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

• 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
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0180853

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.