Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia

Abstract

The differentiation of bone marrow–derived progenitor cells into monocytes, tissue macrophages and some dendritic cell (DC) subtypes requires the growth factor CSF1 and its receptor, CSF1R. Langerhans cells (LCs) and microglia develop from embryonic myeloid precursor cells that populate the epidermis and central nervous system (CNS) before birth. Notably, LCs and microglia are present in CSF1-deficient mice but absent from CSF1R-deficient mice. Here we investigated whether an alternative CSF1R ligand, interleukin 34 (IL-34), is responsible for this discrepancy. Through the use of IL-34-deficient (Il34LacZ/LacZ) reporter mice, we found that keratinocytes and neurons were the main sources of IL-34. Il34LacZ/LacZ mice selectively lacked LCs and microglia and responded poorly to skin antigens and viral infection of the CNS. Thus, IL-34 specifically directs the differentiation of myeloid cells in the skin epidermis and CNS.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Tissue specific expression of IL-34.
Figure 2: IL-34 deficiency leads to the absence of LCs.
Figure 3: IL-34 deficiency leads to diminished DNFB-mediated CHS.
Figure 4: Impaired microglial development in IL-34-deficient mice.
Figure 5: IL-34-deficient mice are more susceptible to infection after intracranial inoculation with attenuated WNV.
Figure 6: IL-34 deficiency does not affect the development of myeloid cells in the liver but partially affects the frequency of CD11b+ DCs in the lungs.
Figure 7: IL-34 is required for the development of microglia and LCs in neonatal mice but is dispensable for recolonization of LCs in adult mice after exposure to ultraviolet light.

Similar content being viewed by others

References

  1. Gordon, S. & Mantovani, A. Diversity and plasticity of mononuclear phagocytes. Eur. J. Immunol. 41, 2470–2472 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Liu, K. & Nussenzweig, M.C. Origin and development of dendritic cells. Immunol. Rev. 234, 45–54 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. Merad, M. & Manz, M.G. Dendritic cell homeostasis. Blood 113, 3418–3427 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Shortman, K. & Naik, S.H. Steady-state and inflammatory dendritic-cell development. Nat. Rev. Immunol. 7, 19–30 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Chitu, V. & Stanley, E.R. Colony-stimulating factor-1 in immunity and inflammation. Curr. Opin. Immunol. 18, 39–48 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Hamilton, J.A. Colony-stimulating factors in inflammation and autoimmunity. Nat. Rev. Immunol. 8, 533–544 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Teitelbaum, S.L. & Ross, F.P. Genetic regulation of osteoclast development and function. Nat. Rev. Genet. 4, 638–649 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Choi, J.H. et al. Flt3 signaling-dependent dendritic cells protect against atherosclerosis. Immunity 35, 819–831 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Cecchini, M.G. et al. Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse. Development 120, 1357–1372 (1994).

    CAS  PubMed  Google Scholar 

  11. Yoshida, H. et al. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345, 442–444 (1990).

    Article  CAS  PubMed  Google Scholar 

  12. Dai, X.M. et al. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood 99, 111–120 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Ransohoff, R.M. & Cardona, A.E. The myeloid cells of the central nervous system parenchyma. Nature 468, 253–262 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Witmer-Pack, M.D. et al. Identification of macrophages and dendritic cells in the osteopetrotic (op/op) mouse. J. Cell Sci. 104, 1021–1029 (1993).

    PubMed  Google Scholar 

  15. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lin, H. et al. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science 320, 807–811 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Ma, X. et al. Structural basis for the dual recognition of helical cytokines IL-34 and CSF-1 by CSF-1R. Structure 20, 676–687 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Wei, S. et al. Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells. J. Leukoc. Biol. 88, 495–505 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chihara, T. et al. IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation. Cell Death Differ. 17, 1917–1927 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Chorro, L. et al. Langerhans cell (LC) proliferation mediates neonatal development, homeostasis, and inflammation-associated expansion of the epidermal LC network. J. Exp. Med. 206, 3089–3100 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Merad, M., Ginhoux, F. & Collin, M. Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. Nat. Rev. Immunol. 8, 935–947 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Ginhoux, F. & Merad, M. Ontogeny and homeostasis of Langerhans cells. Immunol. Cell Biol. 88, 387–392 (2010).

