Lymphoid tissue phospholipase A2 group IID resolves contact hypersensitivity by driving antiinflammatory lipid mediators

Miki, Yoshimi; Yamamoto, Kei; Taketomi, Yoshitaka; Sato, Hiroyasu; Shimo, K; Kobayashi, Tetsuyuki; Ishikawa, Yukio; Ishii, Toshiharu; Nakanishi, Hiroki; Ikeda, Kazutaka; Taguchi, Ryo; Kabashima, Kenji; Arita, Makoto; Arai, Hiroyuki; Lambeau, Gérard; Bollinger, James; Hara, Shuntaro; Gelb, Michael H.; Murakami, Makoto

doi:10.1084/jem.20121887

Cited by 127 publications

(205 citation statements)

References 80 publications

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“…These differences can be explained, at least in part, by distinct localizations of these two sPLA 2 s in skin niches (see above) as well as by their distinct substrate specificities (see below), which could have different impacts on epidermal homeostasis and diseases. This view also contrasts with the exacerbation of psoriasis and contact dermatitis with augmented Th1/Th17 immune responses in mice lacking sPLA 2 -IID, a "resolving sPLA 2 " that is expressed in dendritic cells and regulates the functions of immune cells rather than keratinocytes by producing 3 PUFA-derived pro-resolving lipid mediators (37,48).…”

Section: Discussionmentioning

confidence: 94%

Expression and Function of Group IIE Phospholipase A2 in Mouse Skin

Yamamoto

Miki²,

Sato³

et al. 2016

Journal of Biological Chemistry

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Recent studies using knock-out mice for various secreted phospholipase A 2 (sPLA 2 ) isoforms have revealed their non-redundant roles in diverse biological events. In the skin, group IIF sPLA 2 (sPLA 2 -IIF), an "epidermal sPLA 2 " expressed in the suprabasal keratinocytes, plays a fundamental role in epidermal-hyperplasic diseases such as psoriasis and skin cancer. In this study, we found that group IIE sPLA 2 (sPLA 2 -IIE) was expressed abundantly in hair follicles and to a lesser extent in basal epidermal keratinocytes in mouse skin. Mice lacking sPLA 2 -IIE exhibited skin abnormalities distinct from those in mice lacking sPLA 2 -IIF, with perturbation of hair follicle ultrastructure, modest changes in the steady-state expression of a subset of skin genes, and no changes in the features of psoriasis or contact dermatitis. Lipidomics analysis revealed that sPLA 2 -IIE and -IIF were coupled with distinct lipid pathways in the skin. Overall, two skin sPLA 2 s, hair follicular sPLA 2 -IIE and epidermal sPLA 2 -IIF, play non-redundant roles in distinct compartments of mouse skin, underscoring the functional diversity of multiple sPLA 2 s in the coordinated regulation of skin homeostasis and diseases.Lipids constitute an essential component of skin homeostasis and diseases. The epidermis is a highly organized stratified epithelium having four distinctive layers comprising the innermost stratum basale, the stratum spinosum, the stratum granulosum, and the outermost stratum corneum (SC) 2 (1). The hair follicle, a skin appendage formed by interactions between epidermal keratinocytes committed to hair follicle differentiation and dermal fibroblasts committed to formation of the dermal papilla, undergoes repeated cycles of growth (anagen), regression (catagen), and rest (telogen) during life span (2). Nutritional insufficiency of essential fatty acids causes epidermal and hair abnormalities (1), and genetic mutations in several steps of skin lipid metabolism variably and often severely affect SC barrier function or hair cycling, thereby causing or exacerbating skin disorders such as ichthyosis, psoriasis, atopic dermatitis, and alopecia (3-6). Linoleic acid (LA), by far the most abundant polyunsaturated fatty acid (PUFA) in the SC, is crucial for the formation of acylceramide, an essential component of the cornified lipid envelope (7,8). Fatty acids have also been implicated in SC acidification (9 -11). Furthermore, dysregulated production of lipid mediators derived from PUFAs or lysophospholipids can be linked to skin disorders such as hair loss, epidermal hyperplasia, dermatitis, and cancer (6, 12, 13).Phospholipase A 2 (PLA 2 ) enzymes hydrolyze the sn-2 position of phospholipids to release fatty acids and lysophospholipids, which act as precursors of a variety of lipid mediators. Of the PLA 2 enzymes, cytosolic PLA 2 ␣ plays a central role in eicosanoid generation by selectively releasing arachidonic acid (AA) (14, 15), and Ca 2ϩ -independent PLA 2 s are involved in energy metabolism and neurodegeneration (16,17). ...

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Section: Discussionmentioning

confidence: 94%

Expression and Function of Group IIE Phospholipase A2 in Mouse Skin

Yamamoto

Miki²,

Sato³

et al. 2016

Journal of Biological Chemistry

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“…1 and 2 ) ( 64,70,74,112,121,132,134,135 ). It is now obvious that individual sPLA 2 s play unique and tissue-specifi c roles by acting on extracellular phospholipids, which include adjacent cell membranes, noncellular lipid components, and foreign phospholipids, such as those in microbes and food.…”

Section: Discussionmentioning

confidence: 99%

“…Nonetheless, several functions of sPLA 2 s in mice, as depicted in Fig. 2 , appear to be conserved in humans ( 55,70,74,93,117,134 ). Further advances in this research fi eld and their integration for therapeutic applications are expected to benefi t from improved lipidomics that will allow monitoring of individual sPLA 2 s and associated lipid metabolisms within specifi c tissue niches.…”

