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

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.

Targeting L-type amino acid transporter 1 in innate and adaptive T cells efficiently controls skin inflammation

“…39 Its aberrant induction is mediated by proinflammatory cytokines, such as IL-1b, IL-17A, and TNF-a, increasing proliferation and reducing expression of differentiation markers. 40 Our results indicate that LAT1 expression in keratinocytes is not essential for control of keratinocyte proliferation, indicating a functional compensation with alternative amino acid transporters, such as LAT2 or LAT3, which are also expressed in the epidermal layer in patients with psoriasis.…”

Protein kinases involved in epidermal barrier formation: The AKT family and other animals

“…There are two mTOR complexes: mTORC1, which controls protein metabolism [36] ; and mTORC2, which activates AKT signalling. [37] We and others have shown that mTORC1 and mTORC2 activity is present in suprabasal layers of the epidermis [38][39][40] with mTORC1 activity, measured by S6 phosphorylation, concentrated in the granular layer of in vitro skin models. [38,39] mTORC1 and mTORC2 complexes contain the subunits Raptor and Rictor, respectively, [41] and selective deficiency of these subunits allows manipulation of mTORC1 and mTORC2 activity to dissect their roles in the epidermis.…”

Optimising platelet secretomes to deliver robust tissue‐specific regeneration

“…To our knowledge, we are the first to replicate these results with platelet releasate on NHEKs and HaCaTs. Typical keratinocyte differentiation involves an increase in cell density (Buerger et al, ). Further to this, the observed morphological differences between platelet releasate and growth media on the inhibition of proliferation in high density keratinocyte populations support the lineage progression results, exiting the cell cycle faster and upregulating terminal differentiation genes greater than normal culture conditions.…”