Besides promoting inflammation by mobilizing lipid mediators, group IIA secreted phospholipase A ₂ (sPLA ₂ -IIA) prevents bacterial infection by degrading bacterial membranes. Here, we show that, despite the restricted intestinal expression of sPLA ₂ -IIA in BALB/c mice, its genetic deletion leads to amelioration of cancer and exacerbation of psoriasis in distal skin. Intestinal expression of sPLA ₂ -IIA is reduced after treatment with antibiotics or under germ-free conditions, suggesting its upregulation by gut microbiota. Metagenome, transcriptome, and metabolome analyses have revealed that sPLA ₂ -IIA deficiency alters the gut microbiota, accompanied by notable changes in the intestinal expression of genes related to immunity and metabolism, as well as in the levels of various blood metabolites and fecal bacterial lipids, suggesting that sPLA ₂ -IIA contributes to shaping of the gut microbiota. The skin phenotypes in Pla2g2a ^–/– mice are lost (a) when they are cohoused with littermate WT mice, resulting in the mixing of the microbiota between the genotypes, or (b) when they are housed in a more stringent pathogen-free facility, where Pla2g2a expression in WT mice is low and the gut microbial compositions in both genotypes are nearly identical. Thus, our results highlight a potentially new aspect of sPLA ₂ -IIA as a modulator of gut microbiota, perturbation of which affects distal skin responses.

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.

Among the phospholipase A₂ (PLA₂) family, the secreted PLA₂ (sPLA₂) family in mammals contains 11 members that exhibit unique tissue or cellular distributions and enzymatic properties. Current studies using knockout and/or transgenic mice for a nearly full set of sPLA₂s, in combination with comprehensive lipidomics, have revealed the diverse pathophysiological roles of sPLA₂s in various biological events. Individual sPLA₂s exert specific functions within tissue microenvironments, likely through the hydrolysis of extracellular phospholipids. Lipids are an essential biological component for skin homeostasis, and disturbance of lipid metabolism by deletion or overexpression of lipid-metabolizing enzymes or lipid-sensing receptors often leads to skin abnormalities that are easily visible on the outside. Over the past decades, our studies using knockout and transgenic mice for various sPLA₂s have uncovered several new aspects of these enzymes as modulators of skin homeostasis and disease. This article summarizes the roles of several sPLA₂s in skin pathophysiology, providing additional insight into the research fields of sPLA₂s, lipids, and skin biology.