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 s...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 110; no. 48; pp. 19537 - 19542
Main Authors Lessard, Juliane C., Piña-Paz, Sylvia, Rotty, Jeremy D., Hickerson, Robyn P., Kaspar, Roger L., Balmain, Allan, Coulombe, Pierre A.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 26.11.2013
NATIONAL ACADEMY OF SCIENCES
National Acad Sciences
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Abstract 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.
AbstractList 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.
Here we report that keratin 16 (Krt16), a type I intermediate filament cytoskeletal protein, is an integral and functionally important component of a genetic network regulating danger signals, innate immunity, and barrier function in skin epidermis. Our findings help explain the pathogenesis of the conspicuous skin lesions arising in genetic skin disorders caused by mutations in Krt16, such as pachyonychia congenita and focal palmoplantar keratoderma, and in diseases in which Krt16 is induced and misregulated, such as psoriasis and cancer. 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.
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. [PUBLICATION ABSTRACT]
Author Kaspar, Roger L.
Piña-Paz, Sylvia
Rotty, Jeremy D.
Lessard, Juliane C.
Hickerson, Robyn P.
Balmain, Allan
Coulombe, Pierre A.
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Author contributions: J.C.L., R.P.H., R.L.K., A.B., and P.A.C. designed research; J.C.L., S.P.-P., J.D.R., R.P.H., R.L.K., and A.B. performed research; R.P.H., R.L.K., and A.B. contributed new reagents/analytic tools; J.C.L., J.D.R., R.P.H., R.L.K., A.B., and P.A.C. analyzed data; and J.C.L. and P.A.C. wrote the paper.
Edited by Terry Lechler, Duke University, Durham, NC, and accepted by the Editorial Board October 17, 2013 (received for review May 21, 2013)
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Snippet 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...
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...
Here we report that keratin 16 (Krt16), a type I intermediate filament cytoskeletal protein, is an integral and functionally important component of a genetic...
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StartPage 19537
SubjectTerms Animals
Biological Sciences
Blotting, Western
Cytokines
DNA Primers - genetics
Epidermis
Gene expression
Gene Expression Profiling
Gene expression regulation
Gene Regulatory Networks - genetics
Gene Regulatory Networks - immunology
Genetic disorders
Humans
Immunity, Innate - genetics
Immunity, Innate - immunology
Immunology
Inflammation
Keratin
Keratin-16 - metabolism
Keratin-6 - metabolism
Keratinocytes
Keratins
Lesions
Messenger RNA
Mice
Microarray Analysis
Microscopy, Electron, Transmission
Mutation
Pachyonychia Congenita - immunology
Pachyonychia Congenita - pathology
Physiology
Real-Time Polymerase Chain Reaction
Rodents
Skin
Title Keratin 16 regulates innate immunity in response to epidermal barrier breach
URI https://www.jstor.org/stable/23757294
http://www.pnas.org/content/110/48/19537.abstract
https://www.ncbi.nlm.nih.gov/pubmed/24218583
https://www.proquest.com/docview/1466133605
https://search.proquest.com/docview/1462370338
https://search.proquest.com/docview/1492638533
https://pubmed.ncbi.nlm.nih.gov/PMC3845144
Volume 110
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