Vitamin D Analogs Differentially Control Antimicrobial Peptide/“Alarmin”Expression in Psoriasis

Mark Peric,Ulrich Zügel,Amanda Büchau,Jürgen Schauber,Andreas Steinmeyer,Eva Bradac,Thomas Ruzicka,Yvonne Dombrowski,Sarah Koglin,Katrin Groß,Derya Unutmaz

doi:10.1371/journal.pone.0006340

Abstract

Antimicrobial peptides (AMPs) are strongly expressed in lesional skin in psoriasis and play an important role as proinflammatory “alarmins” in this chronic skin disease. Vitamin D analogs like calcipotriol have antipsoriatic effects and might mediate this effect by changing AMP expression. In this study, keratinocytes in lesional psoriatic plaques showed decreased expression of the AMPs β-defensin (HBD) 2 and HBD3 after topical treatment with calcipotriol. At the same time, calcipotriol normalized the proinflammatory cytokine milieu and decreased interleukin (IL)-17A, IL-17F and IL-8 transcript abundance in lesional psoriatic skin. In contrast, cathelicidin antimicrobial peptide expression was increased by calcipotriol while psoriasin expression remained unchanged. In cultured human epidermal keratinocytes the effect of different vitamin D analogs on the expression of AMPs was further analyzed. All vitamin D analogs tested blocked IL-17A induced HBD2 expression by increasing IκB-α protein and inhibition of NF-κB signaling. At the same time vitamin D analogs induced cathelicidin through activation of the vitamin D receptor and MEK/ERK signaling. These studies suggest that vitamin D analogs differentially alter AMP expression in lesional psoriatic skin and cultured keratinocytes. Balancing AMP “alarmin” expression might be a novel goal in treatment of chronic inflammatory skin diseases.

Highlights

Psoriasis is a chronic inflammatory skin disorder which affects approximately 2% of the general population
Expression of cathelicidin, HBD2, HBD3 and psoriasin were significantly increased in psoriatic plaques (Figure 1A)
Increased gene copy numbers of the b-defensins (HBDs) correlate with the risk to develop this disease [1] and cathelicidin peptide, which is increased in psoriatic skin, induces an autoinflammatory cascade leading to skin inflammation [11]

Summary

Introduction

Psoriasis is a chronic inflammatory skin disorder which affects approximately 2% of the general population. A large body of evidence has identified a dysregulated interplay between keratinocytes and infiltrating immune cells underlying cutaneous inflammation in psoriasis [3]. Cytokines and other soluble factors such as antimicrobial peptides (AMPs) secreted by resident or infiltrating cells are essential elements in this process of cell-cell communication. AMPs were characterized as effector molecules of innate immunity as they provide a first barrier of defence against microbial pathogens [4]. An array of additional functions of AMPs has been identified and due to their multiple functions as activators of adaptive immune responses and inflammation the term ‘‘alarmins’’ has been introduced [5]. Two families of AMPs are among the best characterized for their ‘‘alarmin’’ function: the defensins and the cathelicidins

Methods

Results

Conclusion