STAT2 is involved in the pathogenesis of psoriasis by promoting CXCL11 and CCL5 production by keratinocytes.

Claus Johansen,Maike Mose,Isabella Weimar,Jakob Nielsen,Lars Iversen,Bent Deleuran,Anne Hald Rittig,Trine Bertelsen,Tue Kruse Rasmussen,Thomas Andersen,Mauro Picardo

doi:10.1371/journal.pone.0176994

Abstract

The JAK/STAT signaling pathway is suggested to play an important role in the pathogenesis of psoriasis, and recently JAK/STAT inhibitors have shown promising results in psoriasis treatment. The present study aimed to characterize the role of STAT2 in psoriasis. We demonstrated an increased expression of STAT2 and an increased level of phosphorylated/activated STAT2 in lesional compared with nonlesional psoriatic skin. Gene silencing of STAT2 by siRNA in human keratinocytes revealed that upon IFNα stimulation CXCL11 and CCL5 were the only two cytokines, among 102 analyzed, found to be regulated through a STAT2-dependent mechanism. Moreover, the regulation of CXCL11 and CCL5 depended on IRF9, but not on STAT1 and STAT6. The CXCL11 and CCL5 expression was increased in lesional compared with nonlesional psoriatic skin, and analysis demonstrated positive correlation between the expression of CXCL11 and IFNγ and between the expression of CCL5 and IFNγ in lesional psoriatic skin. In contrast, no correlation between the expression of CXCL11 and IL-17A and the expression of CCL5 and IL-17A in lesional psoriatic skin was found. Our data suggest that STAT2 plays a role in the psoriasis pathogenesis by regulating the expression of CXCL11 and CCL5, and thereby attracting IFNγ-producing immune cells to the skin.

Highlights

Psoriasis is a chronic incurable systemic inflammatory disease affecting 2–3% of the total population worldwide [1]
Using qPCR analysis, we demonstrated a significantly elevated STAT2 mRNA expression in lesional psoriatic skin compared with nonlesional psoriatic skin and normal healthy controls, with a mean approximately 2.5-fold increase
In order to study if the observed increase in STAT2 expression was specific to psoriasis or due to increased inflammation in the skin we investigated the STAT2 expression in the inflammatory skin disease atopic dermatitis

Summary

Introduction

Psoriasis is a chronic incurable systemic inflammatory disease affecting 2–3% of the total population worldwide [1]. It is characterized by hyperproliferation and an abnormal differentiation of the keratinocytes as well as infiltration of immune cells into both the dermis and the epidermis [1]. Advances in our understanding of the role of intracellular signaling in psoriatic inflammation have led to the recognition that many key psoriatic cytokines converge on and initiate intracellular signaling through specific pathways [1, 3] One such intracellular signaling pathway, which is believed to play a key role in the pathogenesis of psoriasis is the JAK/STAT signaling pathway [4,5,6,7].

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