Key Points
-
The study of animals with global knockouts of genes encoding various cytokines, cytokine receptors and transcription factors has been crucial for understanding the development and homeostatic requirements of monocytes, macrophages and dendritic cells.
-
Depletion models — such as those using clodronate liposomes or animals that express the diphtheria toxin receptor under the control of a myeloid cell-specific gene promoter — have allowed for inducible and more precise elimination of various mononuclear phagocyte populations.
-
Crossing mice that express Cre recombinase under the control of myeloid cell-specific promoters with animals that have 'floxed' genes has been used to achieve cell-type specific deletion of a particular gene.
-
Identifying myeloid promoters with improved specificity for particular mononuclear phagocyte populations will be crucial in order to more precisely dissect the different functions of particular populations.
-
Molecular profiling of specific mononuclear phagocyte populations will help to identify more specific promoters and candidate genes to analyse functionally.
-
The development of new humanized mouse models holds the promise of accelerating the study of the human mononuclear phagocyte compartment.
Abstract
The mononuclear phagocyte system (MPS) comprises monocytes, macrophages and dendritic cells. Tissue phagocytes share several cell surface markers, phagocytic capability and myeloid classification; however, the factors that regulate the differentiation, homeostasis and function of macrophages and dendritic cells remain largely unknown. The purpose of this manuscript is to review the tools that are currently available and those that are under development to study the origin and function of mononuclear phagocytes.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 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
References
Fogg, D. K. et al. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311, 83–87 (2006). This study was the first to characterize a dedicated macrophage and DC progenitor.
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).
Onai, N. et al. Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow. Nature Immunol. 8, 1207–1216 (2007).
Naik, S. H. et al. Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo. Nature Immunol. 8, 1217–1226 (2007). References 3 and 4 were the first characterizations of a DC-restricted progenitor (termed the CDP) that gives rise to classical DCs and plasmacytoid DCs.
Liu, K. et al. In vivo analysis of dendritic cell development and homeostasis. Science 324, 392–397 (2009). This was the first characterization of pre-DCs and how they are related to MDPs and CDPs.
Reizis, B., Bunin, A., Ghosh, H. S., Lewis, K. L. & Sisirak, V. Plasmacytoid dendritic cells: recent progress and open questions. Annu. Rev. Immunol. 29, 163–183 (2011).
Ingersoll, M. A., Platt, A. M., Potteaux, S. & Randolph, G. J. Monocyte trafficking in acute and chronic inflammation. Trends Immunol. 10 Jun 2011 (doi:10.1016/j.it.2011.05.001).
Chow, A. et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J. Exp. Med. 208, 261–271 (2011).
Iannacone, M. et al. Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus. Nature 465, 1079–1083 (2010).
Hildner, K. et al. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322, 1097–1100 (2008).
Ginhoux, F. et al. The origin and development of nonlymphoid tissue CD103+ DCs. J. Exp. Med. 206, 3115–3130 (2009).
Bogunovic, M. et al. Origin of the lamina propria dendritic cell network. Immunity 31, 513–525 (2009).
Edelson, B. T. et al. Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8α+ conventional dendritic cells. J. Exp. Med. 207, 823–836 (2010). This was the first report that BATF3 is a crucial transcription factor for both CD8α+ and CD103+ DCs, a basis for the future classification of DC subsets.
Hashimoto, D., Miller, J. & Merad, M. Characterizing DC and macrophage heterogeneity in vivo. Immunity 35, 323–335 (2011).
Chitu, V. & Stanley, E. R. Colony-stimulating factor-1 in immunity and inflammation. Curr. Opin. Immunol. 18, 39–48 (2006).
Merad, M. & Manz, M. G. Dendritic cell homeostasis. Blood 113, 3418–3427 (2009).
van Rooijen, N. & van Kesteren-Hendrikx, E. Clodronate liposomes: perspectives in research and therapeutics. J. Liposome Res. 12, 81–94 (2002).
Sudo, T. et al. Functional hierarchy of c-kit and c-fms in intramarrow production of CFU-M. Oncogene 11, 2469–2476 (1995).
