title: Skin microbiome promotes mast cell maturation by triggering stem cell factor production in keratinocytes.
abstract: BACKGROUND
  Mast cell (MC) progenitors leave the bone marrow, enter the circulation, and settle in the skin and other tissues. Their maturation in tissues is influenced by the surrounding microenvironment.
  
  
  OBJECTIVE
  We tested the hypothesis that environmental factors play a role in MC maturation in the skin.
  
  
  METHODS
  MCs were numerically, phenotypically, and functionally compared between germ-free (GF), specific pathogen-free, and GF mice reconstituted with microbiota. The maturity of MCs was then correlated with skin levels of stem cell factor (SCF), a critical MC differentiation factor, and lipoteichoic acid (LTA), a Toll-like receptor 2 ligand. MCs were also evaluated in mice with keratinocyte-specific deletion of Scf.
  
  
  RESULTS
  We found that GF mice express abnormally low amounts of SCF, a critical MC differentiation factor, and contain MCs that are largely undifferentiated. Reconstituting the GF microbiota reverted this MC phenotype to normal, indicating that the phenotype is related to ongoing interactions of the microbiota and skin. Consistent with the immaturity of GF MCs, degranulation-provoking compound 48/80 induced less edema in the skin of GF mice than in conventional mice. Our results show that the skin microbiome drives SCF production in keratinocytes, which triggers the differentiation of dermal MCs. Because the skin microbiome is a rich source of LTA, a Toll-like receptor 2 ligand, we mimicked the GF microbiome's effect on MCs by applying LTA to the skin of GF mice. We also demonstrated that MC migration within the skin depends exclusively on keratinocyte-produced SCF.
  
  
  CONCLUSIONS
  This study has revealed a novel mechanism by which the skin microbiota signals the recruitment and maturation of MCs within the dermis through SCF production by LTA-stimulated keratinocytes.
authors.affiliation: Department of Dermatology, School of Medicine, University of California, San Diego, La Jolla, Calif.
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Dermatology, School of Medicine, University of California, San Diego, La Jolla, Calif.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mascarenhas
authors.affiliation: Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, Calif.
authors.forename: Lars
authors.initials: L
authors.lastname: Eckmann
authors.affiliation: Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, Calif.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Department of Dermatology, School of Medicine, University of California, San Diego, La Jolla, Calif.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Sun
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, Calif.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kawakami
authors.affiliation: Department of Dermatology, School of Medicine, University of California, San Diego, La Jolla, Calif. Electronic address: adinardo@ucsd.edu.
authors.forename: Anna
authors.initials: A
authors.lastname: Di Nardo
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005856:Germ-Free Life; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D061346:Laser Capture Microdissection; D008070:Lipopolysaccharides / Q000494:pharmacology; D008407:Mast Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D060888:Real-Time Polymerase Chain Reaction; D012867:Skin / Q000166:cytology / Q000378:metabolism / Q000382:microbiology*; D019089:Stem Cell Factor / Q000096:biosynthesis*; D013682:Teichoic Acids / Q000494:pharmacology
chemical_list: D008070:Lipopolysaccharides; D019089:Stem Cell Factor; D013682:Teichoic Acids; C009900:lipoteichoic acid
keywords: LTA; Mast cell; SCF; germ free; keratinocyte; microbiome