    Article  PubMed  Google Scholar 

  24. Valladeau, J. et al. Identification of mouse langerin/CD207 in Langerhans cells and some dendritic cells of lymphoid tissues. J. Immunol. 168, 782–792 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Takahara, K. et al. Identification and expression of mouse Langerin (CD207) in dendritic cells. Int. Immunol. 14, 433–444 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Poulin, L.F. et al. The dermis contains langerin+ dendritic cells that develop and function independently of epidermal Langerhans cells. J. Exp. Med. 204, 3119–3131 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ginhoux, F. et al. Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state. J. Exp. Med. 204, 3133–3146 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bursch, L.S. et al. Identification of a novel population of Langerin+ dendritic cells. J. Exp. Med. 204, 3147–3156 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Romani, N., Clausen, B.E. & Stoitzner, P. Langerhans cells and more: langerin-expressing dendritic cell subsets in the skin. Immunol. Rev. 234, 120–141 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bennett, C.L., Noordegraaf, M., Martina, C.A. & Clausen, B.E. Langerhans cells are required for efficient presentation of topically applied hapten to T cells. J. Immunol. 179, 6830–6835 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bacci, S., Alard, P., Dai, R., Nakamura, T. & Streilein, J.W. High and low doses of haptens dictate whether dermal or epidermal antigen-presenting cells promote contact hypersensitivity. Eur. J. Immunol. 27, 442–448 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Enk, A.H. & Katz, S.I. Early events in the induction phase of contact sensitivity. J. Invest. Dermatol. 99, 39S–41S (1992).

    Article  CAS  PubMed  Google Scholar 

  34. 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).

    Article  CAS  PubMed  Google Scholar 

  35. Ruedl, C., Koebel, P., Bachmann, M., Hess, M. & Karjalainen, K. Anatomical origin of dendritic cells determines their life span in peripheral lymph nodes. J. Immunol. 165, 4910–4916 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Christensen, A.D. & Haase, C. Immunological mechanisms of contact hypersensitivity in mice. APMIS 120, 1–27 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Igyártó, B.Z. et al. Skin-resident murine dendritic cell subsets promote distinct and opposing antigen-specific T helper cell responses. Immunity 35, 260–272 (2011).

    Article  PubMed  Google Scholar 

  38. Getts, D.R. et al. Ly6c+ “inflammatory monocytes” are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis. J. Exp. Med. 205, 2319–2337 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Crispe, I.N. The liver as a lymphoid organ. Annu. Rev. Immunol. 27, 147–163 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Kinoshita, M. et al. Characterization of two F4/80-positive Kupffer cell subsets by their function and phenotype in mice. J. Hepatol. 53, 903–910 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Merad, M. et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nat. Immunol. 3, 1135–1141 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Takahashi, K., Naito, M. & Shultz, L.D. Differentiation of epidermal Langerhans cells in macrophage colony-stimulating-factor-deficient mice homozygous for the osteopetrosis (op) mutation. J. Invest. Dermatol. 99, 46S–47S (1992).

    Article  CAS  PubMed  Google Scholar 

  43. Anandasabapathy, N. et al. Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain. J. Exp. Med. 208, 1695–1705 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ajami, B., Bennett, J.L., Krieger, C., McNagny, K.M. & Rossi, F.M. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat. Neurosci. 14, 1142–1149 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Jiang, A. et al. Disruption of E-cadherin-mediated adhesion induces a functionally distinct pathway of dendritic cell maturation. Immunity 27, 610–624 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Romani, N., Brunner, P.M. & Stingl, G. Changing views of the role of langerhans cells. J. Invest. Dermatol. 132, 872–881 (2012).