MacDonald, K. P. et al. An antibody against the colony-stimulating factor 1 receptor depletes the resident subset of monocytes and tissue- and tumor-associated macrophages but does not inhibit inflammation. Blood 116, 3955–3963 (2010).
Hashimoto, D. et al. Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation. J. Exp. Med. 208, 1069–1082 (2011).
Irvine, K. M. et al. A CSF-1 receptor kinase inhibitor targets effector functions and inhibits pro-inflammatory cytokine production from murine macrophage populations. FASEB J. 20, 1921–1923 (2006).
Ohno, H. et al. A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol. Cancer Ther. 5, 2634–2643 (2006).
Conway, J. G. et al. Inhibition of colony-stimulating-factor-1 signaling in vivo with the orally bioavailable cFMS kinase inhibitor GW2580. Proc. Natl Acad. Sci. USA 102, 16078–16083 (2005).
Burns, C. J. & Wilks, A. F. c-FMS inhibitors: a patent review. Expert Opin. Ther. Pat. 21, 147–165 (2011).
Zhang, Y. et al. APCs in the liver and spleen recruit activated allogeneic CD8+ T cells to elicit hepatic graft-versus-host disease. J. Immunol. 169, 7111–7118 (2002).
Wang, H. et al. Activated macrophages are essential in a murine model for T cell-mediated chronic psoriasiform skin inflammation. J. Clin. Invest. 116, 2105–2114 (2006).
Junt, T. et al. Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells. Nature 450, 110–114 (2007).
McGill, J., Van Rooijen, N. & Legge, K. L. Protective influenza-specific CD8 T cell responses require interactions with dendritic cells in the lungs. J. Exp. Med. 205, 1635–1646 (2008).
Mircescu, M. M., Lipuma, L., van Rooijen, N., Pamer, E. G. & Hohl, T. M. Essential role for neutrophils but not alveolar macrophages at early time points following Aspergillus fumigatus infection. J. Infect. Dis. 200, 647–656 (2009).
Traeger, T. et al. Selective depletion of alveolar macrophages in polymicrobial sepsis increases lung injury, bacterial load and mortality but does not affect cytokine release. Respiration 77, 203–213 (2009).
Qualls, J. E., Kaplan, A. M., van Rooijen, N. & Cohen, D. A. Suppression of experimental colitis by intestinal mononuclear phagocytes. J. Leukoc. Biol. 80, 802–815 (2006).
Bennett, C. L. & Clausen, B. E. DC ablation in mice: promises, pitfalls, and challenges. Trends Immunol. 28, 525–531 (2007).
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).
Stoneman, V. et al. Monocyte/macrophage suppression in CD11b diphtheria toxin receptor transgenic mice differentially affects atherogenesis and established plaques. Circ. Res. 100, 884–893 (2007).
Cailhier, J. F. et al. Resident pleural macrophages are key orchestrators of neutrophil recruitment in pleural inflammation. Am. J. Respir. Crit. Care Med. 173, 540–547 (2006).
Cailhier, J. F. et al. Conditional macrophage ablation demonstrates that resident macrophages initiate acute peritoneal inflammation. J. Immunol. 174, 2336–2342 (2005).
Saxena, V., Ondr, J. K., Magnusen, A. F., Munn, D. H. & Katz, J. D. The countervailing actions of myeloid and plasmacytoid dendritic cells control autoimmune diabetes in the nonobese diabetic mouse. J. Immunol. 179, 5041–5053 (2007).
Devey, L. et al. Tissue-resident macrophages protect the liver from ischemia reperfusion injury via a heme oxygenase-1-dependent mechanism. Mol. Ther. 17, 65–72 (2009).
Fallowfield, J. A. et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J. Immunol. 178, 5288–5295 (2007).
Duffield, J. S. et al. Conditional ablation of macrophages halts progression of crescentic glomerulonephritis. Am. J. Pathol. 167, 1207–1219 (2005).
Henderson, N. C. et al. Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. Am. J. Pathol. 172, 288–298 (2008).
Lin, S. L., Castano, A. P., Nowlin, B. T., Lupher, M. L. & Duffield, J. S. Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations. J. Immunol. 183, 6733–6743 (2009).
