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Metabolic pathways of eicosanoids—derivatives of arachidonic acid and their significance in skin

Abstract

The skin is a barrier that protects the human body against environmental factors (physical, including solar radiation, chemicals, and pathogens). The integrity and, consequently, the effective metabolic activity of skin cells is ensured by the cell membrane, the important structural and metabolic elements of which are phospholipids. Phospholipids are subject to continuous transformation, including enzymatic hydrolysis (with the participation of phospholipases A, C, and D) to free polyunsaturated fatty acids (PUFAs), which under the influence of cyclooxygenases (COX1/2), lipoxygenases (LOXs), and cytochrome P450 (CYPs P450) are metabolized to various classes of oxylipins, depending on the type of PUFA being metabolized and the enzyme acting. The most frequently analyzed oxylipins, especially in skin cells, are eicosanoids, which are derivatives of arachidonic acid (AA). Their level depends on both environmental factors and endogenous metabolic disorders. However, they play an important role in homeostasis mechanisms related to the structural and functional integrity of the skin, including maintaining redox balance, as well as regulating inflammatory processes arising in response to endogenous and exogenous factors reaching skin cells. Therefore, it is believed that dysregulation of eicosanoid levels may contribute to the development of skin diseases, such as psoriasis or atopic dermatitis, which in turn suggests that targeted control of the generation of specific eicosanoids may have diagnostic significance and beneficial therapeutic effects. This review is the first systemic and very detailed approach presenting both the causes and consequences of changes in phospholipid metabolism leading to the generation of eicosanoids, changes in the level of which result in specific metabolic disorders in skin cells leading to the development of various diseases. At the same time, existing literature data indicate that further detailed research is necessary to understand a clear relationship between changes in the level of specific eicosanoids and the pathomechanisms of specific skin diseases, as well as to develop an effective diagnostic and therapeutic approach.

Introduction

The skin, acting as a barrier between the human body and the external environment, protects the body from mechanical injuries and the effects of external factors, such as physical [solar radiation, including ultraviolet (UV), temperature, and wind] and chemical (e.g., disinfectants, detergents) factors, as well as pathogens (bacteria, viruses, etc.) [1]. Additionally, it performs secretory and excretory functions [2]. Skin is also responsible for the biosynthesis of many hormones and hormone-like substances, including corticosteroids, androgens, and estrogens [3, 4], e.g., the biosynthesis of cholecalciferol (vitamin D3) and its active metabolites [5]. Furthermore, skin is involved in the metabolism of glucose, proteins, and lipids [6, 7].

The skin has a multilayered structure consisting of the epidermis, dermis, and subcutaneous tissue, where keratinocytes are the dominant epidermal cells. In the basal layer of the epidermis there are melanocytes that produce pigment and perform protective functions [8] and Langerhans cells, which, among others, process microbial antigens, playing a key role in immune mechanisms of the skin [9]. However, in the dermis, fibroblasts are surrounded by an extracellular matrix composed of glycosaminoglycans, proteoglycans, and structural proteins, such as collagen and elastin, as well as macromolecules, fibrin, and hyaluronic acid, which ensure skin elasticity and mechanical resistance [10]. Blood and lymphatic vessels are also located in this part of the skin, supplying oxygen and performing nutritional functions, as well as providing a transport route for immune cells [11].

The integrity and, consequently, the effective metabolic activity of individual skin cells is ensured by the cell membrane, which separates the cell’s interior from its environment and regulates transport and signaling between skin cells and their surroundings [7, 12]. The cell membranes of epidermal and dermal cells contain various types of lipids, including sterols, phospholipids, ceramides, and glycosphingolipids [13]. Among the structural components of the cell membrane, a metabolically important group are phospholipids [12, 13], which are found in the largest amounts in the cells of the basal layer, including keratinocytes, where they constitute about 70% of all cellular lipids [12]. The stability of the lipid bilayer structures of membranes depends on the composition of phospholipids as well as lipid-lipid and lipid-integral membrane proteins interactions [14, 15]. The functions of proteins and other membrane biomolecules are influenced by cholesterol, which, by modifying the rotation and diffusion of phospholipids, ensures the appropriate fluidity of the cell membrane [16, 17]. In addition to providing physiological conditions, membrane phospholipids also act as a barrier against environmental microorganisms by inhibiting bacterial cell membrane biosynthesis and modifying their metabolism [18].

Animal studies have shown that UV radiation contained in sunlight (UVA and UVB) modifies the level of various classes of lipids in animal skin keratinocytes (in vivo) [19], as well as in human fibroblasts irradiated in vitro [20]. Moreover, the development of skin diseases, such as psoriasis and atopic dermatitis, is accompanied by disorders of phospholipid metabolism in skin cells [21, 22].

In psoriasis, T lymphocytes are activated, which results in hyperproliferation of keratinocytes leading to increased production of free arachidonic acid and, consequently, proinflammatory mediators from the eicosanoid group [23]. This is accompanied by reduced levels of free short-chain fatty acids and increased cholesterol levels [24] as well as dysregulation of ceramide levels along with changes in their stratum corneum subtypes [25]. However, it should be noted that extracellular ceramides are necessary to maintain the skin’s water-holding capacity and permeability barrier, while intracellular ceramides play a key role in promoting keratinocyte differentiation [26]. One of the consequences of dysregulation of ceramide levels is damage to the epidermis, disruption of the epidermal barrier and, consequently, increased transepidermal water loss [27]. Moreover, it has been shown that the reduction of ceramide synthesis and their level in the epidermis positively correlates with the Psoriasis Area and Severity Index (PASI) in psoriasis [28]. Moreover, changes in the level of most groups of skin cell lipids were also found in keratinocytes isolated from patients with psoriasis [29].

However, in atopic dermatitis (AD), a decrease in the level of total lipids and dysregulation of the level of individual lipids is observed, as well as a decrease in the level of ceramides and a decrease in the length of the fatty acid chains of stratum corneum ceramides [12], which is accompanied by the accumulation of phospholipids [30]. It has also been found that oxidative stress accompanying the development of atopic dermatitis leads to increased trans isomerization of polyunsaturated fatty acids (PUFA) in membrane lipids, which contributes to increased lipid peroxidation, which disturbs the physiology of biological membranes and intracellular metabolism [31]. Moreover, in AD, there is an increased generation of lipid mediators, including arachidonic acid derivatives, which favors the modification of inflammation [32].

Skin lipids and their metabolism

Skin lipids are primarily produced by keratinocytes, sebocytes, and the skin microbiome [33]. Moreover sebocytes generate substances, such as squalene, triglycerides, fatty acids, wax esters, cholesterol, and cholesterol esters, which are secreted onto the skin’s surface. In keratinocytes, the synthesis of lipid precursors for the stratum corneum takes place, which, through the action of lipid synthases, leads to the formation of lipids in the stratum corneum, mainly ceramides, fatty acids, and cholesterol [34].

Lipid analysis of epidermal and dermal cell membranes showed that they contain twelve types of these compounds, including phospholipids, such as phosphatidic acid (PA), phosphatidylethanolamines (PE), cardiolipins (CL), phosphatidylserine (PS), lysophosphatidylcholines (LPC), phosphatidylinositols (PI), alkylacylglycerophosphocholines (AAPC), plasmalogen ethanolamines (Epla), and phosphatidylcholines (PC), as well as sphingolipids (SP), such as dihydrosphingomyelins (DHSM), sphingomyelins (SM), and ceramides (Cer) [13, 35]. The lipids forming the skin’s lamellar barrier consist of 50% ceramides in the stratum corneum, primarily CER[AH], CER[NS] and CER[AS] [36]. The source of lipids is also the skin microbiome, whose metabolism is based mainly on short-chain fatty acids [1]. Furthermore, lipids, mainly ceramides, are also synthesized in other cells such as fibroblasts and melanocytes, though in much smaller quantities [37, 38]. Among them, PCs are found in the largest amounts and higher levels of PEs are observed in the deeper layers of the epidermis, while in the stratum corneum ceramides are found in greater amounts [13].

It is known that the metabolic stability of skin cells is largely dependent on the phospholipid composition of the bilayer of their cell membranes [12, 13]. However, the structure and level of individual phospholipids in biological membranes depend on both the biosynthesis and metabolism of these compounds. In the process of phospholipid biosynthesis in mammalian cells, which is a complex and multidirectional process, phosphatidic acid plays a key role [12, 39].

