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Keratin 1 maintains skin integrity and participates in an inflammatory network in skin via interleukin-18


Roth, Wera; Kumar, Vinod; Beer, Hans-Dietmar; Richter, Miriam; Wohlenberg, Claudia; Reuter, Ursula; Thiering, Sören; Staratschek-Jox, Andrea; Hofmann, Andrea; Kreusch, Fatima; Schultze, Joachim L; Vogl, Thomas; Roth, Johannes; Reichelt, Julia; Hausser, Ingrid; Magin, Thomas M (2012). Keratin 1 maintains skin integrity and participates in an inflammatory network in skin via interleukin-18. Journal of Cell Science, 125(22):5269-5279.

Abstract

Keratin 1 (KRT1) and its heterodimer partner keratin 10 (KRT10) are major constituents of the intermediate filament cytoskeleton in suprabasal epidermis. KRT1 mutations cause epidermolytic ichthyosis in humans, characterized by loss of barrier integrity and recurrent erythema. In search of the largely unknown pathomechanisms and the role of keratins in barrier formation and inflammation control, we show here that Krt1 is crucial for maintenance of skin integrity and participates in an inflammatory network in murine keratinocytes. Absence of Krt1 caused a prenatal increase in interleukin-18 (IL-18) and S100A8/A9, accompanied by a barrier defect and perinatal lethality. Depletion of IL-18 partially rescued Krt1(-/-) mice. IL-18 release was keratinocyte-autonomous, KRT1- and caspase-1-dependent, supporting an upstream role of KRT1 in the pathology. Finally, transcriptome profiling revealed a Krt1-mediated gene expression signature similar to atopic eczema (AE) and psoriasis, but different from Krt5-deficiency and epidermolysis bullosa simplex (EBS). Our data suggest a functional link between KRT1 and human inflammatory skin diseases.

Abstract

Keratin 1 (KRT1) and its heterodimer partner keratin 10 (KRT10) are major constituents of the intermediate filament cytoskeleton in suprabasal epidermis. KRT1 mutations cause epidermolytic ichthyosis in humans, characterized by loss of barrier integrity and recurrent erythema. In search of the largely unknown pathomechanisms and the role of keratins in barrier formation and inflammation control, we show here that Krt1 is crucial for maintenance of skin integrity and participates in an inflammatory network in murine keratinocytes. Absence of Krt1 caused a prenatal increase in interleukin-18 (IL-18) and S100A8/A9, accompanied by a barrier defect and perinatal lethality. Depletion of IL-18 partially rescued Krt1(-/-) mice. IL-18 release was keratinocyte-autonomous, KRT1- and caspase-1-dependent, supporting an upstream role of KRT1 in the pathology. Finally, transcriptome profiling revealed a Krt1-mediated gene expression signature similar to atopic eczema (AE) and psoriasis, but different from Krt5-deficiency and epidermolysis bullosa simplex (EBS). Our data suggest a functional link between KRT1 and human inflammatory skin diseases.

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37 citations in Web of Science®
37 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:6 December 2012
Deposited On:04 Feb 2013 12:49
Last Modified:05 Apr 2016 16:22
Publisher:The Company of Biologists
ISSN:0021-9533
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1242/jcs.116574
PubMed ID:23132931

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