Phospholipase A2 in skin biology: new insights from gene-manipulated mice and lipidomics

Abstract

The skin represents one of the tissues that are most profoundly influenced by alterations in the quality of lipids (lipoquality). Lipids not only constitute cellular membranes, but also serve as bioactive lipid mediators and essential components of the skin barrier. Phospholipase A2 (PLA2) enzymes supply fatty acids and lysophospholipids from membrane phospholipids, thereby variably affecting cutaneous homeostasis. Accordingly, perturbation of particular PLA2-driven lipid pathways can be linked to various forms of skin disease. In this review article, we highlight the roles of several PLA2 subtypes in cutaneous pathophysiology, as revealed by transgenic/knockout studies in combination with comprehensive lipidomics. We focus mainly on secreted PLA2 group IIF (sPLA2-IIF), which is associated with epidermal hyperplasia through mobilization of a unique lipid metabolite. We also address the distinct roles of sPLA2-IIE in hair follicles and sPLA2-IID in lymphoid immune cells that secondarily affect cutaneous inflammation, and provide some insights into species differences in sPLA2s. Additionally, we briefly overview the patatin-like phospholipase PNPLA1, which belongs to the Ca2+-independent PLA2 (iPLA2) family, as a key regulator of skin barrier function through catalysis of a unique non-PLA2 reaction. These knowledges on lipid metabolism driven by various PLA2 subtypes will open novel opportunities for translated studies toward diagnosis and therapy of human skin diseases.

Logical and experimental modeling of cytokine and eicosanoid signaling in psoriatic keratinocytes

“…Interestingly, the inhibition of cPLA 2 ɑ (rows 4-6) mainly affects proliferation markers and only some inflammatory and immune cell markers. These results agree with previous studies of the role of PLA2 enzymes and their downstream products in psoriasis (Ashcroft et al , 2020) and skin biology in general (Murakami et al , 2018). Moreover, it is worth noting that the targeting of cPLA 2 ɑ appears to mainly act on the Th17 cell-related markers, but not on the Th1 markers.…”

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

“…The PLA2 family is a major regulator of lipid metabolism ( 20 ). To determine the immune regulatory roles of PLA2-regulated lipids in psoriasis, we first performed liquid or gas chromatography–mass spectrometry (LC/GC-MS) analysis of phospholipids and eicosanoids in normal (NC), nonlesional, and psoriatic skin (PV).…”

“…The PLA2G2F, PLA2G4D, and PLA2G4E enzymes are part of the phospholipase A2 family, which has over 30 members, consisting of both cytosolic PLA2s (such as PLA2G4D and PLA2G4E), and secreted PLA2s (i.e., PLA2G2F), with variable expression of different members in a broad range of tissues (11,20). Studies have demonstrated that PLA2 enzymes regulate lipid pathways, and that many of these lipid species generated by these enzymes serve as bioactive mediators and essential components of the skin barrier (20,27). In addition, individual PLA2 enzymes exhibit unique tissue and cellular distribution, suggesting that they have distinct biological roles in production of pro-and anti-inflammatory lipid mediators (20,28).…”

“…The PLA2G2F, PLA2G4D, and PLA2G4E enzymes are part of the PLA2 family, which has over 30 members, consisting of both cPLA2s (such as PLA2G4D and PLA2G4E), and sPLA2s (i.e., PLA2G2F), with variable expression of different members in a broad range of tissues ( 11 , 20 ). Studies have demonstrated that PLA2 enzymes regulate lipid pathways, and that many of these lipid species generated by these enzymes serve as bioactive mediators and essential components of the skin barrier ( 20 , 27 ).…”

Transcriptomic analysis reveals dynamic molecular changes in skin induced by mechanical forces secondary to tissue expansion

“…However, our report of differential expression of these genes for at least three days after initiation of TE indicates that it may be valuable to investigate their role in the mechanotransduction process. Of notable interest are genes SFRP2, which enhances the osteogenic differentiation of apical papilla stem cells by antagonizing the canonical WNT pathway 41 , and PLA2G2F, which regulates skin homeostasis and keratinocyte differentiation 42,43 . Additional genes include SPPI, which is involved in post-injury tissue remodeling in mice 44 , and SAA3, which regulates collagenase expression an in vitro in rabbit fibroblast, substantiating their roles in tissue remodeling 45 .…”