    Article  CAS  PubMed  Google Scholar 

  47. Kaplan, D.H., Jenison, M.C., Saeland, S., Shlomchik, W.D. & Shlomchik, M.J. Epidermal langerhans cell-deficient mice develop enhanced contact hypersensitivity. Immunity 23, 611–620 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Kaplan, D.H. In vivo function of Langerhans cells and dermal dendritic cells. Trends Immunol. 31, 446–451 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Prinz, M., Priller, J., Sisodia, S.S. & Ransohoff, R.M. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat. Neurosci. 14, 1227–1235 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. Paolicelli, R.C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Schwenk, F., Baron, U. & Rajewsky, K. A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res. 23, 5080–5081 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kanki, H., Suzuki, H. & Itohara, S. High-efficiency CAG-FLPe deleter mice in C57BL/6J background. Exp. Anim. 55, 137–141 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Szretter, K.J. et al. The immune adaptor molecule SARM modulates tumor necrosis factor α production and microglia activation in the brainstem and restricts West Nile Virus pathogenesis. J. Virol. 83, 9329–9338 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Samuel, M.A., Morrey, J.D. & Diamond, M.S. Caspase 3-dependent cell death of neurons contributes to the pathogenesis of West Nile virus encephalitis. J. Virol. 81, 2614–2623 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Kinoshita, M. et al. Characterization of two F4/80-positive Kupffer cell subsets by their function and phenotype in mice. J. Hepatol. 53, 903–910 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Daffis, S. et al. 2′-O methylation of the viral mRNA cap evades host restriction by IFIT family members. Nature 468, 452–456 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Vogt, M.R. et al. Human monoclonal antibodies against West Nile virus induced by natural infection neutralize at a postattachment step. J. Virol. 83, 6494–6507 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Fuchs, A., Pinto, A.K., Schwaeble, W.J. & Diamond, M.S. The lectin pathway of complement activation contributes to protection from West Nile virus infection. Virology 412, 101–109 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Girardi, M. et al. Resident skin-specific gammadelta T cells provide local, nonredundant regulation of cutaneous inflammation. J. Exp. Med. 195, 855–867 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Xu, H., DiIulio, N.A. & Fairchild, R.L. T cell populations primed by hapten sensitization in contact sensitivity are distinguished by polarized patterns of cytokine production: interferon gamma-producing (Tc1) effector CD8+ T cells and interleukin (Il) 4/Il-10-producing (Th2) negative regulatory CD4+ T cells. J. Exp. Med. 183, 1001–1012 (1996).

    Article  CAS  PubMed  Google Scholar 

  61. Igyártó, B.Z. et al. Skin-resident murine dendritic cell subsets promote distinct and opposing antigen-specific T helper cell responses. Immunity 35, 260–272 (2011).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Swiecki for help with flow cytometry and confocal microscopy; the European Conditional Mouse Mutagenesis Consortium for generating embryonic stem clones with the targeted allele Il34tm1a(EUCOMM)Wtsi; M. White for injection of Il34tm1a(EUCOMM)Wtsi embryonic stem cells; and T. Doering (Department of Molecular Microbiology, Washington University School of Medicine) for C. albicans strain SC5314. Supported by the National Heart, Lung and Blood Institute (2T32HL007317-31 to Y.W.), Fondazione Beretta (C.R.), Programma di Ricerca di interesse Nazionale of the Ministero dell'Istruzione dell'Università e della Ricerca, 2009 (W.V.), the European Commission Seventh Framework Programme (A.D.B.) and the US National Institutes of Health (GM77279 and HL097805 to M.Co.).

Author information

Authors and Affiliations

Authors

Contributions

Y.W., K.J.S. and M.Ce. designed, did and analyzed experiments and wrote the manuscript; W.V. and C.R. did immunohistochemical analysis; M.S.D. supervised CNS-infection experiments; S.G. and A.D.B. generated Il34LacZ/LacZ mice; and M.Co. supervised research and wrote the manuscript.

Corresponding author

Correspondence to Marco Colonna.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 632 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, Y., Szretter, K., Vermi, W. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat Immunol 13, 753–760 (2012). https://doi.org/10.1038/ni.2360

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2360

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing