google Scholar 

  26. Jia, T. et al. Additive roles for MCP-1 and MCP-3 in CCR2-mediated recruitment of inflammatory monocytes during Listeria monocytogenes infection. J. Immunol. 180, 6846–6853 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Auffray, C. et al. CX3CR1+ CD115+ CD135+ common macrophage/DC precursors and the role of CX3CR1 in their response to inflammation. J. Exp. Med. 206, 595–606 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Landsman, L. et al. CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival. Blood 113, 963–972 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Mack, M. et al. Expression and characterization of the chemokine receptors CCR2 and CCR5 in mice. J. Immunol. 166, 4697–4704 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Kaufmann, A., Salentin, R., Gemsa, D. & Sprenger, H. Increase of CCR1 and CCR5 expression and enhanced functional response to MIP-1α during differentiation of human monocytes to macrophages. J. Leukoc. Biol. 69, 248–252 (2001).

    CAS  PubMed  Google Scholar 

  31. Charo, I. F. & Ransohoff, R. M. The many roles of chemokines and chemokine receptors in inflammation. N. Engl. J. Med. 354, 610–621 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Weber, C. et al. Specialized roles of the chemokine receptors CCR1 and CCR5 in the recruitment of monocytes and TH1-like/CD45RO+ T cells. Blood 97, 1144–1146 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Eis, V. et al. Chemokine receptor CCR1 but not CCR5 mediates leukocyte recruitment and subsequent renal fibrosis after unilateral ureteral obstruction. J. Am. Soc. Nephrol. 15, 337–347 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Broxmeyer, H. E., Cooper, S., Hangoc, G., Gao, J. L. & Murphy, P. M. Dominant myelopoietic effector functions mediated by chemokine receptor CCR1. J. Exp. Med. 189, 1987–1992 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gao, J. L. et al. Impaired host defense, hematopoiesis, granulomatous inflammation and type 1–type 2 cytokine balance in mice lacking CC chemokine receptor 1. J. Exp. Med. 185, 1959–1968 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gerard, C. et al. Targeted disruption of the β-chemokine receptor CCR1 protects against pancreatitis-associated lung injury. J. Clin. Invest. 100, 2022–2027 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Braunersreuther, V. et al. Ccr5 but not Ccr1 deficiency reduces development of diet-induced atherosclerosis in mice. Arterioscler. Thromb. Vasc. Biol. 27, 373–379 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Zernecke, A. et al. Deficiency in CCR5 but not CCR1 protects against neointima formation in atherosclerosis-prone mice: involvement of IL-10. Blood 107, 4240–4243 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Gautier, E. L., Jakubzick, C. & Randolph, G. J. Regulation of the migration and survival of monocyte subsets by chemokine receptors and its relevance to atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 29, 1412–1418 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Weber, C., Zernecke, A. & Libby, P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nature Rev. Immunol. 8, 802–815 (2008).

    Article  CAS  Google Scholar 

  41. Tacke, F. et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J. Clin. Invest. 117, 185–194 (2007). This study showed the differential recruitment patterns and functions of monocyte subsets.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mahad, D. J. et al. Expression of chemokine receptors CCR1 and CCR5 reflects differential activation of mononuclear phagocytes in pattern II and pattern III multiple sclerosis lesions. J. Neuropathol. Exp. Neurol. 63, 262–273 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Trebst, C. et al. CCR1+/CCR5+ mononuclear phagocytes accumulate in the central nervous system of patients with multiple sclerosis. Am. J. Pathol. 159, 1701–1710 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Balashov, K. E., Rottman, J. B., Weiner, H. L. & Hancock, W. W. CCR5+ and CXCR3+ T cells are increased in multiple sclerosis and their ligands MIP-1α and IP-10 are expressed in demyelinating brain lesions. Proc. Natl Acad. Sci. USA 96, 6873–6878 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. McManus, C. et al. MCP-1, MCP-2 and MCP-3 expression in multiple sclerosis lesions: an immunohistochemical and in situ hybridization study. J. Neuroimmunol. 86, 20–29 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. Rottman, J. B. et al. Leukocyte recruitment during onset of experimental allergic encephalomyelitis is CCR1 dependent. Eur. J. Immunol. 30, 2372–2377 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Neote, K., DiGregorio, D., Mak, J. Y., Horuk, R. & Schall, T. J. Molecular cloning, functional expression, and signaling characteristics of a C-C chemokine receptor. Cell 72, 415–425 (1993).