As a result of oxidation processes intensified by external factors (UV radiation, chemical factors, pathogens), there is an overproduction of reactive oxygen species (ROS) in skin, which is usually accompanied by a reduction in antioxidant capacity, which intensifies, among others, oxidative metabolism of phospholipids to produce lipid peroxidation products, such as small unsaturated aldehydes, including 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), as well as cyclic fatty acid derivatives [isoprostanes (IsoP), isothromboxanes (IsoTX), isolevuglandins (IsoLG), and isofurans (IsoFS)] [40, 41]. However, phospholipid metabolism is primarily associated with their enzymatic hydrolysis involving phospholipases, leading to the release of free fatty acids, including polyunsaturated fatty acids (PUFAs), and their enzymatic metabolism generating reactive products, such as eicosanoids and endocannabinoids [42,43,44]. As a result of the hydrolysis of phospholipid ester bonds by phospholipases, bioactive metabolites are generated, which not only affect cellular metabolism but also cause continuous remodeling of cell membranes [44, 45], thereby ensuring their proper functioning adapted to the cell’s requirements [42, 45]. Consequently, it is believed that modifications in the activity of phospholipases controlling the level of membrane phospholipids may constitute a component of skin disease therapy [42] (Fig. 1).

Fig. 1
figure 1

Metabolism of membrane phospholipids and endocannabinoids with the release of arachidonic acid. AA arachidonic acid, DAG diacylglycerol, DAGL diacylglycerol lipase, FAAH fatty acid amide hydrolase, LPP lipid phosphate phosphatase, MAG monoacylglycerol, MAGL monoacylglycerol lipase, PA phosphatidic acid, PLA2 phospholipase A2, PLC phospholipase C, PLD phospholipase D

In skin, there are enzymes belonging to four main classes of phospholipases, designated as: A (A1, A2), B, C, and D, among which phospholipases A1/2 and B release fatty acids, while phospholipases C and D act as phosphodiesterases, participating in the generation of phosphatidic acid and 1,2-diacylglycerol (DAG), which undergo metabolism into free fatty acids [46]. Phospholipase A1 (PLA1) catalyzes the hydrolysis of the ester bond at the sn-1 position, where saturated fatty acids are located; whereas phospholipase A2 (PLA2) catalyzes the hydrolysis of the ester bond at the sn-2 position of glycerophospholipids, mainly phosphatidylcholine and phosphatidylethanolamine, usually leading to the release of polyunsaturated fatty acids, including arachidonic acid (AA) [47,48,49], while phospholipase B (PLB) hydrolyzes acyl chains from both the sn-1 and sn-2 positions; however, the full catalytic mechanism of phospholipase B is not yet fully understood [50]. However, phospholipase C (PLC) catalyzes the hydrolysis of 4,5-bisphosphate phosphatidylinositol (PIP2) to generate inositol-1,4,5-triphosphate (IP3) and DAG [51], which, under the action of diacylglycerol lipase (DAGL), undergoes metabolism into AA and monoacylglycerol (MAG), which then, under the action of monoacylglycerol lipase (MAGL), is hydrolyzed into glycerol and free AA [44]. Phospholipase D (PLD) is responsible for hydrolyzing the phosphodiester bond of phosphatidylcholine, releasing choline and PA—a glycerophospholipid, which under the action of PLA2 is then hydrolyzed into free arachidonic acid and lysophosphatidic acid (LPA). Phosphatidic acid is metabolized by lipid-phosphate phosphatase (LPP) to DAG, and further, as shown above, to arachidonic acid [52]. Additionally, endocannabinoids and their derivatives, belonging to the group of ester, ether, or amide derivatives of fatty acids, are hydrolyzed by fatty acid amide hydrolase (FAAH) to ethanolamine and fatty acid, and by MAGL to glycerol and fatty acid [43]. Owing to the low concentration of endocannabinoids in the skin, the level of free fatty acids arising from endocannabinoids is several orders of magnitude lower than those arising from phospholipids [53].

Skin phospholipases

PLA2

The primary phospholipase found in skin is PLA2, with the mammalian genome encoding over 50 isoforms of PLA2 or related enzymes, which are divided into several families on the basis of their structure and function. There are three main families of phospholipase A2: secretory—(sPLA2), cytosolic calcium dependent (cPLA2), and cytosolic calcium independent (iPLA2). The cPLA2 family comprises six isoforms (α-ζ), while the iPLA2 family consists of nine isoforms. Isoenzymes from the iPLA2 family are designated as PNPLA1–9. The sPLA2 family contains 10 catalytically active isoforms (IB, IIA, IIC, IID, IIE, IIF, III, V, X, XIIA) and 1 inactive isoform (XIIB) [54]. Table 1 presents the classification of the phospholipase A2 family.

Table 1 Classification of the PLA2 isozyme families present in human and mouse skin depending on cellular location and substrate specificity

The cytosolic isoforms of PLA2 (cPLA2) primarily hydrolyze PC and PE, with cPLA2 isoenzymes exhibiting varied specificity in releasing fatty acids from the sn-2 position of phospholipids. The phospholipase cPLA2-IIα specifically releases AA, whereas other isoforms, including both cPLA2-IIβ and cPLA2-IIγ, lack fatty acid specificity. However, the cPLA2-IIδ isoform is a specific hydrolase for linoleic acid (LA), and the isoforms cPLA2-IIε and cPLA2-IIζ release both AA and LA from phospholipids [55, 56]. Isoenzymes from the iPLA2 family do not exhibit specificity toward any fatty acid [55].

Considering the metabolic changes in keratinocytes resulting from diverse phospholipase activities, it has been demonstrated that inhibition of cPLA2-α phospholipase limits the release of proinflammatory prostaglandin PGE2, thus alleviating inflammation and keratinocyte proliferation in human immortalized keratinocytes (HaCaT) [57]. Furthermore, it has been found that in HaCaT stimulated by proinflammatory cytokines (IL-17A, IL-17F, IL-1β, TNF-α, IL-6, IL-22), activation of the cPLA2ε isoform increases the generation of anti-inflammatory N-acylethanolamines (NAEs), which alleviate epidermal hyperplasia, skin swelling, and reduce the expression of psoriatic markers, such as S100A9 proteins [60]. Conversely, the opposite effect is observed during the deletion of the cPLA2ε gene [60], and inhibition of the cPLA2β isoform in murine keratinocytes (PAM212) suppresses cell proliferation and migration [58].

Isoenzymes from the sPLA2 family, such as sPLA2-IB and sPLA2-IIA, primarily hydrolyze anionic phospholipids, such as phosphatidylglycerols prostaglandin (PG), PS, and PE, but are practically inactive toward PC. Similar dependencies have been shown for sPLA2 isoforms II and III. However, sPLA2 isoforms V and X hydrolyze PC with significantly higher efficiency compared with other members of the sPLA2 family [65]. It has been demonstrated that both activation and inhibition of sPLA2 isoforms elicit biological effects in keratinocytes. Among sPLA2 phospholipases, the dominant isoform in keratinocytes, both human (human primary epidermal keratinocytes—HPEK) and mouse (murine primary epidermal keratinocytes—MPEK), is the sPLA2-IIF isoform. Its increased activity enhances the generation of plasmalogen-type lysoPE (P-LPE), which may lead to the development of epidermal hyperproliferative diseases, such as psoriasis or skin tumor induced by 9,10-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) [54, 66]. Additionally, it has been shown that the sPLA2-IB isoform of murine fibroblasts (NIH3T3) activates extracellular matrix metalloproteinase 2 (MMP-2) [64]. Moreover, it is known that the sPLA2 phospholipase isoform (sPLA2-IIA), by degrading bacterial cell membranes, prevents bacterial infections, and its genetic deletion leads, among other things, to the exacerbation of psoriasis in the distal areas of the mouse skin and weakening of carcinogenesis by reducing the activation of mast cells and increasing lymphocytes Th17 (Th17) immunity and macrophage infiltration [67]. Meanwhile, the isoform sPLA2 (sPLA2-IIE) localized in murine hair follicles regulates hair cell homeostasis [68].

Moreover, it has been shown that the phospholipase PNPLA1 belonging to the iPLA2 family in murine keratinocytes plays a crucial role in the biosynthesis of ω-O-acylceramide, a lipid component essential for the functioning of the skin barrier [61], and mutations in the PNPLA1 enzyme in both C- and N-terminal domains are associated with the development of autosomal recessive congenital ichthyosis (ARCI) [69, 70] causing abnormal lipid accumulation in fibroblasts and impairing the biosynthesis of ω-O-acylceramide [62]. However, other iPLA2 isoforms have not been thoroughly investigated regarding their metabolic actions at the level of skin [71].

