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

Buerger, Claudia
Shirsath, Nitesh
Lang, Victoria
Berard, Alina
Diehl, Sandra
Kaufmann, Roland
Wolf, Peter
Published in PLOS ONE. 2017, vol. 12, no. 7, p. e0180853
Abstract 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.
Keywords AdolescentAdultAgedAnimalsCell Differentiation/genetics/physiologyCell LineCell Proliferation/genetics/physiologyFemaleHumansImmunoassayImmunohistochemistryKeratinocytes/metabolism/physiologyMaleMechanistic Target of Rapamycin Complex 1MiceMiceInbred BALB CMiddle AgedMultiprotein Complexes/genetics/metabolismRNASmall Interfering/geneticsReverse Transcriptase Polymerase Chain ReactionSignal Transduction/genetics/physiologyTOR Serine-Threonine Kinases/genetics/metabolismYoung Adult
PMID: 28700632
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Research group Mécanismes des pathologies de l'inflammation cutanée (919)
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BUERGER, Claudia et al. Inflammation dependent mTORC1 signaling interferes with the switch from keratinocyte proliferation to differentiation. In: PLOS ONE, 2017, vol. 12, n° 7, p. e0180853. doi: 10.1371/journal.pone.0180853 https://archive-ouverte.unige.ch/unige:107100

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Deposited on : 2018-08-16

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