Cathelicidin Antimicrobial Peptide LL‐37 in Cholesteatoma Enables Keratinocyte Reactivity with Cytosolic DNA

Abstract

The purpose of this study was to determine whether self-DNA can trigger the inflammatory response in cholesteatoma. Specimens were collected from nine patients with invasive cholesteatoma, nine patients with attic-type cholesteatoma (pars flaccida was perforated in five patients and intact in four) and four healthy skins. Expression and localization of LL-37 and interferon-alpha were detected by immunofluorescence and immunoblot analysis. Cultures of human cholesteatomatous keratinocytes were exposed to CpG DNA, LL-37 or CpG DNA complexed to LL-37 for 24h. Expression of interferon-alpha was detected by RT-PCR. We detected abundant cytosolic DNA, increased LL-37 and interferon-alpha in keratinocytes in invasive cholesteatoma and attic-type cholesteatoma with pars flaccida perforation, but not in attic-type cholesteatoma with pars flaccida intact and normal skin. In cultured keratinocytes, LL-37-DNA complexes induced IFN-α expression. These data suggest that cytosolic DNA is an important disease-associated molecular pattern that triggers the inflammation response in cholesteatoma. Furthermore, LL-37 played an important role in DNA-triggered inflammation. Thus, we have identified a link between cytosolic DNA, LL-37 and autoinflammation in cholesteatoma, providing new potential targets for the treatment of this disease.