Phosphoinositide-3 Kinase/Protein Kinase-B/Mammalian Target of Rapamycin Pathway in Psoriasis Pathogenesis. A Potential Therapeutic Target?

Abstract

Psoriasis is a common chronic inflammatory disease of the skin. Its pathogenesis has not been completely elucidated. Phosphoinositide-3 kinase/protein kinase-B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway has been identified as a key signaling pathway for important cellular functions. The data collected in this review suggest that overexpression of the PI3K/Akt/mTOR pathway may play an important role in the pathogenesis of psoriasis by mediating the immune-pathogenesis, the epidermal hyperplasia or/and the angiogenesis in the disease. Advances in understanding the pathogenesis of psoriasis has provided new insight into potential therapeutic targets, including the development of biological therapies, resulting in remarkable clinical responses in patients with severe psoriasis. More recently, small molecule oral preparations targeting intracellular signaling that may prove effective have been developed. Data suggest that PI3K/Akt/mTOR pathway may be a potential target for treatment of psoriasis.

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

“…It is currently hypothesized that the PI3-K/Akt/mTOR cascade plays a role in the pathogenesis of psoriasis by regulating the function of immune cells as well as intrinsic alterations within the epidermis (reviewed in [18]). Thus, we aimed at deciphering the contribution of mTORC1 signaling to epidermal homeostasis and its pathogenic role in the psoriatic epidermis.…”

Upregulation of PI3K/AKT/mTOR, FABP5 and PPARβ/δ in Human Psoriasis and Imiquimod-induced Murine Psoriasiform Dermatitis Model

“…This pathway is tightly regulated through feedback loops in part via two mTOR complexes, (C1 and 2), linkage is through Akt. PI3K activation triggers the phosphorylation of phosphatidylinositol on the 3-hydroxyl group to PI (3, 4, 5) P3, which then activates Akt kinase and promotes keratinocyte hyperproliferation and inhibit differentiation, as observed in psoriasis {Huang, 2014 #7}. Initial clinical data suggest that mTOR inhibitors, especially the second-generation inhibitors (targeting both mTOR and PI3-K kinases) provide therapeutic benefit for psoriasis {Frigerio, 2007 #9}.…”

Blocking mTOR Signalling with Rapamycin Ameliorates Imiquimod-induced Psoriasis in Mice

“…We have shown previously that the mTOR kinase itself and its downstream target, ribosomal protein S6, are hyper-activated in psoriatic lesions (9,10). In addition, the PI3-K/mTOR pathway is thought to play a role in Th1-Th2-Th17 imbalance in the pathogenesis of psoriasis (11). The mTOR inhibitor rapamycin, also known as sirolimus, was initially investigated as an antifungal agent and was used for its immunosuppressant properties (12) and also showed anti-tumourigenic potential.…”