Machida, Y. et al. Renal fibrosis in murine obstructive nephropathy is attenuated by depletion of monocyte lineage, not dendritic cells. J. Pharmacol. Sci. 114, 464–473 (2010).
Qi, F. et al. Depletion of cells of monocyte lineage prevents loss of renal microvasculature in murine kidney transplantation. Transplantation 86, 1267–1274 (2008).
Chua, A. C. L., Hodson, L. J., Moldenhauer, L. M., Robertson, S. A. & Ingman, W. V. Dual roles for macrophages in ovarian cycle-associated development and remodelling of the mammary gland epithelium. Development 137, 4229–4238 (2010).
Jasper, M. J. et al. Macrophage-derived LIF and IL1B regulate α(1,2)fucosyltransferase 2 (Fut2) expression in mouse uterine epithelial cells during early pregnancy. Biol. Reprod. 84, 179–188 (2011).
Withers, S. B. et al. Macrophage activation is responsible for loss of anticontractile function in inflamed perivascular fat. Arterioscler. Thromb. Vasc. Biol. 31, 908–913 (2011).
Burnett, S. H. et al. Conditional macrophage ablation in transgenic mice expressing a Fas-based suicide gene. J. Leukoc. Biol. 75, 612–623 (2004).
Burnett, S. H. et al. Development of peritoneal adhesions in macrophage depleted mice. J. Surg. Res. 131, 296–301 (2006).
Miyake, Y. et al. Critical role of macrophages in the marginal zone in the suppression of immune responses to apoptotic cell-associated antigens. J. Clin. Invest. 117, 2268–2278 (2007).
Asano, K. et al. CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens. Immunity 34, 85–95 (2011).
Jung, S. et al. In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. Immunity 17, 211–220 (2002).
Bar-On, L. & Jung, S. Defining dendritic cells by conditional and constitutive cell ablation. Immunol. Rev. 234, 76–89 (2010).
Sapoznikov, A. et al. Organ-dependent in vivo priming of naive CD4+, but not CD8+, T cells by plasmacytoid dendritic cells. J. Exp. Med. 204, 1923–1933 (2007).
Plaks, V. et al. Uterine DCs are crucial for decidua formation during embryo implantation in mice. J. Clin. Invest. 118, 3954–3965 (2008).
Lucas, M., Schachterle, W., Oberle, K., Aichele, P. & Diefenbach, A. Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 26, 503–517 (2007).
Hochweller, K., Striegler, J., Hammerling, G. J. & Garbi, N. A novel CD11c.DTR transgenic mouse for depletion of dendritic cells reveals their requirement for homeostatic proliferation of natural killer cells. Eur. J. Immunol. 38, 2776–2783 (2008).
Kissenpfennig, A. et al. Dynamics and function of Langerhans cells in vivo: dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans cells. Immunity 22, 643–654 (2005).
Bennett, C. L. et al. Inducible ablation of mouse Langerhans cells diminishes but fails to abrogate contact hypersensitivity. J. Cell Biol. 169, 569–576 (2005).
Nagao, K. et al. Murine epidermal Langerhans cells and langerin-expressing dermal dendritic cells are unrelated and exhibit distinct functions. Proc. Natl Acad. Sci. USA 106, 3312–3317 (2009).
Ginhoux, F. et al. Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state. J. Exp. Med. 204, 3133–3146 (2007).
Bursch, L. S. et al. Identification of a novel population of Langerin+ dendritic cells. J. Exp. Med. 204, 3147–3156 (2007).
Farrand, K. J. et al. Langerin+ CD8α+ dendritic cells are critical for cross-priming and IL-12 production in response to systemic antigens. J. Immunol. 183, 7732–7742 (2009).
GeurtsvanKessel, C. H. et al. Clearance of influenza virus from the lung depends on migratory langerin+CD11b− but not plasmacytoid dendritic cells. J. Exp. Med. 205, 1621–1634 (2008).
Birnberg, T. et al. Lack of conventional dendritic cells is compatible with normal development and T cell homeostasis, but causes myeloid proliferative syndrome. Immunity 29, 986–997 (2008).