PLC

Another class of phospholipases catalyzing the hydrolysis of the ester bond between glycerol and the phosphate residue are the phospholipases PLC, which are activated by calcium ions, heterotrimeric large G proteins, small G proteins, and receptor/nonreceptor tyrosine kinases [72]. PLC are enzymes involved in the hydrolysis of PIP2, a minor phospholipid present in the cell membrane [73], which plays a crucial role in regulating many cellular processes. Reducing PIP2 levels is highly metabolically relevant because PIP2 acts as an activator of phospholipase D and phospholipase A2 and modulates actin polymerization by interacting with various actin-binding proteins and serves as a membrane-binding site for proteins containing pleckstrin homology (PH) domains [73, 74]. In addition to enzymatic activity, some PLC subtypes also function in other metabolic aspects, including: as a guanine nucleotide exchange factor, GTPase-activating protein, and adapter protein, independently of their lipase activity, thereby regulating cell polarization, cell cycle progression, and cell death [75]. Consequently the existence of 13 different PLC isoenzymes has been demonstrated, which are divided into six different groups, β, γ, δ, ε, ζ, and η, owing to the characteristic domains present in the isoenzymes. The common core of these isoenzymes includes a PH domain, a series of four EF-hands, a catalytic TIM barrel, and a C2 domain [72, 76] (Table 2).

Table 2 Classification of PLC isoenzyme families present in human and mouse skin depending on cellular location and substrate specificity

Individual PLC isoenzymes participate in various metabolic activities in skin. It has been found that inhibition of the PLCδ1 isoenzyme leads to a decrease in intracellular Ca2+ ion concentration and nuclear factor of activated T cells (NFAT) activity, as well as hyperactivation of mitogen-activated protein kinase (MAPK) protein kinase and inactivation of Ras-homolog of protein Ras homolog family member A (RhoA) in normal human epidermal keratinocytes (NHEK), which consequently may lead to a decrease in both ROS generation and inflammatory state [79]. Meanwhile, a crucial role in the development of skin inflammation is played by phospholipase PLCε, an isoenzyme that induces the production of proinflammatory cytokines, including IL-23, leading to the activation of IL-22-producing T cells (in transgenic murine keratinocytes K5-PLCe-TG) [80]. Increased expression of proinflammatory cytokines was also observed in the skin of mice with PLCδ1 knockout [82]. Furthermore, dysregulation at the phosphoinositide-specific phospholipase C (PI-PLC) level in the PI signaling transduction in human skin fibroblasts may lead to the development of melanoma [83].

PLD

A class of phospholipases that hydrolyze the phosphodiester bond of phosphatidylcholine is phospholipase D, whose action leads to the formation of a signaling molecule, phosphatidic acid, which participates in many fundamental cellular processes such as vesicular transport, exocytosis, autophagy, and consequently regulates cellular metabolism, including contributing to tumorigenesis [52]. The two best-characterized mammalian isoforms of PLD are phospholipase D1 (PLD1) and phospholipase D2 (PLD2), which mainly differ in their N- and C-terminal regions in the polypeptide chain and their cellular localization. PLD1 is mainly localized in the Golgi apparatus, endosomes, and perinuclear region, while PLD2 is almost exclusively found in lipid raft fractions of the cell membrane [84]. Phospholipase D plays a dual role in cells as it is responsible for maintaining the integrity of cell membranes and participates in cell signaling, including the transport of intracellular proteins to the cell membrane surface [85, 86]. Moreover, phospholipase PLD1 is involved in the fibrogenesis of organs, such as the liver, heart, or lungs, as well as in autophagy [87]. On the other hand, PLD2 is involved in cell migration and proliferation owing to epidermal growth factor receptor (EGFR) synthesis, as well as in the formation and transport of secretory vesicles and endocytosis, and also in cytoskeleton rearrangement [85, 87, 88]. As a result, changes in the efficiency of phospholipase D activity affect cellular metabolism in various pathological conditions of the skin, and the application of 1α,25-dihydroxyvitamin D3 increases both gene expression and protein level of PLD1 in HaCaT keratinocytes [89]. It has been shown, among others, that the expression of both PLD1 and PLD2 is significantly higher in the epidermis and dermis of patients with psoriasis compared with healthy individuals [86]. Additionally, it has been found that in a mouse model of psoriatic skin inflammation induced by IL-23, genetic deletion of PLD2 has anti-inflammatory effects by reducing macrophage infiltration and decreasing the generation of two representative inflammatory markers, IL-6 and CXCL10 [86]. Increased activity of the glycerol transporter, keratinocytes aquaporin-3 (AQP3), located in membrane microdomains, leads to increased glycerol transport to PLD2, resulting in the differentiation of keratinocytes derived from ICR CD-1 outbred mice, as evidenced by increased expression of epidermal differentiation markers, such as keratin 1, keratin 10, and loricrin [90]. Activation of the glycerol channel AQP3 and increased activity of the PLD2 isoform were observed in murine epidermal keratinocytes isolated from wounded skin, which increased the generation of phosphatidylglycerol, consequently promoting cell membrane repair and wound healing [88, 91].

The highest activity of phospholipases has been demonstrated in keratinocytes; however, through the hydrolysis of phospholipids, phospholipases regulate inflammation and carcinogenesis processes in various skin cells, which can contribute to the development of skin pathological conditions when their activity is dysregulated [42, 92]. Table 3 presents the influence of changes in phospholipase activity on the metabolic response of skin cells.

Table 3 The impact of changes in phospholipases activity on the metabolic response of skin cells

PUFAs

Phospholipases, by hydrolyzing phospholipids, contribute to the release of PUFAs and intermediate products, such as endocannabinoids, which can then be metabolized mainly by FAAH and MAGL into free PUFAs [43]. Consequently, free fatty acids account for about 10–15% of the dry weight of healthy human epidermis [12]. Human skin contains many saturated and unsaturated fatty acids (Fig. 2), with arachidonic acid constituting approximately 6% of all free fatty acids [12]. However, literature data regarding the level of AA in primary epidermal cells—keratinocytes—are varied, from similar levels of AA and docosahexaenoic acid (DHA) in HaCaT cells [93] to significantly higher levels of AA compared with DHA and eicosapentaenoic acid (EPA) in human immortalized keratinocytes CDD 1102 KERTr (CRL2310) [53], which may be due to the origin of the cells. Free AA presence has also been demonstrated in human fibroblasts (CCD 1112Sk) and normal human dermal fibroblasts (NHDF); although its level is lower than other investigated PUFAs, such as DHA, EPA, and LA [94, 95].

Fig. 2
figure 2

Fatty acids, both saturated and unsaturated present in human skin

However, since the quoted data concern skin cells obtained from cell culture, it should be remembered that the PUFA content in these cells also depends on the composition of the medium. The cited publications used media enriched with bovine serum [10% fetal bovine serum (FBS)], one of the components of which are PUFA (1% PUFA and 0.3% linoleic acid (18:2n-6) [96]. Moreover, since cells in culture easily take up lipids with the medium, it should be taken into account that this may have an impact on the level of cellular PUFAs, especially since the fatty acid level of cells in culture is approximately 2.5 times lower compared with cells in vivo, indicating the possibility of an impact PUFA derived from the medium on the level of fatty acids determined in cells from cell culture [96].

Free fatty acid metabolism

This review focuses only on the metabolism of arachidonic acid and bioactive metabolites, eicosanoids derived from arachidonic acid.

PUFAs undergo both nonenzymatic and enzymatic transformations. As a result of ROS-dependent peroxidation, PUFAs undergo oxidative fragmentation generating unsaturated aldehydes (4-HNE, MDA) [40]. Additionally, oxidative cyclization results in the formation of isoprostanes, isofurans, and isoketals [97].

The enzymatic metabolism of free PUFAs, such as AA, LA, DHA, or EPA, which occurs under the action of cyclooxygenases (COX1/2), lipoxygenases (LOXs), or cytochrome P450 (CYPs P450), leads to the formation of oxylipins, which are bioactive lipid mediators [98]. The type of oxylipin formed depends on the type of enzyme acting and the type of fatty acid being metabolized. The most frequently analyzed oxylipins, especially in skin, are derivatives of AA, known as eicosanoids [99]. In skin diseases, such as psoriasis and atopic dermatitis, there are changes in the levels of eicosanoids in response to metabolic changes resulting from the inflammatory conditions accompanying these skin diseases [32, 45, 98, 100] as well as environmental factors (e.g., UV radiation) [93]. The eicosanoid biosynthesis pathways are shown in Figs. 3, 4 and 5.

Fig. 3
figure 3

Metabolism of arachidonic acid under the action of cyclooxygenases (COXs). The eicosanoids marked in green have been discussed in detail in the later chapters. 12-HHTrE 12-hydroxyheptadecatrienoic acid, COX2-ASA aspirin-acetylated COX-2, COX2-SN S-nitrosylated COX-2, DiHETE dihydroxy-eicosatetraenoic acid, HETE hydroxy-eicosatetraenoic acid, HpETE hydroperoxy-eicosatetraenoic acid, LOX lipoxygenase, PGX prostaglandin, PGXS prostaglandin synthase, TX thromboxane, TXS thromboxane synthase.

