title: Increased Bacterial Load and Expression of Antimicrobial Peptides in Skin of Barrier-Deficient Mice with Reduced Cancer Susceptibility.
abstract: Mice lacking three epidermal barrier proteins-envoplakin, periplakin, and involucrin (EPI-/- mice)-have a defective cornified layer, reduced epidermal γδ T cells, and increased dermal CD4(+) T cells. They are also resistant to developing skin tumors. The tumor-protective mechanism involves signaling between Rae-1 expressing keratinocytes and the natural killer group 2D receptor on immune cells, which also plays a role in host defenses against infection. Given the emerging link between bacteria and cancer, we investigated whether EPI-/- mice have an altered skin microbiota. The bacterial phyla were similar in wild-type and EPI-/- skin. However, bacteria were threefold more abundant in EPI-/- skin and penetrated deeper into the epidermis. The major epithelial defense mechanism against bacteria is production of antimicrobial proteins (AMPs). EPI-/- skin exhibited enhanced expression of antimicrobial peptides. However, reducing the bacterial load by antibiotic treatment or breeding mice under specific pathogen-free conditions did not reduce AMP expression or alleviate the abnormalities in T-cell populations. We conclude that the atopic characteristics of EPI-/- skin are a consequence of the defective barrier rather than a response to the increased bacterial load. It is therefore unlikely that the increase in skin microbiota contributes directly to the observed cancer resistance.
authors.affiliation: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom; Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Natsuga
authors.affiliation: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom; Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Cipolat
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom. Electronic address: Fiona.watt@kcl.ac.uk.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Watt
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D058491:Bacterial Load / Q000379:methods; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000453:epidemiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D017404:In Situ Hybridization, Fluorescence; D008565:Membrane Proteins / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D011498:Protein Precursors / Q000172:deficiency; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012867:Skin / Q000187:drug effects / Q000382:microbiology*; D012869:Skin Absorption / Q000187:drug effects; D012878:Skin Neoplasms / Q000473:pathology* / Q000517:prevention & control; D018709:Statistics, Nonparametric
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D008565:Membrane Proteins; D011498:Protein Precursors; C100754:envoplakin; C032253:involucrin; D009195:Peroxidase