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

Abstract

Psoriasis is an inflammatory disorder characterized by keratinocyte hyper‐proliferation and Th17‐type immune responses. However, the roles of bioactive lipids and the regulation of their biosynthesis in this chronic skin disease are not fully understood. Herein, we show that group IVE cytosolic phospholipase A2 (cPLA2ε/PLA2G4E) plays a counterregulatory role against psoriatic inflammation by producing the anti‐inflammatory lipid N‐acylethanolamine (NAE). Lipidomics analysis of mouse skin revealed that NAE species and their precursors (N‐acyl‐phosphatidylethanolamine and glycerophospho‐N‐acylethanolamine) were robustly increased in parallel with the ongoing process of imiquimod (IMQ)‐induced psoriasis, accompanied by a marked upregulation of cPLA2ε in epidermal keratinocytes. Genetic deletion of cPLA2ε exacerbated IMQ‐induced ear swelling and psoriatic marker expression, with a dramatic reduction of NAE‐related lipids in IMQ‐treated, and even normal, skin. Stimulation of cultured human keratinocytes with psoriatic cytokines concomitantly increased PLA2G4E expression and NAE production, and supplementation with NAEs significantly attenuated the cytokine‐induced upregulation of the psoriatic marker S100A9. Increased expression of cPLA2ε was also evident in the epidermis of psoriatic patients. These findings reveal for the first time the in vivo role of cPLA2ε, which is highly induced in the keratinocytes of the psoriatic skin, promotes the biosynthesis of NAE‐related lipids, and contributes to limiting psoriatic inflammation.

A BRAF mutation-associated gene risk model for predicting the prognosis of melanoma

“…In addition, a few other studies revealed that FUT8, PLA2G5, PLA2G1B, and B3GNT2 were involved in the immune response [ [32] , [33] , [34] ]. Furthermore, PLA2G4E has also been reported to play an anti-inflammatory role in skin or adipose tissue inflammation [ 35 , 36 ]. Taken together, these results indicate that the prognostic signature based on these seven genes was related to immune cell infiltration and immune checkpoint.…”

Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years

“…The high-resolution crystal structure of antagonist-bound CB 2 R was determined in 2019, which firstly discloses the binding mode of antagonist AM10257 (Li et al, 2019). The latter locates at the orthosteric ligand-binding pocket and mainly forms hydrophobic and aromatic interactions with residues from extracellular loop 2, as well as the cytoplasmic parts of transmembrane helices 2, 3, 5 and 6 of CB 2 R (Fig.…”

“…Recently, several 3D structures of CB 2 R in complex with ligands have been reported (Li et al, 2019;Hua et al, 2020;Xing et al, 2020). Furthermore, a broad variety of labelled chemical probes was generated and applied in mechanistic studies (Basagni et al, 2020;Haider et al, 2020;Sarott et al, 2020;Gazzi et al, 2022;Guberman et al, 2022), and have contributed to understand the structural basis of selective CB 2 R activation (Li et al, 2023).…”

The Roles of sPLA2s in Skin Homeostasis and Disease

“…Furthermore, dysregulated production of lipid mediators derived from FFAs or LPLs can be linked to various skin disorders such as hair loss, epidermal hyperplasia, dermatitis, and cancer [ 49 , 55 , 56 ]. For instance, arachidonic acid (AA)-oxygenated lipid mediators, including prostaglandins and leukotrienes, whose production is in many cases regulated by cytosolic PLA 2 α (cPLA 2 α; PLA2G4A) coupled with cyclooxygenases and lipoxygenases [ 57 ], variably regulate immunological responses in skin diseases [ 58 ]; N -acylethanolamines, a distinct class of lipid mediators having a structure of FFA condensed with ethanolamine, are produced by cPLA 2 ε (PLA2G4E) in epidermal keratinocytes and suppress psoriatic inflammation [ 59 ]; and lysophosphatidic acid (LPA), spatiotemporally generated by phosphatidic acid-specific phospholipase A 1 (PA-PLA 1 α) in hair follicles, regulates hair growth and quality [ 55 ].…”