Date Published: July 10, 2017
Publisher: Public Library of Science
Author(s): Claudia Buerger, Nitesh Shirsath, Victoria Lang, Alina Berard, Sandra Diehl, Roland Kaufmann, Wolf-Henning Boehncke, Peter Wolf, Miroslav Blumenberg.
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.
To maintain homeostasis of the healthy epidermis keratinocyte stem cells divide asymmetrically, leave the basal layer and successively develop into the spinous, granular and corneal layers, characterized by ordered expression of keratins and other marker such as involucrin, loricrin, filaggrin or transglutaminase . Upon maturation, keratinocytes undergo a form of programmed cell death and are shed as corneocytes . The balance between keratinocyte proliferation and differentiation is tightly regulated, but is deregulated in certain skin diseases such as psoriasis. Psoriasis is a chronic inflammatory skin disease presenting with red scaly plaques, mostly on the head, trunk and extensor sites of arms and legs . These lesions are characterized by thickened, irregular stratum corneum with parakeratosis, epidermal thickening with acanthosis and absence of the granular layer. This is caused by hyperproliferating keratinocytes that are unable to properly initiate the epidermal differentiation program .
We could show that healthy skin keratinocyte stem cells of the basal layer display high PI3-K/ mTOR activity, that correlates with Ki-67 staining and thus with their proliferative activity. This is supported by a recent study by Ding et al. that shows that epidermal loss of mTORC1 signaling results in reduced proliferation of epidermal progenitors cells in the basal layer leading to a hypoplastic epidermis during development . Interestingly, we could not see a strong effect of mTOR inhibition on proliferation in vitro, which can be explained with the fact that cultivated keratinocytes represent a mixed population with a large proportion of cells, that have already left the cell cycle and are committed to differentiation.