Increased Bacterial Load and Expression of Antimicrobial Peptides in Skin of Barrier-Deficient Mice With Reduced Cancer Susceptibility

J Invest Dermatol. 2016 Jan;136(1):99-106. doi: 10.1038/JID.2015.383.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Antimicrobial Cationic Peptides / metabolism*
  • Bacterial Load / methods
  • Disease Models, Animal
  • Disease Susceptibility / epidemiology*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • In Situ Hybridization, Fluorescence
  • Membrane Proteins / deficiency
  • Mice
  • Mice, Inbred C57BL
  • Microbiota / drug effects*
  • Peroxidase / metabolism
  • Protein Precursors / deficiency
  • Real-Time Polymerase Chain Reaction / methods
  • Skin / drug effects
  • Skin / microbiology*
  • Skin Absorption / drug effects
  • Skin Neoplasms / pathology*
  • Skin Neoplasms / prevention & control
  • Statistics, Nonparametric

Substances

  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Membrane Proteins
  • Protein Precursors
  • envoplakin
  • involucrin
  • Peroxidase