Keratin 16 regulates innate immunity in response to epidermal barrier breach.
Mutations in the type I keratin 16 (Krt16) and its partner type II keratin 6 (Krt6a, Krt6b) cause pachyonychia congenita (PC), a disorder typified by dystrophic nails, painful hyperkeratotic calluses in glabrous skin, and lesions involving other epithelial appendages. The pathophysiology of these symptoms and its relationship to settings in which Krt16 and Krt6 are induced in response to epidermal barrier stress are poorly understood. We report that hyperkeratotic calluses arising in the glabrous skin of individuals with PC and Krt16 null mice share a gene expression signature enriched in genes involved in inflammation and innate immunity, in particular damage-associated molecular patterns. Transcriptional hyper-activation of damage-associated molecular pattern genes occurs following de novo chemical or mechanical irritation to ear skin and in spontaneously arising skin lesions in Krt16 null mice. Genome-wide expression analysis of normal mouse tail skin and benign proliferative lesions reveals a tight, context-dependent coregulation of Krt16 and Krt6 with genes involved in skin barrier maintenance and innate immunity. Our results uncover a role for Krt16 in regulating epithelial inflammation that is relevant to genodermatoses, psoriasis, and cancer and suggest a avenue for the therapeutic management of PC and related disorders.
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205.
Juliane C
JC
Lessard
Sylvia
S
Piña-Paz
Jeremy D
JD
Rotty
Robyn P
RP
Hickerson
Roger L
RL
Kaspar
Allan
A
Balmain
Pierre A
PA
Coulombe
D000818:Animals; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D053536:Keratin-16 / Q000378:metabolism*; D053553:Keratin-6 / Q000378:metabolism*; D051379:Mice; D046228:Microarray Analysis; D046529:Microscopy, Electron, Transmission; D053549:Pachyonychia Congenita / Q000276:immunology* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction
D017931:DNA Primers; D053536:Keratin-16; D053553:Keratin-6
epidermis; intermediate filament