Zhenping Wang1, Nicholas Mascarenhas1, Lars Eckmann2, Yukiko Miyamoto2, Xiaojun Sun1, Toshiaki Kawakami3, Anna Di Nardo4. 1. Department of Dermatology, School of Medicine, University of California, San Diego, La Jolla, Calif. 2. Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, Calif. 3. Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, Calif. 4. Department of Dermatology, School of Medicine, University of California, San Diego, La Jolla, Calif. Electronic address: adinardo@ucsd.edu.
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. CONCLUSION: 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.
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. CONCLUSION: 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.