    Article  CAS  PubMed  Google Scholar 

  48. Gao, J. L. et al. Structure and functional expression of the human macrophage inflammatory protein 1α/RANTES receptor. J. Exp. Med. 177, 1421–1427 (1993).

    Article  CAS  PubMed  Google Scholar 

  49. Combadiere, C., Ahuja, S. K., Tiffany, H. L. & Murphy, P. M. Cloning and functional expression of CC CKR5, a human monocyte CC chemokine receptor selective for MIP-1α, MIP-1β, and RANTES. J. Leukoc. Biol. 60, 147–152 (1996).

    Article  CAS  PubMed  Google Scholar 

  50. Raport, C. J., Gosling, J., Schweickart, V. L., Gray, P. W. & Charo, I. F. Molecular cloning and functional characterization of a novel human CC chemokine receptor (CCR5) for RANTES, MIP-1β, and MIP-1α. J. Biol. Chem. 271, 17161–17166 (1996).

    Article  CAS  PubMed  Google Scholar 

  51. Vanbervliet, B. et al. Sequential involvement of CCR2 and CCR6 ligands for immature dendritic cell recruitment: possible role at inflamed epithelial surfaces. Eur. J. Immunol. 32, 231–242 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Le Borgne, M. et al. Dendritic cells rapidly recruited into epithelial tissues via CCR6/CCL20 are responsible for CD8+ T cell crosspriming in vivo. Immunity 24, 191–201 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Ravindran, R., Rusch, L., Itano, A., Jenkins, M. K. & McSorley, S. J. CCR6-dependent recruitment of blood phagocytes is necessary for rapid CD4 T cell responses to local bacterial infection. Proc. Natl Acad. Sci. USA 104, 12075–12080 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Qu, C. et al. Role of CCR8 and other chemokine pathways in the migration of monocyte-derived dendritic cells to lymph nodes. J. Exp. Med. 200, 1231–1241 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bernhagen, J. et al. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nature Med. 13, 587–596 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Ley, K., Laudanna, C., Cybulsky, M. I. & Nourshargh, S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nature Rev. Immunol. 7, 678–689 (2007).

    Article  CAS  Google Scholar 

  57. Tedder, T. F., Steeber, D. A. & Pizcueta, P. L-selectin-deficient mice have impaired leukocyte recruitment into inflammatory sites. J. Exp. Med. 181, 2259–2264 (1995).

    Article  CAS  PubMed  Google Scholar 

  58. Leon, B. & Ardavin, C. Monocyte migration to inflamed skin and lymph nodes is differentially controlled by L-selectin and PSGL-1. Blood 111, 3126–3130 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Galkina, E. & Ley, K. Immune and inflammatory mechanisms of atherosclerosis. Annu. Rev. Immunol. 27, 165–197 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Blankenberg, S., Barbaux, S. & Tiret, L. Adhesion molecules and atherosclerosis. Atherosclerosis 170, 191–203 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Galkina, E. & Ley, K. Vascular adhesion molecules in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 27, 2292–2301 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Rosen, H. & Gordon, S. Monoclonal antibody to the murine type 3 complement receptor inhibits adhesion of myelomonocytic cells in vitro and inflammatory cell recruitment in vivo. J. Exp. Med. 166, 1685–1701 (1987).

    Article  CAS  PubMed  Google Scholar 

  63. Shi, C. et al. Monocyte trafficking to hepatic sites of bacterial infection is chemokine independent and directed by focal intercellular adhesion molecule-1 expression. J. Immunol. 184, 6266–6274 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Henderson, R. B., Hobbs, J. A., Mathies, M. & Hogg, N. Rapid recruitment of inflammatory monocytes is independent of neutrophil migration. Blood 102, 328–335 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Sunderkotter, C. et al. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J. Immunol. 172, 4410–4417 (2004).

