Inflammation dependent mTORC1 signaling interferes with the switch from keratinocyte proliferation to differentiation

Psoriasis is a frequent and often severe inflammatory skin disease, characterized by altered epidermal homeostasis. Since we found previously that Akt/mTOR signaling is hyperactivated in psoriatic skin, we aimed at elucidating the role of aberrant mTORC1 signaling in this disease. We found that unde...

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Bibliographic Details
Published in:	PloS one Vol. 12; no. 7; p. e0180853
Main Authors:	Buerger, Claudia, Shirsath, Nitesh, Lang, Victoria, Berard, Alina, Diehl, Sandra, Kaufmann, Roland, Boehncke, Wolf-Henning, Wolf, Peter
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 10-07-2017 Public Library of Science (PLoS)
Subjects:	Aberration Activation Adolescent Adult Aged AKT protein Animals Biology and Life Sciences Cell Differentiation - genetics Cell Differentiation - physiology Cell Line Cell Proliferation - genetics Cell Proliferation - physiology Collagen Cytokines Dermatology Differentiation Female Gene expression Homeostasis Humans Immunoassay Immunohistochemistry Interleukin 1 Keratin Keratinocytes Keratinocytes - metabolism Keratinocytes - physiology Kinases Male Markers Mechanistic Target of Rapamycin Complex 1 Medicine and Health Sciences Mice Mice, Inbred BALB C Middle Aged Multiprotein Complexes - genetics Multiprotein Complexes - metabolism Pathogenesis Phosphorylation Proteins Psoriasis Research and Analysis Methods Reverse Transcriptase Polymerase Chain Reaction RNA, Small Interfering - genetics Signal Transduction - genetics Signal Transduction - physiology Skin diseases TOR protein TOR Serine-Threonine Kinases - genetics TOR Serine-Threonine Kinases - metabolism Tumor necrosis factor Young Adult
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Summary:	Psoriasis is a frequent and often severe inflammatory skin disease, characterized by altered epidermal homeostasis. Since we found previously that Akt/mTOR signaling is hyperactivated in psoriatic skin, we aimed at elucidating the role of aberrant mTORC1 signaling in this disease. We found that under healthy conditions mTOR signaling was shut off when keratinocytes switch from proliferation to terminal differentiation. Inflammatory cytokines (IL-1β, IL-17A, TNF-α) induced aberrant mTOR activity which led to enhanced proliferation and reduced expression of differentiation markers. Conversely, regular differentiation could be restored if mTORC1 signaling was blocked. In mice, activation of mTOR through the agonist MHY1485 also led to aberrant epidermal organization and involucrin distribution. In summary, these results not only identify mTORC1 as an important signal integrator pivotal for the cells fate to either proliferate or differentiate, but emphasize the role of inflammation-dependent mTOR activation as a psoriatic pathomechanism.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Competing Interests: The authors have declared that no competing interests exist. Conceptualization: CB PW W-HB.Formal analysis: CB NS.Funding acquisition: CB PW W-HB.Investigation: CB NS AB VL SD.Methodology: CB NS PW.Resources: CB NS PW.Validation: CB PW W-HB.Writing – original draft: CB NS PW W-HB RK.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0180853