Ohnmacht, C. et al. Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J. Exp. Med. 206, 549–559 (2009).
Teichmann, L. L. et al. Dendritic cells in lupus are not required for activation of T and B cells but promote their expansion, resulting in tissue damage. Immunity 33, 967–978 (2010).
Christopher, M. J., Rao, M., Liu, F., Woloszynek, J. R. & Link, D. C. Expression of the G-CSF receptor in monocytic cells is sufficient to mediate hematopoietic progenitor mobilization by G-CSF in mice. J. Exp. Med. 208, 251–260 (2011).
Kuipers, H., Schnorfeil, F. M., Fehling, H. J., Bartels, H. & Brocker, T. Dicer-dependent microRNAs control maturation, function, and maintenance of Langerhans cells in vivo. J. Immunol. 185, 400–409 (2010).
Buch, T. et al. A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nature Methods 2, 419–426 (2005).
Brockschnieder, D., Pechmann, Y., Sonnenberg-Riethmacher, E. & Riethmacher, D. An improved mouse line for Cre-induced cell ablation due to diphtheria toxin A, expressed from the Rosa26 locus. Genesis 44, 322–327 (2006).
Voehringer, D., Liang, H. E. & Locksley, R. M. Homeostasis and effector function of lymphopenia-induced “memory-like” T cells in constitutively T cell-depleted mice. J. Immunol. 180, 4742–4753 (2008).
Faust, N., Varas, F., Kelly, L. M., Heck, S. & Graf, T. Insertion of enhanced green fluorescent protein into the lysozyme gene creates mice with green fluorescent granulocytes and macrophages. Blood 96, 719–726 (2000).
Sasmono, R. T. et al. A macrophage colony-stimulating factor receptor–green fluorescent protein transgene is expressed throughout the mononuclear phagocyte system of the mouse. Blood 101, 1155–1163 (2003).
Jung, S. et al. Analysis of fractalkine receptor CX3CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell. Biol. 20, 4106–4114 (2000).
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).
Boes, M. et al. T-cell engagement of dendritic cells rapidly rearranges MHC class II transport. Nature 418, 983–988 (2002).
Lindquist, R. L. et al. Visualizing dendritic cell networks in vivo. Nature Immunol. 5, 1243–1250 (2004).
Hume, D. A. Applications of myeloid-specific promoters in transgenic mice support in vivo imaging and functional genomics but do not support the concept of distinct macrophage and dendritic cell lineages or roles in immunity. J. Leukoc. Biol. 89, 525–538 (2011).
MacDonald, K. P. et al. The colony-stimulating factor 1 receptor is expressed on dendritic cells during differentiation and regulates their expansion. J. Immunol. 175, 1399–1405 (2005).
Sasmono, R. T. et al. Mouse neutrophilic granulocytes express mRNA encoding the macrophage colony-stimulating factor receptor (CSF-1R) as well as many other macrophage-specific transcripts and can transdifferentiate into macrophages in vitro in response to CSF-1. J. Leukoc. Biol. 82, 111–123 (2007).
Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). This report showed that adult microglia are derived from primitive macrophages that arise prior to embryonic day 8.
Helft, J., Ginhoux, F., Bogunovic, M. & Merad, M. Origin and functional heterogeneity of non-lymphoid tissue dendritic cells in mice. Immunol. Rev. 234, 55–75 (2010).
Mempel, T. R., Scimone, M. L., Mora, J. R. & von Andrian, U. H. In vivo imaging of leukocyte trafficking in blood vessels and tissues. Curr. Opin. Immunol. 16, 406–417 (2004).
Samokhvalov, I. M., Samokhvalova, N. I. & Nishikawa, S. Cell tracing shows the contribution of the yolk sac to adult haematopoiesis. Nature 446, 1056–1061 (2007). This was the first published technique for the fate mapping of yolk sac-derived haematopoietic cells in adult mice.
Brown, B. D., Venneri, M. A., Zingale, A., Sergi Sergi, L. & Naldini, L. Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer. Nature Med. 12, 585–591 (2006). This was the first demonstration that microRNAs can be used for de-targeting transgenes and vectors.
