Phospholipase A2 enzymes represent a shared pathogenic pathway in psoriasis and pityriasis rubra pilaris.

Shuai Shao,Nicole L Ward,Victoria E Scott,J Michelle Kahlenberg,Olesya Plazyo,Paul W Harms,Rachael Wasikowski,Lam C Tsoi,Jiaoling Chen,Kathleen M Smith,Gang Wang,Ranjitha Uppala,William R Swindell,Emanual Maverakis,Mrinal K Sarkar,Xianying Xing,Allison C Billi,Feiyang Ma,Prisca Honoré ,Jóhann E Guðjónsson

doi:10.1172/jci.insight.151911

Abstract

Altered epidermal differentiation along with increased keratinocyte proliferation is a characteristic feature of psoriasis and pityriasis rubra pilaris (PRP). However, despite this large degree of overlapping clinical and histologic features, the molecular signatures these skin disorders share are unknown. Using global transcriptomic profiling, we demonstrate that plaque psoriasis and PRP skin lesions have high overlap, with all differentially expressed genes in PRP relative to normal skin having complete overlap with those in psoriasis. The major common pathway shared between psoriasis and PRP involves the phospholipases PLA2G2F, PLA2G4D, and PLA2G4E, which were found to be primarily expressed in the epidermis. Gene silencing each of the 3 PLA2s led to reduction in immune responses and epidermal thickness both in vitro and in vivo in a mouse model of psoriasis, establishing their proinflammatory roles. Lipidomic analyses demonstrated that PLA2s affect mobilization of a phospholipid-eicosanoid pool, which is altered in psoriatic lesions and functions to promote immune responses in keratinocytes. Taken together, our results highlight the important role of PLA2s as regulators of epidermal barrier homeostasis and inflammation, identify PLA2s as a shared pathogenic mechanism between PRP and psoriasis, and as potential therapeutic targets for both diseases.

Highlights

Psoriasis and pityriasis rubra pilaris (PRP) have marked clinical and histological overlap, with both characterized by hyperplastic and hyperproliferative epidermis and varying degrees of dermal inflammatory infiltration [1,2,3]
To determine if PRP and psoriasis share pathogenic mechanisms, we performed a transcriptomic study using archived formalin-fixed, paraffin-embedded (FFPE) biopsy samples from a cohort of patients with PRP along with available FFPE samples from previous psoriasis studies [24,25,26] for comparison. This led to our identification of 3 members of the Phospholipase A2 (PLA2) family, both soluble (PLA2G2F) and cytoplasmic (PLA2G4D and PLA2G4E), as a critical pathogenic pathway shared between PRP and psoriasis
Our data further suggest that these enzymes are critical components downstream of tumor necrosis factor (TNF) and IL-17A, a major circuit in psoriasis pathogenesis, and are sufficient to promote abnormal differentiation and expression of additional proinflammatory cytokines, thereby providing a plausible pathway by which they may promote many of the changes in both psoriasis and PRP

Summary

Introduction

Psoriasis and pityriasis rubra pilaris (PRP) have marked clinical and histological overlap, with both characterized by hyperplastic and hyperproliferative epidermis and varying degrees of dermal inflammatory infiltration [1,2,3]. These two conditions share many molecular features such as skin barrier abnormalities [1, 4, 5], which has further led to the description of an intermediate psoriasis/familial PRP phenotype referred to as caspase recruitment domain family member 14–associated (CARD14-associated) papulosquamous eruption [4], and possibly a shared interleukin 17 (IL-17) response [6, 7]. Lipid metabolism and PLA2 enzymes are likely to play a pathogenic role in psoriasis

Methods

Results

Conclusion