    Article  PubMed  Google Scholar 

  66. Varol, C. et al. Monocytes give rise to mucosal, but not splenic, conventional dendritic cells. J. Exp. Med. 204, 171–180 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ginhoux, F. et al. Langerhans cells arise from monocytes in vivo. Nature Immunol. 7, 265–273 (2006).

    Article  CAS  Google Scholar 

  68. Mildner, A. et al. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nature Neurosci. 10, 1544–1553 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Saederup, N. et al. Selective chemokine receptor usage by central nervous system myeloid cells in CCR2–red fluorescent protein knock-in mice. PLoS ONE 5, e13693 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Varol, C. et al. Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity 31, 502–512 (2009). This study demonstrated that lamina propria DC subsets have distinct origins. LY6Chi monocytes give rise to gut CX 3 CR1+ DCs after depletion.

    Article  CAS  PubMed  Google Scholar 

  71. Bogunovic, M. et al. Origin of the lamina propria dendritic cell network. Immunity 31, 513–525 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Merad, M. et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nature Immunol. 3, 1135–1141 (2002). This paper showed that Langerhans cells are maintained by local self-renewal.

    Article  CAS  Google Scholar 

  73. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). This study showed that microglia are derived from primitive progenitors that are distinct from inflammatory monocytes. It suggested that monocyte-mediated replenishment of tissue-resident cell populations following their experimental depletion does not necessarily reflect a natural process that occurs during the development of different tissues or under homeostatic conditions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Geissmann, F. et al. Development of monocytes, macrophages, and dendritic cells. Science 327, 656–661 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Varol, C., Zigmond, E. & Jung, S. Securing the immune tightrope: mononuclear phagocytes in the intestinal lamina propria. Nature Rev. Immunol. 10, 415–426 (2010).

    Article  CAS  Google Scholar 

  76. Niess, J. H. et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254–258 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Schulz, O. et al. Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions. J. Exp. Med. 206, 3101–3114 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Jakubzick, C. et al. Blood monocyte subsets differentially give rise to CD103+ and CD103− pulmonary dendritic cell populations. J. Immunol. 180, 3019–3027 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Ginhoux, F. et al. The origin and development of nonlymphoid tissue CD103+ DCs. J. Exp. Med. 206, 3115–3130 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Landsman, L. & Jung, S. Lung macrophages serve as obligatory intermediate between blood monocytes and alveolar macrophages. J. Immunol. 179, 3488–3494 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Landsman, L., Varol, C. & Jung, S. Distinct differentiation potential of blood monocyte subsets in the lung. J. Immunol. 178, 2000–2007 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Pamer, E. G. Immune responses to Listeria monocytogenes. Nature Rev. Immunol. 4, 812–823 (2004).

    Article  CAS  Google Scholar 

  83. Rosen, H., Gordon, S. & North, R. J. Exacerbation of murine listeriosis by a monoclonal antibody specific for the type 3 complement receptor of myelomonocytic cells. Absence of monocytes at infective foci allows Listeria to multiply in nonphagocytic cells. J. Exp. Med. 170, 27–37 (1989).

    Article  CAS  PubMed  Google Scholar 

  84. Serbina, N. V., Salazar-Mather, T. P., Biron, C. A., Kuziel, W. A. & Pamer, E. G. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19, 59–70 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Copin, R., De Baetselier, P., Carlier, Y., Letesson, J. J. & Muraille, E. MyD88-dependent activation of B220−CD11b+LY-6C+ dendritic cells during Brucella melitensis infection. J. Immunol. 178, 5182–5191 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Serbina, N. V. & Pamer, E. G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nature Immunol. 7, 311–317 (2006). This study identified the function of CCR2 in monocyte egress from the bone marrow.

