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

Nature Immunology volume 13, pages 753–760 (2012)Cite this article

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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.

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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.

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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.).

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Authors and Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA

    Yaming Wang, Kristy J Szretter, William Vermi, Susan Gilfillan, Marina Cella, Alexander D Barrow, Michael S Diamond & Marco Colonna

  2. Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

    Kristy J Szretter & Michael S Diamond

  3. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA

    Kristy J Szretter & Michael S Diamond

  4. Department of Pathology, University of Brescia, Brescia, Italy

    William Vermi & Cristina Rossini

  5. Department of Pathology, University of Cambridge, Cambridge, UK

    Alexander D Barrow

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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.

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Correspondence to Marco Colonna.

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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

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