PI3Kδ Sustains Keratinocyte Hyperproliferation and Epithelial Inflammation: Implications for a Topically Druggable Target in Psoriasis.

Laura Mercurio,Cristina Albanesi,Sabatino Pallotta,Stefania Madonna,Claudia Scarponi,Giovanni Luca Scaglione,Martina Morelli

doi:10.3390/cells10102636

Abstract

The phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathway is aberrantly activated in psoriatic lesions and contributes to disease pathogenesis. Among PI3Ks enzymes, PI3Kα, β, and δ isoforms are known to bind the p85 regulatory subunit and mediate activation of AKT and other downstream effectors. In this study, we deepened our understanding of the expression and function of PI3Kδ in skin lesions of patients affected by psoriasis. For the first time, we found that PI3Kδ is overexpressed in psoriatic plaques, and its expression is not only confined to infiltrating immune cells but also accumulates in proliferating keratinocytes of the epidermal basal layer. We investigated the function of PI3Kδ in psoriatic skin by evaluating the impact of seletalisib, a newly developed selective PI3Kδ inhibitor, in both in vitro and in vivo experimental models of psoriasis. Of note, we found that PI3Kδ sustains keratinocyte hyperproliferation and impaired terminal differentiation induced by IL-22, as well as induces epithelial inflammation and resistance to apoptosis mediated by TNF-α in human keratinocytes. Mechanistically, PI3Kδ promotes PDK1 phosphorylation and signals through AKT-dependent or -independent pathways. It is worth mentioning that PI3Kδ inhibition by seletalisib attenuates the severity of psoriasiform phenotype induced in the Imiquimod-induced mouse model of psoriasis by restoring the physiological proliferation and differentiation programs in epidermal keratinocytes and contrasting the cutaneous inflammatory responses. Therefore, we suggest PI3Kδ as a potential topically druggable target in psoriasis and skin diseases characterized by epidermal hyperproliferation and skin inflammation.

Highlights

Psoriasis is a chronic inflammatory skin disease characterized by epidermal alterations and a high number of skin-infiltrating immune cells [1,2]
In order to investigate on the expression of phosphatidylinositol 3-kinase (PI3K) isoforms in skin of patients affected by psoriasis, two RNA-seq datasets (GSE13355 and GSE41662) relative to differentially expressed genes among healthy skin and diseased skin of patients with psoriasis were questioned
We further explored the expression of PI3K isoforms in response to IL-22, IL-17A, tumor necrosis factor α (TNF-α), and IFN-γ, pro-inflammatory cytokines deeply involved in psoriasis pathogenesis

Summary

Introduction

Psoriasis is a chronic inflammatory skin disease characterized by epidermal alterations and a high number of skin-infiltrating immune cells [1,2]. The inflammatory cell infiltrate includes polarized T-helper lymphocytes (Th); Th17- and Th22-releasing pro-inflammatory cytokines such as interleukin (IL)-17; IL-22; tumor necrosis factor α (TNF-α); and IFN-γ with a pathogenic action on epidermal keratinocytes. These lymphocyte-released cytokines promote epidermal hyperproliferation and aberrant differentiation and induce the secretion of pro-inflammatory molecules, contributing to skin alterations and the manifestation of erythematous plaques [3,4,5,6]. The modulation or inhibition of PI3K/AKT/mTOR signaling resulted in the amelioration of dermatitis, with reduction of epidermal hyperproliferation and skin inflammation [15,16]

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Results

Conclusion