Fig. 4
figure 4

The metabolism of arachidonic acid under the influence of lipoxygenases (LOXs). The eicosanoids marked in green have been discussed in detail in the later chapters. COX-2 cyclooxygenase 2, DHs hydroxyeicosanoid dehydrogenases, DiHETE dihydroxy-eicosatetraenoic acid, EHS epoxide hydrolases, EX eoxin, GPx glutathione peroxidase, HETE hydroxy-eicosatetraenoic acid, HpETE hydroperoxy-eicosatetraenoic acid, HX hepoxilin, LT leukotriene, LTA4H hydrolase LTA4, LTC4S synthase LTC4, LX lipoxin, oxo-ETE oxo-eicosatetraenoic acid, TrX trioxilin

Fig. 5
figure 5

The metabolism of arachidonic acid involving cytochrome P450 (CYP450) isoenzymes. DHET dihydroxy-eicosatrienoic acid, DiHETE dihydroxy-eicosatetraenoic acid, EET epoxyeicosa-trienoic acid, HETE hydroxy-eicosatetraenoic acid, HpETE hydroperoxy-eicosatetraenoic acid, LOX lipoxygenase

COXs

In skin, as in other tissues of the human body, there are two isoforms of cyclooxygenases: the constitutive isoform, COX-1, which is constitutively expressed in most human tissues, including skin [101, 102] and the inducible isoform, COX-2 [103], which shares 60% amino acid homology with COX-1 [104]. COX-2 is induced by various stimuli, including exposure to proinflammatory factors such as growth factors, cytokines, carcinogens, endotoxins, and UV radiation [105, 106]. The highest levels of COX-2 are found mainly in suprabasal keratinocytes [103, 107].

Under the action of COXs, free arachidonic acid is metabolized to prostaglandin G2 (PGG2), which is an unstable product. The hydroperoxide group of PGG2 is reduced to an alcohol group by hemoperoxidase, generating prostaglandin H2 (PGH2). Then, through the action of prostaglandin synthase (PGXS) and thromboxane synthase (TXS), PGH2 is converted into a subclass of eicosanoids called prostanoids, which includes prostaglandins (PGD2, PGE2, PGI2) and thromboxane A2 (TXA2), all containing the prostanoid acid as a structural element. The activity of these enzymes also leads to the formation of 12-hydroxyheptadecatrienoic acid (12-HHTrE), which does not contain the prostanoic acid structure [108].

Prostanoids are rapidly metabolized, producing numerous metabolites, including the prostaglandin PGI2, which is formed by the action of PGI synthase on PGH2 and rapidly hydrolyzes to a stable but biologically inactive metabolite, 6-ketoprostaglandin F1α (6-keto PGF) [109]. As a result of dehydration of the hydroxyl groups of prostaglandins PGE2 and PGD2, the family of cyclopentenone prostaglandins (cyPGs) is formed. PGE2 undergoes dehydration to generate prostaglandin A2 (PGA2) and isomerization, resulting in prostaglandin B2 (PGB2) and 8-[(1R,2R,5R)−2-(2-carboxyethyl)−5-hydroxy-3-oxocyclopentyl]−6-oxooctanoic acid (tetranor PGEM). Similarly, during the dehydration of PGD2, prostaglandin J2 (PGJ2) is formed, which isomerizes into Δ12-PGJ2. The hydroxyl group (C-15) of Δ12-PGJ2 dehydrates to form 15-deoxy-Δ12,14-PGJ2 (15-d-PGJ2). Additionally, PGD2 is metabolized by dehydrogenase to 15-keto-PGD2, which is further metabolized by 15-keto-PG-Δ13-reductase to 13,14-dihydro-15-keto-PGD2. Moreover, PGD2 is metabolized by 11-ketoreductase to 9α,11β-PGF2 [109].

Regardless of the above metabolic transformations of prostaglandins, it has been observed that through the action of TXS on PGH2, active TXA2 is formed, which possesses an unstable ether bond that undergoes hydrolysis, generating the biologically inert thromboxane B2 (TXB2). TXB2, in turn, undergoes multifaceted metabolism, resulting in the β-oxidation pathway producing 2,3-dinor-TXB2, and the action of 11-hydroxythromboxane dehydrogenase generates 11-dehydro TXB2, which through its isomerization leads to the formation of tetranor TXB2 [109, 110]. Conversely, the action of enzymes blocking prostaglandin biosynthesis, such as aspirin-acetylated COX-2 and S-nitrosylated COX-2, leads to the generation of 15-hydroperoxy-eicosatetraenoic acid (15-HpETE) [111]. Oxidation of HpETE acids by COX-1 or COX-2 produces 11-hydroxy-eicosatetraenoic acid (11-HETE), as well as COX-2 action yields 15-HETE [108].

The enzymatic metabolism of arachidonic acid, including primarily COX-2-dependent prostaglandin synthesis, influences keratinocyte differentiation, hair follicle development, and hair growth [112]. Additionally, it is known that COX-2 mediates the development of inflammatory processes in the skin, while administering specific COX-2 inhibitors reduces the levels of inflammatory markers, such as macrophage inflammatory protein 2 (MIP-2) and TNF-α in skin with inflammatory hypersensitivity and nociception, as well as decreasing edema and vascular permeability [112]. Therefore, preparations containing COX-2 inhibitors are used topically in the treatment of skin diseases mediated by COX-2 [113].

LOXs

Regardless of the metabolic activity of cyclooxygenases, mammalian skin possess a diverse set of non-heme iron-containing enzymes, such as LOXs, which also oxidize polyunsaturated fatty acids, including arachidonic acid. LOXs are classified on the basis of positional specificity in the oxidation of arachidonic acid (e.g., 5-, 8-, 12-, and 15-LOX); the tissue of their occurrence, such as platelet-type 12-LOX (p12-LOX), leukocyte-type 12-LOX (l12-LOX), and epidermal-type 12-LOX (e12-LOX). On the basis of the phylogenetic relationship of mammalian LOXs, they are divided into four subfamilies: 5-LOX, 12-LOX, and 12/15-LOX (reticulocyte-type 15-LOX-1 and leukocyte-type 12-LOX). Epidermal-type LOXs [12R-LOX, 15-LOX-2, 8-LOX, epidermis-type lipoxygenase-3 (LOX-3)] (Table 4) [114].

Table 4 Classification of the LOX skin human and mouse isoforms

As a result of the action of lipoxygenases (LOXs: 5-, 8-, 9-, 11-, 12-, and 15-LOX) on arachidonic acid, the generation of hydroperoxyeicosatetraenoic acids (HpETEs; 5, 8, 9, 11, 12, and 15-HpETE) occurs, which are then transformed into hydroxyeicosatetraenoic acids (HETEs; 5, 8, 9, 11, 12, and 15-HETE) by glutathione peroxidase (GPx) (Fig. 4) [108, 124], which then undergo metabolism to oxo-eicosatetraenoic acids (oxo-ETEs) under the influence of hydroxyeicosanoid dehydrogenases (DHS), while under the action of LOXs they are transformed into dihydroxyeicosatetraenoic acid (DiHETE) [108]. Additionally, 5-LOX oxidizes 5-HpETE to leukotriene A4 (LTA4), which is metabolized to leukotriene B4 (LTB4) by LTA4 hydrolase (LTA4H), and C-20 LTB4 is subsequently hydroxylated to generate 20-hydroxy-leukotriene B4 (20-OH-LTB4), which is oxidized to 20-carboxy-LTB4 (20-COOH-LTB4) [125]. Conversely, LTC4 synthase (LTC4S) conjugates leukotriene A4 (LTA4) with glutathione (GSH) to form leukotriene C4 (LTC4), which serves as a precursor for leukotriene D4 (LTD4) and leukotriene E4 (LTE4) through sequential removal of amino acids from the glutathione residue [126]. Oxidation of LTA4 can also occur with the involvement of 12-LOX and 15-LOX, resulting in lipoxins, such as LXA4 and LXB4 [127]. 12-HpETE undergoes isomerization to hepoxilins (HXX3) through rearrangement of the-OOH group. So far, two hepoxilins have been identified, HXA3 and HXB3, both containing an epoxide group as well as an additional hydroxyl group. The epoxide group of hepoxilins is labile and undergoes hydrolysis under the action of epoxide hydrolases (EHS) or in acidic environments, forming trioxilin A3 or B3 (TrXA3, TrXB3), respectively [128].

On the other hand, the action of 15-LOX leads to the metabolism of 15-HpETE to eoxin A4 (EXA4) [108], which, analogous to the biosynthesis of leukotrienes, is conjugated with glutathione, forming eoxins C4, D4, and E4 (EXC4-EXE4) [129]. Additionally, under the influence of 5-LOX on 15-HpETE, lipoxins LXA4 and LXB4 are also formed, which are the first discovered lipid mediators exhibiting anti-inflammatory effects [127].