    Article  CAS  Google Scholar 

  87. Serbina, N. V. et al. Sequential MyD88-independent and -dependent activation of innate immune responses to intracellular bacterial infection. Immunity 19, 891–901 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Jia, T., Leiner, I., Dorothee, G., Brandl, K. & Pamer, E. G. MyD88 and type I interferon receptor-mediated chemokine induction and monocyte recruitment during Listeria monocytogenes infection. J. Immunol. 183, 1271–1278 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Serbina, N. V., Hohl, T. M., Cherny, M. & Pamer, E. G. Selective expansion of the monocytic lineage directed by bacterial infection. J. Immunol. 183, 1900–1910 (2009).

    Article  CAS  PubMed  Google Scholar 

  90. Kang, S. J., Liang, H. E., Reizis, B. & Locksley, R. M. Regulation of hierarchical clustering and activation of innate immune cells by dendritic cells. Immunity 29, 819–833 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Cooper, A. M. Cell-mediated immune responses in tuberculosis. Annu. Rev. Immunol. 27, 393–422 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Scott, H. M. & Flynn, J. L. Mycobacterium tuberculosis in chemokine receptor 2-deficient mice: influence of dose on disease progression. Infect. Immun. 70, 5946–5954 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Peters, W. et al. Chemokine receptor 2 serves an early and essential role in resistance to Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 98, 7958–7963 (2001). This study demonstrated the role of LY6Chi monocytes in M. tuberculosis infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Peters, W. et al. CCR2-dependent trafficking of F4/80dim macrophages and CD11cdim/intermediate dendritic cells is crucial for T cell recruitment to lungs infected with Mycobacterium tuberculosis. J. Immunol. 172, 7647–7653 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Skold, M. & Behar, S. M. Tuberculosis triggers a tissue-dependent program of differentiation and acquisition of effector functions by circulating monocytes. J. Immunol. 181, 6349–6360 (2008).

    Article  PubMed  Google Scholar 

  96. Antonelli, L. R. et al. Intranasal poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population. J. Clin. Invest. 120, 1674–1682 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Robben, P. M., LaRegina, M., Kuziel, W. A. & Sibley, L. D. Recruitment of Gr-1+ monocytes is essential for control of acute toxoplasmosis. J. Exp. Med. 201, 1761–1769 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Dunay, I. R. et al. Gr1+ inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii. Immunity 29, 306–317 (2008). This study showed the role of LY6Chi monocytes in mucosal defence against a protozoal pathogen.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Dunay, I. R., Fuchs, A. & Sibley, L. D. Inflammatory monocytes but not neutrophils are necessary to control infection with Toxoplasma gondii in mice. Infect. Immun. 78, 1564–1570 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Leon, B., Lopez-Bravo, M. & Ardavin, C. Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against Leishmania. Immunity 26, 519–531 (2007). This study identified the role of LY6Chi monocytes in the development of adaptive immunity during protozoal infection.

    Article  CAS  PubMed  Google Scholar 

  101. De Trez, C. et al. iNOS-producing inflammatory dendritic cells constitute the major infected cell type during the chronic Leishmania major infection phase of C57BL/6 resistant mice. PLoS Pathog. 5, e1000494 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Sponaas, A. M. et al. Migrating monocytes recruited to the spleen play an important role in control of blood stage malaria. Blood 114, 5522–5531 (2009).

    Article  CAS  PubMed  Google Scholar 

  103. Bosschaerts, T. et al. Tip-DC development during parasitic infection is regulated by IL-10 and requires CCL2/CCR2, IFN-γ and MyD88 signaling. PLoS Pathog. 6, e1001045 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Guilliams, M. et al. IL-10 dampens TNF/inducible nitric oxide synthase-producing dendritic cell-mediated pathogenicity during parasitic infection. J. Immunol. 182, 1107–1118 (2009).

