Hair Follicular Expression and Function of Group X Secreted Phospholipase A2 in Mouse Skin

Abstract

Although perturbed lipid metabolism can often lead to skin abnormality, the role of phospholipase A 2 (PLA 2 ) in skin homeostasis is poorly understood. In the present study we found that group X-secreted PLA 2 (sPLA 2 -X) was expressed in the outermost epithelium of hair follicles in synchrony with the anagen phase of hair cycling. Transgenic mice overexpressing sPLA 2 -X (PLA2G10-Tg) displayed alopecia, which was accompanied by hair follicle distortion with reduced expression of genes related to hair development, during a postnatal hair cycle. Additionally, the epidermis and sebaceous glands of PLA2G10-Tg skin were hyperplasic. Proteolytic activation of sPLA 2 -X in PLA2G10-Tg skin was accompanied by preferential hydrolysis of phosphatidylethanolamine species with polyunsaturated fatty acids as well as elevated production of some if not all eicosanoids. Importantly, the skin of Pla2g10-deficient mice had abnormal hair follicles with noticeable reduction in a subset of hair genes, a hypoplasic outer root sheath, a reduced number of melanin granules, and unexpected up-regulation of prostanoid synthesis. Collectively, our study highlights the spatiotemporal expression of sPLA 2 -X in hair follicles, the presence of skin-specific machinery leading to sPLA 2 -X activation, a functional link of sPLA 2 -X with hair follicle homeostasis, and compartmentalization of the prostanoid pathway in hair follicles and epidermis.Hair follicle morphogenesis is regulated by interactions between epidermal keratinocytes committed to hair follicle differentiation and dermal fibroblasts committed to form the dermal papilla of the developing hair follicles (1-3). These epithelialmesenchymal interactions culminate in the formation of the hair shaft, which is surrounded by the multilayered inner root sheath (IRS) 3 and outer root sheath (ORS), the latter being the outermost concentric layer of epithelial cells. Hair follicles undergo repeated cycles of growth (anagen), regression (catagen), and rest (telogen) during their life span. Distinct signaling pathways and transcription factors control hair follicle morphogenesis, postnatal hair growth, and hair cycling in a coordinated manner. Accordingly, disturbance in the expression or function of these genes by point mutations, transgenic (Tg) overexpression, or targeted disruption often culminates in a hairless phenotype. Because hair loss due to various factors, such as diseases, hormonal imbalance, and drug regimens, affects a large population worldwide, there are compelling reasons to understand the fundamentals of hair biology.Current evidence suggests that, in addition to a variety of cytokines and growth factors (4, 5), lipids also play important roles in hair follicle homeostasis (6, 7). The PGE 2 receptors EP3 and EP4 are expressed in the dermal papilla and ORS of hair follicles (8, 9). COX-2 displays a trend of hair cycle-synchronized expression in the ORS of hair follicles (9), and skin-specific Tg overexpression of COX-2 leads to delayed emergence of hair shafts, reduced hair fo...

Expression and Function of Group IIE Phospholipase A2 in Mouse Skin

“…Notably, sPLA 2 -IIE is located in these affected regions (the innermost IRS layer and the companion layer along growing hairs) within hair follicles, lending further support to the idea that sPLA 2 -IIE regulates hair follicle homeostasis at these restricted locations. We previously reported that Pla2g10-transgenic mice displayed alopecia with perturbed hair cycling and that Pla2g10 Ϫ/Ϫ mice showed ORS hypoplasia (21). However, the very low expression of endogenous sPLA 2 -X in mouse skin argues against its hair follicle-intrinsic role.…”

“…This action of sPLA 2 -IIF as an "epidermal sPLA 2 " depends at least in part on the generation of plasmalogen lysophosphatidylethanolamine (P-LPE; lysoplasmalogen), a unique lysophospholipid that can promote keratinocyte activation and epidermal hyperplasia. Beyond sPLA 2 -IIF, transgenic overexpression of sPLA 2 -IIA or -X causes alopecia and epidermal hyperplasia (20,21), although endogenous expression of these two sPLA 2 s as well as sPLA 2 -IB, -IID, and -V in mouse skin is low or almost undetectable (19). sPLA 2 -IIE is an isoform structurally most homologous to sPLA 2 -IIA (22,23).…”

A new era of secreted phospholipase A2

“…In cases such as this, transgenic mice are useful when searching for lipidmetabolic processes driven by a particular sPLA 2 in vivo, because lipid mobilization in the transgenic mice is typically prominent and easy to chase using a lipidomics approach. Another noteworthy issue is that the overall phenotypes of mice transgenic for different sPLA 2 s are not entirely identical (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). If different sPLA 2 s have similar enzymatic properties, then the output phenotypes of mice transgenic for them should be similar.…”

“…LPC is a candidate product responsible for the action of sPLA 2 -X, because it can partially restore the defective fertilization of wild-type sperm treated with anti-sPLA 2 -X antibody ( 132 ). Lastly, a striking skin phenotype characterized by alopecia in Pla2g10 -transgenic mice points to a unique role of sPLA 2 -X in hair homeostasis ( 36 ). Although the coat hairs of Pla2g10 Ϫ / Ϫ mice appear grossly normal, they have ultrastructural abnormalities including a hypoplasic outer root sheath and reduced melanin granules in their hair follicles.…”

A new era of secreted phospholipase A2

“…Some of the biological actions of sPLA 2 s in vivo have been investigated using sPLA 2 -overexpressing transgenic mice (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). However, the results should be interpreted with caution, as a super-physiological level of sPLA 2 , even in tissues or cells where the enzyme is not intrinsically expressed, could result in an artifi cial phenotype.…”