Considering the effects of AA metabolism involving LOXs, this group of enzymes is believed to play a significant role in modulating the proliferation and/or differentiation of epithelial cells, as well as in shaping inflammatory states, including inflammatory skin diseases and cancers, and wound healing [114]. Moreover, lipoxygenases also participate in maintaining the permeability barrier of the skin [130]. Mutations in LOXs genes in human epidermis have also been identified as the second most common cause of autosomal recessive congenital ichthyosis, while disruptions at the level of LOXs genes in mice led to the death of newborns owing to severely impaired skin barrier function [114, 130].

CYP450

Another family of enzymes involved in the metabolism of AA to eicosanoids, but also responsible for the metabolism of sterols, steroids, vitamin A, and vitamin D, are the enzymes from the cytochrome P450 (CYP450) family [131], which are also the most versatile class of enzymes metabolizing xenobiotics, including drugs, both in the liver and extrahepatically, including in the skin [131, 132]. In the human body, 57 functional genes and 58 pseudogenes of CYPs from 18 different families and 44 subfamilies have been identified [133, 134]. CYPs have broad substrate specificity and catalyze various reactions including hydroxylation, heteroatom oxygenation, dealkylation, epoxidation, desaturation, and heme destruction among several others [135]. The classification of human cytochrome P450 enzymes is based on their functions or on the main class of substrates. Enzymes CYP1-4 are responsible for the biotransformation of xenobiotics, chemicals, and drugs, while enzymes from the CYP5 and CYP8 families participate in the biosynthesis of thromboxane and prostacyclin, and enzymes from the CYP11, CYP17, CYP19, and CYP21 families are involved in hydroxylation necessary for bile acid biosynthesis, metabolism of vitamin D3 and cholesterol, whereas CYP26 participates in the hydroxylation of retinoic acid [134]. For isoforms 2A7, 2S1, 2W1, 4A22, and 20A1, there is no definitive data yet [131]. Table 5 presents the family of isoenzymes present in human skin [136, 137].

Table 5 Classification of the cytochrome P450 isoenzymes family found in human skin and its cells based on main classes of compounds metabolized by CYPs

Cytochrome P450 isoenzymes also participate in the generation of eicosanoids from AA (Fig. 5). Nevertheless, metabolites resulting from the action of CYP450 are much less studied than metabolites from other enzymatic pathways. Under the action of ω-hydroxylases (CYP4A, CYP4F), AA undergoes metabolism to HETEs, while the action of CYP2C and CYP2J epoxygenases leads to the formation of epoxyeicosatrienoic acids (EETs). EETs are further metabolized by epoxide hydrolases (EHS) to dihydroxyeicosatrienoic acids (DHETs) [44, 138]. However, it has also been demonstrated that the action of CYP450 enzymes on arachidonic acid leads to the formation of 15-HpETE, and ω-oxidation of 5-HETE, a metabolite resulting from the action of 5-LOX and GPx, by CYP4F3 results in the formation of 5,20-diHETE [111, 139].

In human keratinocytes, expression of constitutive isoforms of CYP1A1, CYP1B1, CYP2B6, CYP2E1, and CYP3A5 has been detected [140]. It has also been observed that after induction by the glucocorticosteroid—dexamethasone, which has strong anti-inflammatory, antiallergic, and immunosuppressive effects and is used in dermatology for conditions, such as psoriasis and allergic skin diseases, the expression of CYP1A, CYP2B, CYP2E, and CYP3A is increased at the mRNA level [140, 144]. Additionally, psoriasis and UVA radiation promote a significant increase in the expression of the CYP2S1 isoform in psoriatic skin lesions compared to healthy skin [145]. Moreover, increased enzymatic activity of CYP1A1 has been demonstrated in the skin of psoriasis patients, which affects the reduction of aryl hydrocarbon receptor (AHR) pathway activation, which acts anti-inflammatory [146]. Owing to the inhibition of cytochrome P4503A4 metabolism, dexamethasone, a corticosteroid inhibiting metabolism in the epidermis, may be used in the topical treatment of skin diseases such as skin allergies, atopic dermatitis, and psoriasis [147]. Another isoform, CYP4F22, is a ω-hydroxylase responsible for ceramide synthesis and participates in mechanisms of skin permeability barrier formation [141].

PUFA metabolites and their functions in the skin

The metabolites of free fatty acids are oxylipins, a subgroup of which are eicosanoids, which are derivatives of arachidonic acid and produced by all types of skin cells [45, 148]. These compounds are not stored in cells but are synthesized and released in response to chemical and physical stimuli as well as various skin disease states. Oxylipins play an integral role in the mechanisms of structural and metabolic homeostasis of skin. However, the most frequently analyzed metabolites are eicosanoids owing to the widespread occurrence of AA and consequently higher concentrations of eicosanoids in the human body. Eicosanoids reveal mainly pro-inflammatory effects, while metabolites of other fatty acids, including EPA and DHA, have mainly anti-inflammatory effects [149, 150]. However eicosanoids mediate the regulation of inflammation caused mainly by environmental factors such as UV exposure, but also inflammatory or allergic disease pathologies, including psoriasis and atopic dermatitis [45, 100]. Changes in eicosanoid levels depend on the type of disease, its severity, as well as the individual characteristics of the patient and the location of these compounds in the skin.

Table 6 presents the directions of changes in eicosanoid levels influenced by physiological processes, diseases, and therapies, observed both in the skin and in epidermal and dermal cells, including those from healthy individuals and patients with skin diseases.

Table 6 Changes in the level of eicosanoids as a result of physiological processes, diseases, or therapies

The biological effects of eicosanoids depend on both their cellular localization and the type of membrane receptor they activate, as the metabolic activity of eicosanoids primarily occurs through the activation of specific G protein-coupled membrane receptors [45, 157]. These receptors represent the largest and highly diverse group of membrane proteins responsible for transmitting signals across the lipid bilayer to effector sites within the cell [157]. Some receptors, such as the prostaglandin F receptor (FP), prostaglandin I2 receptor (IP), and thromboxane receptor (TP), are activated by only one lipid ligand, while others, including prostaglandin E2 receptors (EP1, EP2, EP3, EP4), prostaglandin D2 receptors (DP1, DP2), and cysteinyl leukotriene receptors (CysLT1, CysLT2), can bind to various ligands, thereby having multifaceted effects on cellular metabolism [45, 157]. Additionally, eicosanoids can also act as ligands for receptors such as peroxisome proliferator-activated receptors (PPARs), transient receptor potential cation channel subfamily V member 1 (TRPV1) and transient receptor potential cation channel, subfamily A, member 1 (TRPA1), which are activated by other compounds as well [157, 158].

Prostaglandins

PGE2

PGE2, generated in a COX-dependent pathway (Fig. 3) both in epidermal keratinocytes and dermal fibroblasts, exhibits strong proinflammatory and vasodilatory properties. Additionally, it promotes proliferation and modulates the immunosuppression of cells [159, 160]. PGE2 also participates in the proliferation and differentiation of keratinocytes and, by activating EP1-EP4 receptors, directly influences epidermal barrier functions [161, 162].

As a result of EP1 receptor activation in adult primary human keratinocytes, PGE2 promotes the formation of corneocytes, dead cells that create a protective barrier preventing harmful substances/pathogens from penetrating the skin as well as protecting against injuries and UV radiation. Additionally, PGE2 is involved in the induction of differentiation proteins, such as cytokeratin K10 and transglutaminase, which are responsible for cell division and differentiation, transport, and cell adhesion. These processes are inhibited by two known EP1 receptor antagonists (SC51322 and AH6809) [163]. In normal human dermal fibroblasts (NHDFs), PGE2 also increases extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation and intracellular Ca2+ concentrations via EP1 receptor activation. This leads to a decrease in the type 1 collagen expression and an increase in the extracellular matrix metalloproteinase 1 (MMP-1) expression, resulting in accelerated skin aging [164].

In contrast, activation of EP2 receptors by PGE2 in strains of human dermal fibroblasts leads to increased regulation of cyclic adenosine monophosphate (cAMP), which contributes to the reduction of fibroblast contractility and consequently reduces skin scarring [165]. Additionally, it was found that increased PGE2 production resulting from topical application of a mycotoxin (alternariol-AOH) to mouse skin leads to activation of the EP2 receptor, which increases cAMP levels promoting phosphorylation of the cAMP response element-binding protein (CREB) transcription factor, which regulates the transcription of genes responsible for the proliferation of primary mouse keratinocytes (PMK) [166]. On the other hand, activation of the EP2 receptor by its agonist, such as butaprost, a structural analogue of PGE2, leads to the formation of the β-arrestin1-Src complex, which activates the EGFR and its effectors, including p-ERK1/2, phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and phosphorylated protein kinase B (p-Akt), and also increases the activity of cyclic AMP-dependent protein kinase (PKA) and its downstream effectors, including phosphorylated glycogen synthase kinase 3 (p-GSK3), p-CREB and p-ERK1/2. The above signaling pathways enhance the proliferation of murine keratinocytes, which has been suggested to contribute to the induction of skin cancer [167].

