Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus.
Atopic dermatitis (AD) is associated with eczema vaccinatum (EV), a disseminated viral skin infection that follows inoculation with vaccinia virus (VV). This study examined whether AD skin can control VV replication, and the role of IL-4 and IL-13 in modulating the human cathelicidin LL-37, an antimicrobial peptide that kills VV. AD skin exhibited increased VV replication and decreased LL-37 expression compared to normal or psoriasis skin. IL-4/IL-13 enhanced VV replication while downregulating LL-37 in VV-stimulated keratinocytes. Neutralizing IL-4/IL-13 in AD skin augmented LL-37 and inhibited VV replication. Cathelicidins were induced via toll-like receptor-3 and were inhibited by IL-4/IL-13 through STAT-6. Skin from cathelicidin-deficient mice exhibited reduced ability to control VV replication. Exogenous LL-37 controlled vaccinia viral replication in infected keratinocytes and AD skin explants. The current study demonstrates that Th2 cytokines enhance VV replication in AD skin by subverting the innate immune response against VV in a STAT-6-dependent manner.
Howell
Michael D
MD
Division of Allergy and Immunology, Department of Pediatrics, National Jewish Medical and Research Center, University of Colorado Health Sciences Center, Denver, Colorado 80206, USA.
Gallo
Richard L
RL
Boguniewicz
Mark
M
Jones
James F
JF
Wong
Cathy
C
Streib
Joanne E
JE
Leung
Donald Y M
DY
D000328:Adult; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis*; D002478:Cells, Cultured; D003876:Dermatitis, Atopic / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D018793:Interleukin-13 / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D050800:STAT6 Transcription Factor / Q000502:physiology; D012867:Skin / Q000276:immunology / Q000821:virology*; D012900:Smallpox Vaccine / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000502:physiology; D014616:Vaccinia virus / Q000276:immunology* / Q000502:physiology; D014779:Virus Replication; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D018793:Interleukin-13; D050800:STAT6 Transcription Factor; D012900:Smallpox Vaccine; D051196:Toll-Like Receptor 3; D015847:Interleukin-4; D054804:Cathelicidins