    Article  CAS  PubMed  Google Scholar 

  105. Traynor, T. R., Kuziel, W. A., Toews, G. B. & Huffnagle, G. B. CCR2 expression determines T1 versus T2 polarization during pulmonary Cryptococcus neoformans infection. J. Immunol. 164, 2021–2027 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Traynor, T. R. et al. Differential roles of CC chemokine ligand 2/monocyte chemotactic protein-1 and CCR2 in the development of T1 immunity. J. Immunol. 168, 4659–4666 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Osterholzer, J. J. et al. Accumulation of CD11b+ lung dendritic cells in response to fungal infection results from the CCR2-mediated recruitment and differentiation of Ly-6Chigh monocytes. J. Immunol. 183, 8044–8053 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Hohl, T. M. & Feldmesser, M. Aspergillus fumigatus: principles of pathogenesis and host defense. Eukaryot. Cell 6, 1953–1963 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Hohl, T. M. et al. Inflammatory monocytes facilitate adaptive CD4 T cell responses during respiratory fungal infection. Cell Host Microbe 6, 470–481 (2009). This study showed that LY6Chi monocytes and monocyte-derived DCs deliver fungal spores from the lung to lymph nodes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Rivera, A. et al. Dectin-1 diversifies Aspergillus fumigatus-specific T cell responses by inhibiting T helper type 1 CD4 T cell differentiation. J. Exp. Med. 208, 369–381 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ersland, K., Wuthrich, M. & Klein, B. S. Dynamic interplay among monocyte-derived, dermal, and resident lymph node dendritic cells during the generation of vaccine immunity to fungi. Cell Host Microbe 7, 474–487 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Salazar-Mather, T. P., Orange, J. S. & Biron, C. A. Early murine cytomegalovirus (MCMV) infection induces liver natural killer (NK) cell inflammation and protection through macrophage inflammatory protein 1α (MIP-1α)-dependent pathways. J. Exp. Med. 187, 1–14 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hokeness-Antonelli, K. L., Crane, M. J., Dragoi, A. M., Chu, W. M. & Salazar-Mather, T. P. IFN-αβ-mediated inflammatory responses and antiviral defense in liver is TLR9-independent but MyD88-dependent during murine cytomegalovirus infection. J. Immunol. 179, 6176–6183 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Crane, M. J., Hokeness-Antonelli, K. L. & Salazar-Mather, T. P. Regulation of inflammatory monocyte/macrophage recruitment from the bone marrow during murine cytomegalovirus infection: role for type I interferons in localized induction of CCR2 ligands. J. Immunol. 183, 2810–2817 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. Barbalat, R., Lau, L., Locksley, R. M. & Barton, G. M. Toll-like receptor 2 on inflammatory monocytes induces type I interferon in response to viral but not bacterial ligands. Nature Immunol. 10, 1200–1207 (2009).

    Article  CAS  Google Scholar 

  116. Lim, J. K. et al. Chemokine receptor Ccr2 is critical for monocyte accumulation and survival in west nile virus encephalitis. J. Immunol. 186, 471–478 (2011).

    Article  CAS  PubMed  Google Scholar 

  117. Dawson, T. C., Beck, M. A., Kuziel, W. A., Henderson, F. & Maeda, N. Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus. Am. J. Pathol. 156, 1951–1959 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Aldridge, J. R. Jr. et al. TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection. Proc. Natl Acad. Sci. USA 106, 5306–5311 (2009). This study showed both the beneficial and detrimental roles of monocyte recruitment during influenza virus infection. It also demonstrated pharmacological manipulation of the process to minimize tissue damage while maintaining microbial clearance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Herold, S. et al. Alveolar epithelial cells direct monocyte transepithelial migration upon influenza virus infection: impact of chemokines and adhesion molecules. J. Immunol. 177, 1817–1824 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. Nakano, H. et al. Blood-derived inflammatory dendritic cells in lymph nodes stimulate acute T helper type 1 immune responses. Nature Immunol. 10, 394–402 (2009).

    Article  CAS  Google Scholar 

  121. Napoli, C. et al. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J. Clin. Invest. 100, 2680–2690 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Saederup, N., Chan, L., Lira, S. A. & Charo, I. F. Fractalkine deficiency markedly reduces macrophage accumulation and atherosclerotic lesion formation in CCR2−/− mice: evidence for independent chemokine functions in atherogenesis. Circulation 117, 1642–1648 (2008).

    Article  CAS  PubMed  Google Scholar 

  123. Lesnik, P., Haskell, C. A. & Charo, I. F. Decreased atherosclerosis in CX3CR1−/− mice reveals a role for fractalkine in atherogenesis. J. Clin. Invest. 111, 333–340 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Swirski, F. K. et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J. Clin. Invest. 117, 195–205 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Combadiere, C. et al. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6Chi and Ly6Clo monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation 117, 1649–1657 (2008).