It is also suggested that PGE2 participates in two mechanisms responsible for melanocyte dendrite formation. Activation of proteinase-activated receptor 2 (PAR-2) in human neonatal keratinocytes stimulates the release of PGE2, leading to the activation of EP1 and EP3 receptors in melanocytes and the activation of protein kinase C zeta (PKCζ), resulting in melanocyte dendrite formation [168, 169]. Additionally, it has been shown that activation of EP3 by a synthetic agonist of EP3 receptors (ONO-AE-248) suppresses the generation of chemokine (C-X-C motif) ligand 1 (CXCL1), which recruits neutrophils, induced by TNF-α administration in normal human epidermal keratinocytes. Similar dependencies have been demonstrated in a mouse model of contact hypersensitivity [170]. Therefore, it can be suggested that regulation of EP3 receptor signaling in keratinocytes may be a therapeutic target in the treatment of skin inflammation.

Moreover, it has been demonstrated that through EP2 and EP4 receptors, PGE2 can also play an anti-apoptotic role, as observed in mouse skin exposed to UVB radiation. Agonists of both receptors restore the activation of PKA and Akt, reducing apoptosis by approximately 50% in dorsal skin mice [171]. Activation of EP2 and EP4 receptors by PGE2 induces PKA signaling and AHR receptor activation in T lymphocytes (Th17 and Th22) of C57BL/6 mice, promoting the release of IL-22, which may lead to allergic contact dermatitis (ACD) [172]. PGE2 also affects the interaction between skin layers. IL-1 generated by keratinocytes increases PGE2 levels in fibroblasts, leading to enhanced keratinocyte proliferation [173]. Furthermore, a complex feedback loop was observed in co-culture of fibroblasts and dendritic cells (DCs). This mechanism involves the secretion of IL-1 and TNF-α in DCs, promoting increased PGE2 generation in fibroblasts, and subsequently leading to increased release of IL-23 in DCs, resulting in Th17 cell expansion [174]. On the other hand, other studies have shown that activation of EP2 and EP4 receptors by PGE2 in cultured naïve CD4 lymphocytes T cells (CD4 + CD25) inhibits transforming growth factor beta (TGF-β) signaling, which is responsible for the differentiation of iTreg cells necessary for controlling inflammatory processes through the generation of proinflammatory IL-22 [175].

Furthermore, it has been found that activation of EP2 receptors in murine keratinocytes (PAM212) leads to inhibition of PAR2 receptor activity, which consequently inhibits thymic stromal lymphopoietin (TSLP) expression. Therefore, it is suggested that this mechanism may represent a novel therapeutic strategy in the treatment of atopic dermatitis (AD) [176]. On the other hand, the PGE2 metabolite, 13,14-dihydro-15-keto-PGE2, through activation of EP4 receptors, induces Axl phosphorylation via receptor tyrosine kinase (RTK), leading to activator protein 1 (AP-1) transactivation, which increases oncostatin M (OSM) generation in human macrophages. OSM is a cytokine with strong anti-inflammatory properties, reducing TNF-α and IL-1β expression and thereby accelerating wound healing [177].

Changes in PGE2 levels have also been analyzed in the context of psoriatic skin. However, data obtained indicate both a lack of changes in PGE2 levels in psoriatic skin compared with healthy skin [153], and a significant increase in the level of PGE2 in both psoriatic skin and blood mononuclear cells of patients with psoriasis [155, 178]. Consequently, attempts were also made to treat persistent vitiligo through intradermal administration of PGE2 or PGF supported by NB-UVB phototherapy. In the case of using PGE2, it resulted in a significantly earlier onset of repigmentation and a higher degree of healing in the treated areas compared with the use of PGF [179].

PGD2 and 15-d-PGJ2

Prostaglandins, which are potent mediators of inflammatory and immune responses in human skin, are also important effector molecules in cellular responses to cytokines. However, the direction of action of prostaglandins depends on various factors, including the affected organ/tissue or the receptor they activate and the specific physio/pathological situation. Langerhans cells and mast cells are considered to be the main sites of production of prostaglandins PGD2 and 15-d-PGJ2 in the skin [159, 180]. Both prostaglandins are also generated in keratinocytes and fibroblasts [181,182,183,184]. It was found that as a result of dehydration, PGD2 is converted into prostaglandin J2, which isomerizes to Δ12-PGJ2, and its hydroxyl group (C-15) is dehydrated with the generation of 15-deoxy-Δ12,14-PGJ2 (15-d-PGJ2) [109] (Fig. 3). The action of PGD2 and 15-d-PGJ2 is related to the activation of DP1 and DP2 receptors, respectively [185].

PGD2 is involved in immune and allergic reactions, has strong antiproliferative properties, and regulates inflammation [182,183,184]. It has been shown that increased activity of PLA2 type III (PLA2G3) is characteristic of mast cells cultured with fibroblasts, which promotes an increase in the activity of PGD2 synthase in fibroblasts, which stimulates the maturation of mast cells by activating DP1 receptors [186]. Additionally, PGD2-DP2 signaling, demonstrated after bee venom injection, promotes the production of IgE antibodies, causing dendritic cells to migrate to lymph nodes, contributing to the development of acquired immunity [187]. In contrast, topical application of PGD2 inhibits hair follicle neogenesis in mice and humans by activating DP2 receptors [156].

Furthermore, PGD2, through activation of AP-1 in human foreskin keratinocytes, increases the mRNA expression of beta-defensin 3 (hBD-3), a peptide with antimicrobial properties; this effect is suppressed by ramatroban, a DP2 receptor antagonist [182]. However, primary human keratinocytes (GM22251) exposed to PGD2 show an increased ability to convert the androgen androstenedione into testosterone, which may be a potential therapeutic target for patients with androgenetic alopecia (AGA) [188]. Additionally, PGD2-induced testosterone production is believed to be mediated by ROS, as evidenced by increased production of the unsaturated 4-hydroxynonenal aldehyde and decreased testosterone levels following administration of the antioxidant N-acetylcysteine (NAC) with PGD2 [188]. In human dermal papilla cells (hDPCs), PGD2, through DP2 receptors involved in the signaling pathway downstream of various inflammatory mediators, glycogen metabolism, cell proliferation, and apoptosis, also enhances androgen receptor (AR) signaling and AKT activation (Jeong et al., 2018), involved in the signaling pathway downstream of various inflammatory mediators, glycogen metabolism, cell proliferation, and apoptosis [189]. Additionally, it has also been recognized that the PGD2-DP2 interaction leads to increased production of chemokines from macrophages (MDCs) and lymphocytes (RANTES), which play an important role in the development of chronic allergic dermatitis, such as IgE-mediated very late-phase (vLPR) response and chronic hypersensitivity contact dermatitis (CHS) [184], which was confirmed in a study in which DP2 receptor inhibition reduced chemokine expression in recurrent IgE-induced dermatitis [190].

Increased levels of prostaglandin PGD2, produced by mast cells, was also observed in atopic dermatitis [191, 192]. Additionally, it was indicated that this prostaglandin may have an effect in two directions, namely activation of DP1 receptors, which reduces inflammation and preserves the barrier function of the skin [193], or activation of DP2 receptors, leading to the induction of chemotaxis in leukocytes and promoting the development of inflammation [194]. It was also shown that reducing PGD2 levels can inhibit allergic dermatitis in patients with atopic dermatitis [195]. However, a phase II clinical trial evaluating the effect of the DP2 receptor antagonist timapiprant in atopic dermatitis (NCT02002208) did not show any significant improvement [196] (Tables 7 and 8)

Table 7 Metabolic effects of PGE2 and activation/inhibition of its receptors on skin cells
Table 8 Metabolic effects of PGD2 and activation/inhibition of its receptors on skin cells

PGD2, as well as its metabolite 15-d-PGJ2, when used in in vitro studies, inhibit the growth of human hair follicles explanted and hair growth in mice through the activation of the DP2 receptor [181]. Additionally, 15-d-PGJ2 induces apoptosis in follicular keratinocytes, as evidenced by increased expression of the pro-apoptotic Bcl-2-associated X protein (BAX) and caspase 3, as well as decreased expression of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) [181]. This prostaglandin also arrests the cell cycle in the G1 phase of keratinocytes, thereby inhibiting cell proliferation [197]. In contrast topical application of 15d-PGJ2 on skin wounds in diabetic mice increases the expression of peroxisome proliferator-activated receptor gamma (PPARγ) in macrophages at the wound site, thus reducing inflammation and accelerating wound closure [198].

Prostaglandins are potent mediators of inflammatory and immune responses in human skin and are important effector molecules in cellular responses to cytokines. The action of prostaglandins depends on various factors, including the organ or tissue involved, the receptor to which they attach, and the bodily function or physiological situation [164, 166, 187].