Brown, B. D. & Naldini, L. Exploiting and antagonizing microRNA regulation for therapeutic and experimental applications. Nature Rev. Genet. 10, 578–585 (2009).
Brown, B. D. et al. Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state. Nature Biotech. 25, 1457–1467 (2007).
Gentner, B. et al. Identification of hematopoietic stem cell-specific miRNAs enables gene therapy of globoid cell leukodystrophy. Sci. Transl. Med. 2, 58ra84 (2010).
Luber, C. A. et al. Quantitative proteomics reveals subset-specific viral recognition in dendritic cells. Immunity 32, 279–289 (2010).
Paul, P. et al. A genome-wide multidimensional RNAi screen reveals pathways controlling MHC class II antigen presentation. Cell 145, 268–283 (2011).
Amit, I. et al. Unbiased reconstruction of a mammalian transcriptional network mediating pathogen responses. Science 326, 257–263 (2009).
Bivona, T. G. et al. FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR. Nature 471, 523–526 (2011).
Root, D. E., Hacohen, N., Hahn, W. C., Lander, E. S. & Sabatini, D. M. Genome-scale loss-of-function screening with a lentiviral RNAi library. Nature Methods 3, 715–719 (2006).
Premsrirut, P. K. et al. A rapid and scalable system for studying gene function in mice using conditional RNA interference. Cell 145, 145–158 (2011).
Mestas, J. & Hughes, C. C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).
Willinger, T., Rongvaux, A., Strowig, T., Manz, M. G. & Flavell, R. A. Improving human hemato-lymphoid-system mice by cytokine knock-in gene replacement. Trends Immunol. 32, 321–327 (2011).
Rathinam, C. et al. Efficient differentiation and function of human macrophages in humanized CSF-1 mice. Blood 118, 3119–3128 (2011). This paper demonstrated remarkable improvement in engraftment of human myeloid cells when human CSF1 was knocked into Rag2−/−Il2rg−/− recipient mice.
Strowig, T. et al. Transgenic expression of human signal regulatory protein α in Rag2−/−γc−/− mice improves engraftment of human hematopoietic cells in humanized mice. Proc. Natl Acad. Sci. USA 108, 13218–13223 (2011). This paper demonstrated remarkable improvement in engraftment of human haematopoietic cells when human SIRPA was genetically engineered into Rag2−/−Il2rg−/− recipient mice.
Lugo-Villarino, G. et al. Identification of dendritic antigen-presenting cells in the zebrafish. Proc. Natl Acad. Sci. USA 107, 15850–15855 (2010). This was the first report to characterize a DC population in zebrafish.
White, R. M. et al. Transparent adult zebrafish as a tool for in vivo transplantation analysis. Cell Stem Cell 2, 183–189 (2008).
Wittamer, V., Bertrand, J. Y., Gutschow, P. W. & Traver, D. Characterization of the mononuclear phagocyte system in zebrafish. Blood 117, 7126–7135 (2011).
Jenkins, S. J. et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332, 1284–1288 (2011). This was the first publication to show that, in the context of nematode challenge, macrophages at the site of infection are derived from local populations, rather than from recruited blood precursors.
Merad, M. et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nature Immunol. 3, 1135–1141 (2002).
Li, J., Chen, K., Zhu, L. & Pollard, J. W. Conditional deletion of the colony stimulating factor-1 receptor (c-fms proto-oncogene) in mice. Genesis 44, 328–335 (2006).
Varol, C. et al. Monocytes give rise to mucosal, but not splenic, conventional dendritic cells. J. Exp. Med. 204, 171–180 (2007).
Pollard, J. W. Trophic macrophages in development and disease. Nature Rev. Immunol. 9, 259–270 (2009).
Ghosn, E. E. et al. Two physically, functionally, and developmentally distinct peritoneal macrophage subsets. Proc. Natl Acad. Sci. USA 107, 2568–2573 (2010).
Dorner, B. G. et al. Selective expression of the chemokine receptor XCR1 on cross-presenting dendritic cells determines cooperation with CD8+ T cells. Immunity 31, 823–833 (2009).
Sunderkotter, C. et al. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J. Immunol. 172, 4410–4417 (2004).
