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

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 targeting each of the three PLA2s led to reduction of immune responses and epidermal thickness both in vitro and in vivo in a mouse model of psoriasis, establishing their pro-inflammatory 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 PLA2 lipases as regulators of epidermal barrier homeostasis and inflammation, identify PLA2s as a shared pathogenic mechanism between PRP and psoriasis, and as potential novel therapeutic targets for both diseases.

Group IVE cytosolic phospholipase A 2 limits psoriatic inflammation by mobilizing the anti‐inflammatory lipid N ‐acylethanolamine

“…A recent study by Shao et al using a cPLA 2 inhibitor has suggested that cPLA 2 ε, which is upregulated in keratinocytes by IL‐17A and TNFα, may play an exacerbatory role in psoriasis by producing AA‐derived eicosanoids 28 . However, our present findings argue against this, and in fact indicate that cPLA 2 ε plays a protective role against psoriasis by producing NAEs.…”

“…A recent study by Shao et al using a cPLA 2 inhibitor has suggested that cPLA 2 ε, which is upregulated in keratinocytes by IL-17A and TNFα, may play an exacerbatory role in psoriasis by producing AA-derived eicosanoids. 28 However, our present findings argue against this, and in fact indicate that cPLA 2 ε plays a protective role against psoriasis by producing NAEs. We speculate that the suppressive effect of the cPLA 2 inhibitor on psoriatic inflammation in the study by Shao et al may have resulted from inhibition of cPLA 2 α or some other cPLA 2 isoforms.…”

“…The PLA 2 superfamily, which includes ~50 enzymes in mammals, is classified into several subfamilies based on their structural relationship. 25 Pharmacological or gene targeting studies have revealed that group IVA cytosolic PLA 2 (cPLA 2 α/PLA2G4A) and group IIF secreted PLA 2 (sPLA 2 -IIF/PLA2G2F) promote psoriasis, [26][27][28] while group IID sPLA 2 (sPLA 2 -IID/PLA2G2D) counteracts it, 29,30 by mobilizing distinct PUFA-and LPL-derived lipid mediators.…”

Genome-wide single cell annotation of the human protein-coding genes

“…6B ), suggesting a role in skin barrier function. PLA2G4E is a phospholipase with a proinflammatory function and its expression has been shown to be absent in normal skin, but increased in the upper epidermal layers in patients with psoriasis and pityriasis rubra pillaris ( 53 ). Antibody-based profiling of PLA2G4E ( Fig.…”

Nutritional Therapy in Persons Suffering from Psoriasis

“…Increased levels of phospholipase A2 as well as arachidonic acid and its metabolites are found in psoriatic plaques. These factors may increase epidermal cell proliferation and inflammation [ 39 , 40 ].…”