Epidermal mTORC1 Signaling Contributes to the Pathogenesis of Psoriasis and Could Serve as a Therapeutic Target

Abstract

Although modern biologics targeting different inflammatory mediators show promising therapeutic success, comprehensive knowledge about the molecular events in psoriatic keratinocytes that contribute to the pathogenesis and could serve as therapeutic targets is still scarce. However, recent efforts to understand the deregulated signal transduction pathways have led to the development of small molecule inhibitors e.g., tofacitinib targeting the Jak/Stat cascade that opens additional therapeutic options. Recently, the PI3-K/Akt/mTOR signaling pathway has emerged as an important player in the control of epidermal homeostasis. This review summarizes the current knowledge on the role of this pathway in the pathogenesis of psoriasis, especially the epidermal manifestation of the disease and discusses current approaches to target the pathway therapeutically.

Keywords: keratinocytes; mTORC1; psoriasis; rapamycin; topical agent.

Figure 1

The PI3-K/Akt/mTOR signaling cascade. Stimulation of receptor tyrosine kinases (RTK) and G-protein-coupled receptors (GPCR) leads to activation of PI3-K, which then synthesizes PIP₃ in the membrane. Subsequently, Akt is recruited to the membrane and phosphorylated by PDK-1 and mTORC2. The activated Akt kinase phosphorylates various substrates such as PRAS40, which is then inactivated and releases mTORC1. In addition, TSC2 is inhibited so that the downstream GTPase Rheb remains GTP-bound and can activate mTORC1. The fully activated mTORC1 complex then activates proteins of the translation machinery by phosphorylating S6K-1 or 4E-BP1 [adapted from Manning et al. 23).

Figure 2

Model, how mTORC1 signaling controls epidermal homeostasis and contributes to psoriasis. In healthy, basal keratinocytes, mTORC1 signaling pathway is active and controls proliferation while blocking differentiation. When cells leave the proliferative, basal compartment, mTORC1 is switched off and differentiation is enabled. Under inflammatory conditions, such as in psoriasis, mTORC1 is permanently activated, which leads to massive proliferation in the basal layer and disturbed keratinocyte differentiation in suprabasal layers, resulting in the phenotypic changes typical of psoriasis.