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PMID: 22729249 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature immunology ·Vol. 13 ·No. 8 ·2012-06-24 ·Pages 753-60

Wang Y, Szretter KJ, Vermi W, Gilfillan S, Rossini C, Cella M, Barrow AD, Diamond MS, Colonna M

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 (Il34(LacZ/LacZ)) reporter mice, we found that keratinocytes and neurons were the main sources of IL-34. Il34(LacZ/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.

MeSH Terms
Animals Cell Differentiation Central Nervous System/metabolism Interleukins/deficiency,genetics,metabolism Keratinocytes/metabolism Langerhans Cells/cytology,immunology,physiology Macrophage Colony-Stimulating Factor/genetics,metabolism Macrophages/immunology Mice Mice, Inbred C57BL Mice, Knockout Microglia/cytology,immunology,physiology Myeloid Cells/metabolism Myelopoiesis Neurons/metabolism Receptor, Macrophage Colony-Stimulating Factor/genetics,immunology,metabolism Skin/metabolism West Nile Fever/genetics,immunology West Nile virus/pathogenicity
Chemicals
Interleukins interleukin-34, mouse Macrophage Colony-Stimulating Factor Receptor, Macrophage Colony-Stimulating Factor
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Wang Yaming
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
Szretter Kristy J
Vermi William
Gilfillan Susan
Rossini Cristina
Cella Marina
Barrow Alexander D
Diamond Michael S
Colonna Marco
References (59)
59 references, click to expand
  1. Anatomical origin of dendritic cells determines their life span in peripheral lymph nodes.
    J Immunol. 2000 Nov 1;165(9):4910-6 PMID: 11046016
  2. Epidermal langerhans cell-deficient mice develop enhanced contact hypersensitivity.
    Immunity. 2005 Dec;23(6):611-20 PMID: 16356859
  3. The liver as a lymphoid organ.
    Annu Rev Immunol. 2009;27:147-63 PMID: 19302037
  4. Synaptic pruning by microglia is necessary for normal brain development.
    Science. 2011 Sep 9;333(6048):1456-8 PMID: 21778362
  5. Identification and expression of mouse Langerin (CD207) in dendritic cells.
    Int Immunol. 2002 May;14(5):433-44 PMID: 11978773
  6. In vivo function of Langerhans cells and dermal dendritic cells.
    Trends Immunol. 2010 Dec;31(12):446-51 PMID: 21035396
  7. Langerhans cell (LC) proliferation mediates neonatal development, homeostasis, and inflammation-associated expansion of the epidermal LC network.
    J Exp Med. 2009 Dec 21;206(13):3089-100 PMID: 19995948
  8. Differentiation of epidermal Langerhans cells in macrophage colony-stimulating-factor-deficient mice homozygous for the osteopetrosis (op) mutation.
    J Invest Dermatol. 1992 Nov;99(5):46S-47S PMID: 1431208
  9. Characterization of two F4/80-positive Kupffer cell subsets by their function and phenotype in mice.
    J Hepatol. 2010 Nov;53(5):903-10 PMID: 20739085
  10. The immune adaptor molecule SARM modulates tumor necrosis factor alpha production and microglia activation in the brainstem and restricts West Nile Virus pathogenesis.
    J Virol. 2009 Sep;83(18):9329-38 PMID: 19587044
  11. Changing views of the role of Langerhans cells.
    J Invest Dermatol. 2012 Mar;132(3 Pt 2):872-81 PMID: 22217741
  12. IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation.
    Cell Death Differ. 2010 Dec;17(12):1917-27 PMID: 20489731
  13. Langerhans cells are required for efficient presentation of topically applied hapten to T cells.
    J Immunol. 2007 Nov 15;179(10):6830-5 PMID: 17982073
  14. Identification of a novel population of Langerin+ dendritic cells.
    J Exp Med. 2007 Dec 24;204(13):3147-56 PMID: 18086865
  15. 2'-O methylation of the viral mRNA cap evades host restriction by IFIT family members.
    Nature. 2010 Nov 18;468(7322):452-6 PMID: 21085181
  16. Human monoclonal antibodies against West Nile virus induced by natural infection neutralize at a postattachment step.
    J Virol. 2009 Jul;83(13):6494-507 PMID: 19386704
  17. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene.
    Nature. 1990 May 31;345(6274):442-4 PMID: 2188141
  18. Colony-stimulating factor-1 in immunity and inflammation.
    Curr Opin Immunol. 2006 Feb;18(1):39-48 PMID: 16337366
  19. Development of monocytes, macrophages, and dendritic cells.
    Science. 2010 Feb 5;327(5966):656-61 PMID: 20133564
  20. Ontogeny and homeostasis of Langerhans cells.
    Immunol Cell Biol. 2010 May-Jun;88(4):387-92 PMID: 20309014
  21. Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells.
    J Leukoc Biol. 2010 Sep;88(3):495-505 PMID: 20504948
  22. A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells.
    Nucleic Acids Res. 1995 Dec 25;23(24):5080-1 PMID: 8559668
  23. Early events in the induction phase of contact sensitivity.
    J Invest Dermatol. 1992 Nov;99(5):39S-41S PMID: 1385542
  24. Langerhans cells and more: langerin-expressing dendritic cell subsets in the skin.
    Immunol Rev. 2010 Mar;234(1):120-41 PMID: 20193016
  25. 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. 1996 Mar 1;183(3):1001-12 PMID: 8642241
  26. Fate mapping analysis reveals that adult microglia derive from primitive macrophages.
    Science. 2010 Nov 5;330(6005):841-5 PMID: 20966214