Thromboxane A2

The metabolite of arachidonic acid generated by the action of COX and TX synthase (Fig. 3) is thromboxane TXA2, which under physiological conditions TXA2 is synthesized in very small amounts, and most studies indicate that its level assessed by liquid chromatography with tandem mass spectrometry (LC–MS/MS) methods is below the detection limit [200]. However, during various pathologies, its concentration undergoes a rapid increase. TXA2 has an unstable ether linkage, which undergoes hydrolysis under aqueous conditions, generating the biologically inert TXB2. TXA2 primarily acts through the activation of the thromboxane A2 receptor (TP), which is found in various tissues and cells, including in the vascular system (smooth muscle cells and endothelium), blood platelets, lungs, kidneys, heart, thymus, and spleen [201].

It has been found that the generation of TXA2 significantly increases immediately after skin injury and participates in blood platelet aggregation [202, 203], which is necessary to stop bleeding and promote effective wound healing [204, 205]. In a murine model of skin inflammation, it has been demonstrated that TXA2 generated by blood platelets, through TP receptor activation, induces the synthesis of the proinflammatory cytokine interleukin 6 and PGE2, and also suppresses the expression of the anti-inflammatory marker, mannose receptor C type 1 (CD206) in macrophages [206]. TXA2 generated by mouse keratinocytes through TP receptor activation triggers skin itching in murine atopic dermatitis [207]. Additionally, it has been shown that intradermal injection of IL-31 in mice increases intracellular Ca2+ levels in keratinocytes, which also leads to an increase in TXA2 concentration. TXA2, by activating TP receptors, induces skin itching in mice [208]. Elevated levels of TXA2 have also been demonstrated in population studies of patients with atopic dermatitis, which may be responsible for the course of the disease [209]. In other studies, it has been shown that the TXA2-TP signaling pathway participates in the development of psoriatic skin inflammation in mice induced by imiquimod (IMQ). This mechanism involves increased generation of the proinflammatory IL-17A in Vγ4 + γδ T cells, promoting psoriatic skin inflammation in mice [210].

Leukotrienes, including LTB4

Short-lived lipid mediators include leukotrienes (LTs) (Fig. 4), which act in an autocrine and paracrine manner, and their concentration increases in skin during inflammatory diseases [211]. Leukotrienes are divided into two groups: the first represented by LTB4 and the second comprising cysteinyl leukotrienes (cys-LTs), namely LTC4, LTD4 and LTE4 [212, 213]. Leukotrienes are not stored in cells but are rapidly synthesized de novo and released within minutes of cell activation. Various stimuli induce the generation of leukotrienes, including immunological and proinflammatory stimuli [213]. LTB4 acts through the activation of leukotriene B4 receptor 1 (BLT1), while leukotrienes C4, D4, and E4 primarily act through the activation of CysLT1 and CysLT2 receptors [214].

LTB4, a metabolite of arachidonic acid (Fig. 4), is a classic lipid mediator of inflammation primarily produced by blood cells, such as leukocytes, granulocytes, macrophages, and dendritic cells, in the epidermis and dermis, as well as during host defense against pathogens and in patients with allergies, autoimmune diseases, and metabolic disorders [215, 216]. LTB4 has high affinity for the BLT1 receptor and low affinity for the leukotriene B4 receptor 2 (BLT2) [217]. It has been found that during postoperative incisional pain, activation of BLT1 receptors by LTB4 exacerbates pain responses by promoting local infiltration of inflammatory monocytes and cytokine production (IL-6, IL-1β, and TNF-α) [218]. Furthermore, increased generation of LTB4 is responsible for leukocyte recruitment to sites of tissue damage and infection [215].

Bacterial skin infection caused by methicillin-resistant Staphylococcus aureus (MRSA) has been observed to induce macrophage activation, leading to increased LTB4 production and neutrophil recruitment in diabetic mice; therefore, treatment with a BLT1 receptor antagonist reduces neutrophil recruitment and lowers chemokine/cytokine levels [intercellular adhesion molecule 1 (ICAM1), chemokine (C-X-C motif) ligand 2 (CXCL2)] [219]. Moreover, during MRSA infection, prevention of the LTB4/BLT1 pathway action is a promising therapeutic strategy that inhibits inflammatory responses by inhibiting transcriptional pathways involved in enhancing inflammasome expression [220]. On the other hand, local application of LTB4 in difficult-to-treat skin infections intensifies both the function of local antibacterial effectors and inflammatory response [220].

It has been shown that the production of LTB4 increases significantly in the skin of patients with psoriasis, which is associated with increased neutrophil infiltration and T cell activity, leading to increased LTB4 synthesis in response to increased 5-LOX activity [221]. However, activation of BLT1 receptors by LTB4 leads to the activation of CXCL1, CXCL2, and C-X-C motif chemokine receptor 2 (CXCR2) receptors in neutrophils, accelerating their infiltration. In dendritic cells and lymphocytes, activation of BLT1 receptors facilitates migration and production of cytokines IL-17 and IL-23, contributing to the development of psoriasis [222, 223]. Additionally, LTB4 is also considered an important signaling molecule involved in skin pigmentation in human melanocytes [224]. It has also been shown that LTB4 has an antiproliferative effect on melanocytes in both healthy individuals and those with acquired vitiligo [225].

In the skin of patients with atopic dermatitis, increased production of LTB4 was observed, as well as higher activity of leukotriene-A4 hydrolase in the peripheral blood cells of these patients [226, 227]. However in skin lesions associated with atopic dermatitis or allergic contact dermatitis was indicated that LTB4 increases generation of the chemokine CCL27 induced by TNF-α in human keratinocytes [228]. A pilot study of oral therapy with a 5-LOX inhibitor (zileuton) for AD demonstrated that the compound prevented disease exacerbations and prolonged remission, confirming the functional role of LTB4 in the development of this disease [229]. Considering the significance of both proinflammatory leukotrienes and prostaglandins in the pathophysiology of asthma, inhibition of cPLA2 activity is believed to inhibit the generation of these eicosanoids [230]. Completed phase 1 and 2 clinical trials of the cPLA2 inhibitor, ZPL-521, showed that the drug was safe and well-tolerated even at high doses [231].

The action of thromboxane synthase on PGH2 produces 12-HHTrE (Fig. 3) (Gabbs et al., 2015), which is the main agonist of the BLT2 receptor [232], and whose activation strengthens the skin barrier by activating the p38 MAPK pathway, leading to the production of the adhesion protein claudin 4 (CLDN4) responsible for tight junctions between primary keratinocytes [233]. BLT2 receptor activation is also necessary for protection against epicutaneous sensitization and transepidermal water loss [233]. However, it is known that after skin damage, platelets produce large amounts of 12-HHTrE, which, by activating the BLT2 receptor in epidermal keratinocytes, accelerates wound healing by activating the NF-κB-TNF-α-MMPs metabolic pathway [234].

Conclusions and future prospects

  1. 1.

    The integrity and, consequently, the proper metabolic functioning of skin cells are ensured by cell membranes, the basic structural and functional components of which are phospholipids, which are constantly enzymatically hydrolyzed to generate PUFAs, including arachidonic acid, which is a precursor of eicosanoids.

  2. 2.

    The main physiological function of eicosanoids is the constitutive control of normal and balanced cell proliferation, differentiation, and survival, as well as the regulation of skin cell inflammation.

  3. 3.

    Since dysregulation of eicosanoid levels may contribute to the development of skin diseases, this suggests that pharmacological regulation of eicosanoid generation, especially in psoriasis and atopic dermatitis (by: ZPL-521—cPLA2 inhibitor; zileuton—5-LOX inhibitor; timapiprant (NCT02002208)—DP2 receptor antagonist), as well as in the treatment of vitiligo (intradermal injection of PGE2 supported by NB-UVB phototherapy) is and will be developed.

  4. 4.

    For the purpose of using eicosanoids for identifying metabolic changes in skin disease and evaluating pharmacotherapy progress, further detailed studies are necessary to understand the relationship between specific eicosanoid and disease pathomechanism, as well as to develop an analytical approach for their diagnostic determination.

Data availability

Not applicable.