    Article  CAS  PubMed  Google Scholar 

  126. Swirski, F. K., Weissleder, R. & Pittet, M. J. Heterogeneous in vivo behavior of monocyte subsets in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 29, 1424–1432 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Tsujioka, H. et al. Impact of heterogeneity of human peripheral blood monocyte subsets on myocardial salvage in patients with primary acute myocardial infarction. J. Am. Coll. Cardiol. 54, 130–138 (2009).

    Article  PubMed  Google Scholar 

  128. Nahrendorf, M. et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J. Exp. Med. 204, 3037–3047 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Nahrendorf, M., Pittet, M. J. & Swirski, F. K. Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation 121, 2437–2445 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Swirski, F. K. et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325, 612–616 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Martin, C. et al. Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity 19, 583–593 (2003).

    Article  CAS  PubMed  Google Scholar 

  132. Eash, K. J., Greenbaum, A. M., Gopalan, P. K. & Link, D. C. CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow. J. Clin. Invest. 120, 2423–2431 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Wang, Y. et al. CCR2 and CXCR4 regulate peripheral blood monocyte pharmacodynamics and link to efficacy in experimental autoimmune encephalomyelitis. J. Inflamm. 6, 32 (2009).

    Article  CAS  Google Scholar 

  134. Shi, C. et al. Bone marrow mesenchymal stem and progenitor cells induce monocyte emigration in response to circulating Toll-like receptor ligands. Immunity 34, 590–601 (2011). This paper demonstrated that bone marrow stromal cells induce monocyte emigration by producing CCL2 in response to circulating TLR ligands, providing a mechanism for peripheral infections to promote monocytosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Mendez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Omatsu, Y. et al. The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. Immunity 33, 387–399 (2010).

    Article  CAS  PubMed  Google Scholar 

  137. Clarke, T. B. et al. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nature Med. 16, 228–231 (2010).

    Article  CAS  PubMed  Google Scholar 

  138. Randolph, G. J., Inaba, K., Robbiani, D. F., Steinman, R. M. & Muller, W. A. Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo. Immunity 11, 753–761 (1999).

    Article  CAS  PubMed  Google Scholar 

  139. Cheong, C. et al. Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209+ dendritic cells for immune T cell areas. Cell 143, 416–429 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Strauss-Ayali, D., Conrad, S. M. & Mosser, D. M. Monocyte subpopulations and their differentiation patterns during infection. J. Leukoc. Biol. 82, 244–252 (2007).

    Article  CAS  PubMed  Google Scholar 

  141. Liao, F., Ali, J., Greene, T. & Muller, W. A. Soluble domain 1 of platelet-endothelial cell adhesion molecule (PECAM) is sufficient to block transendothelial migration in vitro and in vivo. J. Exp. Med. 185, 1349–1357 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Liao, F. et al. Migration of monocytes across endothelium and passage through extracellular matrix involve separate molecular domains of PECAM-1. J. Exp. Med. 182, 1337–1343 (1995).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by US National Institutes of Health grants 5R37AI039031 and 5P01CA023766-31 (to E.G.P.).

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  1. Department of Medicine, Infectious Diseases Service, Immunology Program, Sloan-Kettering Institute, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, 10065, New York, USA

    Chao Shi & Eric G. Pamer

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Glossary

Polyinosinic–polycytidylic acid

(polyI:C). A substance that is used as a mimic of viral double-stranded RNA.

CXCL12-abundant reticular cells

(CAR cells). A type of stromal cell found in the bone marrow that expresses high levels of CXC-chemokine ligand 12. CAR cells can function as adipo-osteogenic progenitors, which are required for the proliferation of haematopoietic stem cells (HSCs), B cells and erythroid progenitor cells, and for maintaining HSCs in an undifferentiated state.

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Shi, C., Pamer, E. Monocyte recruitment during infection and inflammation. Nat Rev Immunol 11, 762–774 (2011). https://doi.org/10.1038/nri3070

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