  27. Genetic regulation of osteoclast development and function.
    Nat Rev Genet. 2003 Aug;4(8):638-49 PMID: 12897775
  28. Identification of mouse langerin/CD207 in Langerhans cells and some dendritic cells of lymphoid tissues.
    J Immunol. 2002 Jan 15;168(2):782-92 PMID: 11777972
  29. Flt3 signaling-dependent dendritic cells protect against atherosclerosis.
    Immunity. 2011 Nov 23;35(5):819-31 PMID: 22078798
  30. High-efficiency CAG-FLPe deleter mice in C57BL/6J background.
    Exp Anim. 2006 Apr;55(2):137-41 PMID: 16651697
  31. Structural basis for the dual recognition of helical cytokines IL-34 and CSF-1 by CSF-1R.
    Structure. 2012 Apr 4;20(4):676-87 PMID: 22483114
  32. Diversity and plasticity of mononuclear phagocytes.
    Eur J Immunol. 2011 Sep;41(9):2470-2 PMID: 21952798
  33. Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain.
    J Exp Med. 2011 Aug 1;208(8):1695-705 PMID: 21788405
  34. The lectin pathway of complement activation contributes to protection from West Nile virus infection.
    Virology. 2011 Mar 30;412(1):101-9 PMID: 21269656
  35. Disruption of E-cadherin-mediated adhesion induces a functionally distinct pathway of dendritic cell maturation.
    Immunity. 2007 Oct;27(4):610-24 PMID: 17936032
  36. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool.
    Nat Neurosci. 2011 Jul 31;14(9):1142-9 PMID: 21804537
  37. Origin and development of dendritic cells.
    Immunol Rev. 2010 Mar;234(1):45-54 PMID: 20193011
  38. The dermis contains langerin+ dendritic cells that develop and function independently of epidermal Langerhans cells.
    J Exp Med. 2007 Dec 24;204(13):3119-31 PMID: 18086861
  39. Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells.
    Nat Rev Immunol. 2008 Dec;8(12):935-47 PMID: 19029989
  40. Steady-state and inflammatory dendritic-cell development.
    Nat Rev Immunol. 2007 Jan;7(1):19-30 PMID: 17170756
  41. Immunological mechanisms of contact hypersensitivity in mice.
    APMIS. 2012 Jan;120(1):1-27 PMID: 22151305
  42. Langerhans cells arise from monocytes in vivo.
    Nat Immunol. 2006 Mar;7(3):265-73 PMID: 16444257
  43. Langerhans cells renew in the skin throughout life under steady-state conditions.
    Nat Immunol. 2002 Dec;3(12):1135-41 PMID: 12415265
  44. Caspase 3-dependent cell death of neurons contributes to the pathogenesis of West Nile virus encephalitis.
    J Virol. 2007 Mar;81(6):2614-23 PMID: 17192305
  45. High and low doses of haptens dictate whether dermal or epidermal antigen-presenting cells promote contact hypersensitivity.
    Eur J Immunol. 1997 Feb;27(2):442-8 PMID: 9045915
  46. Ly6c+ "inflammatory monocytes" are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis.
    J Exp Med. 2008 Sep 29;205(10):2319-37 PMID: 18779347
  47. Resident skin-specific gammadelta T cells provide local, nonredundant regulation of cutaneous inflammation.
    J Exp Med. 2002 Apr 1;195(7):855-67 PMID: 11927630
  48. The myeloid cells of the central nervous system parenchyma.
    Nature. 2010 Nov 11;468(7321):253-62 PMID: 21068834
  49. Colony-stimulating factors in inflammation and autoimmunity.
    Nat Rev Immunol. 2008 Jul;8(7):533-44 PMID: 18551128
  50. Inducible ablation of mouse Langerhans cells diminishes but fails to abrogate contact hypersensitivity.
    J Cell Biol. 2005 May 23;169(4):569-76 PMID: 15897263
  51. Skin-resident murine dendritic cell subsets promote distinct and opposing antigen-specific T helper cell responses.
    Immunity. 2011 Aug 26;35(2):260-72 PMID: 21782478
  52. Dendritic cell homeostasis.
    Blood. 2009 Apr 9;113(15):3418-27 PMID: 19176316
  53. Dynamics and function of Langerhans cells in vivo: dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans cells.
    Immunity. 2005 May;22(5):643-54 PMID: 15894281
  54. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome.
    Science. 2008 May 9;320(5877):807-11 PMID: 18467591
  55. Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse.
    Development. 1994 Jun;120(6):1357-72 PMID: 8050349
  56. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration.
    Nat Neurosci. 2011 Sep 27;14(10):1227-35 PMID: 21952260
  57. Identification of macrophages and dendritic cells in the osteopetrotic (op/op) mouse.
    J Cell Sci. 1993 Apr;104 ( Pt 4):1021-9 PMID: 8314887
  58. 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. 2002 Jan 1;99(1):111-20 PMID: 11756160
  59. Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state.
    J Exp Med. 2007 Dec 24;204(13):3133-46 PMID: 18086862
Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.2360
Published
2012-06-24
Epub
2012-00-24
Pages
753-60
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC3941469
Subset
IM
Grants
NHLBI NIH HHS · HL097805 · United States
NIGMS NIH HHS · R01 GM077279 · United States
NIGMS NIH HHS · GM77279 · United States
NHLBI NIH HHS · T32 HL007317 · United States
NHLBI NIH HHS · 2T32HL007317-31 · United States
NHLBI NIH HHS · R01 HL097805 · United States
NIDDK NIH HHS · P30 DK020579 · United States
Corrections
CommentIn
PMID: 22814343
External Links
PubMed source DOI: 10.1038/ni.2360 PMC Full Text View journal details
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