Abbreviations

12-HHTrE:

12-Hydroxyheptadecatrienoic acid

15-d-PGJ2 :

15-Deoxy-Δ12,14-PGJ2

20-COOH-LTB4 :

20-Carboxy-LTB4

20-OH-LTB4 :

20-Hydroxy-leukotriene B4

4-HNE:

4-Hydroxynonenal

6-keto PGF :

6-Ketoprostaglandin F1α

AA:

Arachidonic acid

AAPC:

Alkylacylglycerophosphocholines

ACD:

Allergic contact dermatitis

AD:

Atopic dermatitis

AGA:

Androgenetic alopecia

AHR:

Aryl hydrocarbon receptor

AP-1:

Activator protein 1

AQP3:

Aquaporin-3

AR:

Androgen receptor

ARCI:

Autosomal recessive congenital ichthyosis

AVX001:

1-Octadeca-2,6,9,12,15-pentaenylsulfanyl-propan-2-one

BAX:

Bcl-2-associated X protein

Bcl-2:

B-cell lymphoma 2

BLT1:

Leukotriene B4 receptor 1

BLT2:

Leukotriene B4 receptor 2

cAMP:

Cyclic adenosine monophosphate

CCD 1112Sk:

Human fibroblasts

CD206:

Mannose receptor C type 1

CD25:

CD25 T lymphocytes

CD4:

CD4 T lymphocytes

Cer:

Ceramides

CHS:

Chronic hypersensitivity contact dermatitis

CL:

Cardiolipins

CLDN4:

Claudin 4

COXs:

Cyclooxygenases

cPLA2:

Cytosolic calcium dependent phospholipase A2

CREB:

CAMP response element-binding protein

CRL2310:

Human immortalized keratinocytes CDD 1102 KERTr

CXCL1:

Chemokine (C-X-C motif) ligand 1

CXCL2:

Chemokine (C-X-C motif) ligand 2

CXCR2:

Motif chemokine receptor 2

cyPGs:

Cyclopentenone prostaglandins

CYPs P450:

Cytochromes P450

CysLT1:

Cysteinyl leukotriene receptor 1

CysLT2:

Cysteinyl leukotriene receptor 2

cys-LTs:

Cysteinyl leukotrienes

DAG:

1,2-Diacylglycerol

DAGL:

Diacylglycerol lipase

DCs:

Dendritic cells

DHA:

Docosahexaenoic acid

DHETs:

Dihydroxyeicosatrienoic acids

DHS:

Hydroxyeicosanoid dehydrogenases

DHSM:

Dihydrosphingomyelins

DiHETEs:

Dihydroxyeicosatetraenoic acids

DMBA/TPA:

9,10-Dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate

DP1:

Prostaglandin D2 receptor 1

DP2:

Prostaglandin D2 receptor 2

e12-LOX:

Epidermal-type 12-lipoxygenase

EETs:

Epoxyeicosatrienoic acids

EGFR:

Epidermal growth factor receptor

EHS:

Epoxide hydrolases

EP1:

Prostaglandin E2 receptor 1

EP2:

Prostaglandin E2 receptor 2

EP3:

Prostaglandin E2 receptor 3

EP4:

Prostaglandin E2 receptor 4

EPA:

Eicosapentaenoic acid

Epla:

Plasmalogen ethanolamines

ERK1/2:

Extracellular signal regulated kinase 1/2

EXA4 :

Eoxin A4

EXC4 :

Eoxin C4

EXD4 :

Eoxin D4

EXE4 :

Eoxin E4

FAAH:

Fatty acid amide hydrolase

FP:

Prostaglandin F receptor

GM22251:

Primary human keratinocytes

GPL:

Phosphoglycerides

GPx:

Glutathione peroxidase

GSH:

Glutathione

HaCaT:

Human immortalized keratinocytes

hBD-3:

β-Defensin 3

hDPCs:

Human dermal papilla cells

HETEs:

Hydroxy-eicosatetraenoic acids

HPEK:

Human primary epidermal keratinocytes

HpETEs:

Hydroperoxyeicosatetraenoic acids

HXA3 :

Hepoxilin A3

HXB3 :

Hepoxilin B3

ICAM1:

Intercellular adhesion molecule 1

IL-1:

Interleukin 1

IL-17A:

Interleukin 17A

IL-17F:

Interleukin 17F

IL-1β:

Interleukin 1β

IL-22:

Interleukin 22

IL-23:

Interleukin 23

IL-31:

Interleukin 31

IL-6:

Interleukin 6

IMQ:

Imiquimod

IP:

Prostaglandin I2 receptor

IP3:

Inositol-1,4,5-triphosphate

iPLA2:

Cytosolic calcium independent phospholipase A2

IsoFS:

Isofurans

IsoLG:

Isolevuglandins

IsoP:

Isoprostanes

IsoTX:

Isothromboxanes

l12-LOX:

Leukocyte-type 12lipoxygenase

LA:

Linoleic acid

LC–MS/MS:

Liquid chromatography with tandem mass spectrometry

LOXs:

Lipoxygenases

LPA:

Lysophosphatidic acid

LPC:

Lysophosphatidylcholines

LPP:

Lipid-phosphate phosphatase

LTA4 :

Leukotriene A4

LTA4H:

LTA4 hydrolase

LTB4 :

Leukotriene B4

LTC4 :

Leukotriene C4

LTC4S:

LTC4 synthase

LTD4 :

Leukotriene D4

LTE4 :

Leukotriene E4

LXA4 :

Lipoxin A4

LXB4 :

Lipoxin B4

MAG:

Monoacylglycerol

MAGL:

Monoacylglycerol lipase

MAPK:

Mitogen-activated protein kinase

MDA:

Malondialdehyde

MDCs:

Macrophage-derived chemokine

MIP-2:

Macrophage inflammatory protein 2

MMP-1:

Extracellular matrix metalloproteinase 1

MMP-2:

Extracellular matrix metalloproteinase 2

MPEK:

Murine primary epidermal keratinocytes

MRSA:

Methicillin-resistant Staphylococcus aureus

NAC:

N-acetylcysteine

NAEs:

N-acyl ethanolamines

NFAT:

Nuclear factor of activated T cells

NHDF:

Human dermal fibroblasts

NHEK:

Normal human epidermal keratinocytes

NIH3T3:

Murine fibroblasts

OSM:

Oncostatin M

oxo-ETEs:

Oxo-eicosatetraenoic acids

p12-LOX:

Platelet-type 12-lipoxygenase

p38 MAPK:

P38 mitogen-activated protein kinases

PA:

Phosphatidic acid

p-Akt:

Phosphorylated protein kinase B

PAM212:

Murine keratinocytes

PAR-2:

Proteinase-activated receptor 2

PC:

Phosphatidylcholines

PE:

Phosphatidylethanolamines

PG:

Phosphatidylglycerols

PGA2 :

Prostaglandin A2

PGB2 :

Prostaglandin B2

PGD2 :

Prostaglandin D2

PGE2 :

Prostaglandin E2

PGG2 :

Prostaglandin G2

PGH2 :

Prostaglandin H2

PGI2 :

Prostaglandin I2

PGJ2 :

Prostaglandin J2

p-GSK3:

Phosphorylated glycogen synthase kinase 3

PGXS:

Prostaglandin synthase

PH:

Pleckstrin homology

PI:

Phosphatidylinositols

PIP2:

4,5-Bisphosphate phosphatidylinositol

PKA:

Cyclic AMP-dependent protein kinase

PKCζ:

Protein kinase C zeta

PLA1:

Phospholipase A1

PLA2:

Phospholipase A2

PLB:

Phospholipase B

PLC:

Phospholipase C

PLD:

Phospholipase D

PLD1:

Phospholipase D1

PLD2:

Phospholipase D2

P-LPE:

Plasmalogen-type lysoPE

PMK:

Primary mouse keratinocytes

PPARs:

Peroxisome proliferator-activated receptors

PPARγ:

Peroxisome proliferator-activated receptor γ

PS:

Phosphatidylserines

p-STAT3:

Phosphorylated signal transducer and activator of transcription 3

PUFA:

Polyunsaturated fatty acid

RANTES:

Chemokine regulated upon activation normal T cell expressed and secreted

RhoA:

Ras homolog family member A

ROS:

Reactive oxygen species

RTK:

Receptor tyrosine kinase

SM:

Sphingomyelins

SP:

Sphingolipids

sPLA2:

Secretory phospholipase A2

TAG:

Triacylglycerols

tetranor PGEM:

8-[(1R,2R,5R)-2-(2-carboxyethyl)-5-hydroxy-3-oxocyclopentyl]-6-oxooctanoic acid

TGF-β:

Transforming growth factor beta

Th17:

Lymphocytes Th17

Th22:

Lymphocytes Th22

TNF-α:

Tumor necrosis factor α

TP:

Thromboxane receptor

TRPA1:

Transient receptor potential cation channel, subfamily A, member 1

TRPV1:

Transient receptor potential cation channel subfamily V member 1

TrXA3 :

Trioxilin A3

TrXB3 :

Trioxilin B3

TSLP:

Thymic stromal lymphopoietin

TXA2 :

Thromboxane A2

TXB2 :

Thromboxane B2

TXS:

Thromboxane synthase

UV:

Ultraviolet

vLPR:

Very late-phase

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M.B carried out writing original draft, visualization, and literature review; E.S carried out conceptualization, and review and editing.

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Biernacki, M., Skrzydlewska, E. Metabolic pathways of eicosanoids—derivatives of arachidonic acid and their significance in skin. Cell Mol Biol Lett 30, 7 (2025). https://doi.org/10.1186/s11658-025-00685-y

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