Engel, D. R. et al. CCR2 mediates homeostatic and inflammatory release of Gr1high monocytes from the bone marrow, but is dispensable for bladder infiltration in bacterial urinary tract infection. J. Immunol. 181, 5579–5586 (2008).
Kolaczkowska, E. et al. Resident peritoneal leukocytes are important sources of MMP-9 during zymosan peritonitis: superior contribution of macrophages over mast cells. Immunol. Lett. 113, 99–106 (2007).
Leendertse, M. et al. Peritoneal macrophages are important for the early containment of Enterococcus faecium peritonitis in mice. Innate Immun. 15, 3–12 (2009).
van Rooijen, N., Kors, N. & Kraal, G. Macrophage subset repopulation in the spleen: differential kinetics after liposome-mediated elimination. J. Leukoc. Biol. 45, 97–104 (1989).
Nikolic, T., Geutskens, S. B., van Rooijen, N., Drexhage, H. A. & Leenen, P. J. Dendritic cells and macrophages are essential for the retention of lymphocytes in (peri)-insulitis of the nonobese diabetic mouse: a phagocyte depletion study. Lab. Invest. 85, 487–501 (2005).
Probst, H. C. et al. Histological analysis of CD11c-DTR/GFP mice after in vivo depletion of dendritic cells. Clin. Exp. Immunol. 141, 398–404 (2005).
Hickman-Davis, J. M., Michalek, S. M., Gibbs-Erwin, J. & Lindsey, J. R. Depletion of alveolar macrophages exacerbates respiratory mycoplasmosis in mycoplasma-resistant C57BL mice but not mycoplasma-susceptible C3H mice. Infect. Immun. 65, 2278–2282 (1997).
Leemans, J. C. et al. Depletion of alveolar macrophages exerts protective effects in pulmonary tuberculosis in mice. J. Immunol. 166, 4604–4611 (2001).
Zhang-Hoover, J., Sutton, A., van Rooijen, N. & Stein-Streilein, J. A critical role for alveolar macrophages in elicitation of pulmonary immune fibrosis. Immunology 101, 501–511 (2000).
Bem, R. A. et al. Depletion of resident alveolar macrophages does not prevent Fas-mediated lung injury in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 295, L314–L325 (2008).
Landsman, L., Varol, C. & Jung, S. Distinct differentiation potential of blood monocyte subsets in the lung. J. Immunol. 178, 2000–2007 (2007).
Sitia, G. et al. Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis. PLoS Pathog. 7, e1002061 (2011).
Zhao, A. et al. Th2 cytokine-induced alterations in intestinal smooth muscle function depend on alternatively activated macrophages. Gastroenterology 135, 217–225 (2008).
Carmichael, M. D. et al. Role of brain macrophages on IL-1β and fatigue following eccentric exercise-induced muscle damage. Brain Behav. Immun. 24, 564–568 (2010).
Steel, C. D. et al. Distinct macrophage subpopulations regulate viral encephalitis but not viral clearance in the CNS. J. Neuroimmunol. 226, 81–92 (2010).
Tang, H. et al. The T helper type 2 response to cysteine proteases requires dendritic cell–basophil cooperation via ROS-mediated signaling. Nature Immunol. 11, 608–617 (2010).
King, I. L., Kroenke, M. A. & Segal, B. M. GM-CSF-dependent, CD103+ dermal dendritic cells play a critical role in Th effector cell differentiation after subcutaneous immunization. J. Exp. Med. 207, 953–961 (2010).
van Rijt, L. S. et al. In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J. Exp. Med. 201, 981–991 (2005).
Plitas, G. et al. Dendritic cells are required for effective cross-presentation in the murine liver. Hepatology 47, 1343–1351 (2008).
Vallon-Eberhard, A., Landsman, L., Yogev, N., Verrier, B. & Jung, S. Transepithelial pathogen uptake into the small intestinal lamina propria. J. Immunol. 176, 2465–2469 (2006).
Kurimoto, I., van Rooijen, N., Dijkstra, C. D. & Streilein, J. W. Role of phagocytic macrophages in induction of contact hypersensitivity and tolerance by hapten applied to normal and ultraviolet B-irradiated skin. Immunology 83, 281–287 (1994).
