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

Psoriasis is a common, and currently incurable chronic immune-mediated skin disease (1), with incompletely understood etiology partially due to the unavailability of animal models that can emulate major features of the disease. The phospho-inositol-3 kinase (PI3K)/protein kinase B(Akt) and mammalian target of rapamycin (mTOR) signaling which regulate metabolism, cell proliferation, survival, apoptosis, and frequently deregulated in diverse cancers (2, 3), has recently emerged as a clinically relevant target for inflammatory diseases including psoriasis (4, 5). This pathway is tightly regulated through feedback loops in part via 2 mTOR complexes, (C1 and 2), with linkage through Akt. PI3K activation triggers the phosphorylation of a 3-hydroxyl group, which then activates Akt kinase and promotes keratinocyte hyperproliferation and inhibit differentiation, as observed in psoriasis (4). Initial clinical data suggest that secondgeneration inhibitors (targeting both mTOR and PI3-K kinases) provide therapeutic benefit for psoriasis (6). Additionally, psoriasis-associated epidermal-type fatty acid-binding protein (FABP-5) involved in cytosolic fatty acid-transport, as well as the peroxisome proliferatoractivated receptor β/δ (PPAR β/δ), a ligand-activated transcription factor and member of the nuclear hormone receptors superfamily, are upregulated in psoriasis (7–9). The goal of this study was to assess whether mTOR, its upstream (PI3K and Akt) and downstream S6K1 (specifically S6Ser235/236 and S6Ser240/244) targets, as well as FABP5 and PPARβ/δ, are overexpressed in inflamed toll-like receptor-7/8 ligand imiquimod (IMQ)- induced Balb/c mouse skin lesions and, whether their expressions simulate those observed in inflamed skin lesions from untreated psoriatic patients compared with matched controls. © 2016 The Authors.