Section: Discussionmentioning

confidence: 99%

“…This isoform is expressed preferentially in dendritic cells (DCs) in secondary lymphoid organs such as the spleen and lymph nodes of mice and humans ( 70 ), suggesting its regulatory role in adaptive immunity. In a model of Th1-dependent contact hypersensitivity, resolution of infl ammation is compromised in the skin and lymph nodes of Pla2g2d Ϫ / Ϫ mice ( 70 ).…”

Section: S Participate In Diverse Biologicalmentioning

confidence: 99%

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A new era of secreted phospholipase A₂

et al. 2015

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More than one third of the phospholipase A 2 (PLA 2 ) enzymes belong to the secreted PLA 2 (sPLA 2 ) family, which contains 10 catalytically active isoforms (IB, IIA, IIC, IID, IIE, IIF, III, V, X, and XIIA) and one inactive isoform (XIIB) in mammals ( 1-4 ). Individual sPLA 2 s exhibit unique tissue and cellular distributions and substrate selectivity, suggesting their distinct biological roles. Because sPLA 2 s are secreted and require millimolar Ca 2+ for their catalytic action, they principally target phospholipids in the extracellular space. Individual sPLA 2 s participate in diverse biological This work was supported by

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“…S7 A and B), which we propose is due to colocalization of COX-2, FLAP, and 5-LOX at the perinuclear membrane along with cPLA 2 . A phospholipase that is largely expressed in dendritic cells, group IID sPLA 2 , has also recently been found to contribute to proresolution mediator synthesis as well as the resolution of skin inflammation (26). Thus, coordination between different PLA 2 isoforms may also be required to facilitate maximal proresolution mediator synthesis in physiological contexts.…”

Section: Discussionmentioning

confidence: 99%

Phospholipase A₂regulates eicosanoid class switching during inflammasome activation

Norris¹,

Gosselin

Reichart

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

118

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Initiation and resolution of inflammation are considered to be tightly connected processes. Lipoxins (LX) are proresolution lipid mediators that inhibit phlogistic neutrophil recruitment and promote wound-healing macrophage recruitment in humans via potent and specific signaling through the LXA 4 receptor (ALX). One model of lipoxin biosynthesis involves sequential metabolism of arachidonic acid by two cell types expressing a combined transcellular metabolon. It is currently unclear how lipoxins are efficiently formed from precursors or if they are directly generated after receptor-mediated inflammatory commitment. Here, we provide evidence for a pathway by which lipoxins are generated in macrophages as a consequence of sequential activation of toll-like receptor 4 (TLR4), a receptor for endotoxin, and P2X 7 , a purinergic receptor for extracellular ATP. Initial activation of TLR4 results in accumulation of the cyclooxygenase-2-derived lipoxin precursor 15-hydroxyeicosatetraenoic acid (15-HETE) in esterified form within membrane phospholipids, which can be enhanced by aspirin (ASA) treatment. Subsequent activation of P2X 7 results in efficient hydrolysis of 15-HETE from membrane phospholipids by group IVA cytosolic phospholipase A 2 , and its conversion to bioactive lipoxins by 5-lipoxygenase. Our results demonstrate how a single immune cell can store a proresolving lipid precursor and then release it for bioactive maturation and secretion, conceptually similar to the production and inflammasome-dependent maturation of the proinflammatory IL-1 family cytokines. These findings provide evidence for receptor-specific and combinatorial control of pro-and anti-inflammatory eicosanoid biosynthesis, and potential avenues to modulate inflammatory indices without inhibiting downstream eicosanoid pathways.lipidomics | enzyme coupling | membrane remodeling A complex network of danger-sensing receptors and bioactive peptide and lipid signals, including cytokines and eicosanoids, regulates innate immunity. Toll-like receptor (TLR) priming is suggested as a precautionary step in building a significant inflammatory response by driving production of IL-1 family protokines, which remain inactive until a second stimulus drives them to bioactive maturation and secretion (1). The second step of this process has been most strongly linked to extracellular ATP and specifically to one of its purinergic receptors, P2X 7 (2, 3), particularly in macrophages (4).TLR stimulations also increase prostaglandin synthesis by activating cytosolic phospholipase A 2 (cPLA 2 ) through a Ca 2+ -independent mechanism to release arachidonic acid (AA) from phospholipids, and by increasing expression of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E 2 synthase-1. P2X 7 stimulation activates cPLA 2 through a Ca 2+ -dependent mechanism that couples AA metabolism with 5-lipoxygenase (5-LOX)-activating protein (FLAP), Ca 2+ -activated 5-LOX, and constitutive COX-1 to form leukotrienes (LTs) and prostaglandins (PGs). Short-term (∼1 h) TLR priming of ...

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Lymphoid tissue phospholipase A2 group IID resolves contact hypersensitivity by driving antiinflammatory lipid mediators

Abstract: PLA2G2D ameliorates skin inflammation through mobilizing pro-resolving lipid mediators.

Cited by 127 publications

References 80 publications

Expression and Function of Group IIE Phospholipase A2 in Mouse Skin

Expression and Function of Group IIE Phospholipase A2 in Mouse Skin

A new era of secreted phospholipase A₂

Phospholipase A₂regulates eicosanoid class switching during inflammasome activation

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Lymphoid tissue phospholipase A2 group IID resolves contact hypersensitivity by driving antiinflammatory lipid mediators

Abstract: PLA2G2D ameliorates skin inflammation through mobilizing pro-resolving lipid mediators.

Cited by 127 publications

References 80 publications

Expression and Function of Group IIE Phospholipase A2 in Mouse Skin

Expression and Function of Group IIE Phospholipase A2 in Mouse Skin

A new era of secreted phospholipase A2

Phospholipase A2regulates eicosanoid class switching during inflammasome activation

Contact Info

Product

Resources

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A new era of secreted phospholipase A₂

Phospholipase A₂regulates eicosanoid class switching during inflammasome activation