Acknowledgements
A.C. is funded by a fellowship from the US National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (5F30HL099028-02). B.D.B. is supported by an NIH Pathfinder Award (DP2DK083052-01 and 1R56AI081741-01A1) and funding from the Juvenile Diabetes Research Foundation (17-2010-770). M.M. is supported by NIH grants CA112100, HL086899 and AI080884.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Glossary
- Monocytes
-
Monocytes are mononuclear phagocytes that circulate in the blood. Monocytes are thought to differentiate into macrophages and some dendritic cells in peripheral tissues. They consist of two subsets: classical monocytes and non-classical monocytes.
- Macrophages
-
Macrophages are tissue-resident phagocytes that specialize in the capture and clearance of damaged cells. Macrophages also capture and clear microorganisms and secrete pro-inflammatory molecules in response to microbial infection, and thus have a crucial role in host defence.
- Dendritic cells
-
(DCs). DCs are tissue-resident phagocytes that specialize in the presentation of antigens to T cells to promote immunity to foreign antigens and tolerance to self antigens.
- Classical monocytes
-
(Also known as inflammatory monocytes). This subset of monocytes is important in innate immune protection against infectious pathogens. During infectious challenge, these cells produce pro-inflammatory cytokines and can give rise to TNF- and iNOS-producing (TIP) dendritic cells, which contribute to the development of adaptive immune responses. In mice, these monocytes are characterized by high-level expression of LY6C, CCR2 and L-selectin (CD62L). In humans, classical monocytes are CD14hiCD16−.
- Non-classical monocytes
-
This subset of monocytes patrols the blood circulation and has been shown to promote tissue healing. There is evidence that these cells are derived from classical monocytes and can give rise to tissue-resident macrophages. In mice, these cells are characterized by low-level expression of LY6C and high-level expression of CX3CR1, LFA1 and CD43. In humans, non-classical monocytes are CD14−CD16+ or CD14lowCD16+.
- Graft-versus-host disease
-
(GVHD). Tissue damage in a recipient of allogeneic tissue (usually a bone-marrow transplant) that results from the activity of donor cytotoxic T lymphocytes that recognize the tissues of the recipient as foreign. GVHD varies markedly in extent, but it can be life threatening in severe cases. Damage to the liver, skin and gut mucosa are common clinical manifestations.
- Langerhans cells
-
Dendritic cells that inhabit the epidermis. They are best distinguished by their high-level expression of the C-type lectin receptor langerin and its associated Birbeck granules. In contrast to other dendritic cells, Langerhans cells self-renew locally and are not depleted by high doses of X-ray irradiation.
- Cre recombinase
-
Cre is a site-specific recombinase that recognizes and binds specific DNA sequences known as loxP sites. Two loxP sites recombine in the presence of Cre, enabling excision of the intervening DNA sequence.
- Dicer
-
Dicer is an endoribonuclease that cleaves double-stranded RNA and is important for processing pre-microRNAs.
Rights and permissions
About this article
Cite this article
Chow, A., Brown, B. & Merad, M. Studying the mononuclear phagocyte system in the molecular age. Nat Rev Immunol 11, 788–798 (2011). https://doi.org/10.1038/nri3087
Published:
Issue Date:
DOI: https://doi.org/10.1038/nri3087
This article is cited by
-
Flash nanoprecipitation allows easy fabrication of pH-responsive acetalated dextran nanoparticles for intracellular release of payloads
Discover Nano (2024)
-
Repopulating Kupffer cells originate directly from hematopoietic stem cells
Stem Cell Research & Therapy (2023)
-
Tenofovir-tethered gold nanoparticles as a novel multifunctional long-acting anti-HIV therapy to overcome deficient drug delivery-: an in vivo proof of concept
Journal of Nanobiotechnology (2023)
-
Passive, active and endogenous organ-targeted lipid and polymer nanoparticles for delivery of genetic drugs
Nature Reviews Materials (2023)
-
Mechanistic insights of soluble uric acid-induced insulin resistance: Insulin signaling and beyond
Reviews in Endocrine and Metabolic Disorders (2023)
