Polyunsaturated Fatty Acid-Derived Lipid Mediators That Regulate Epithelial Homeostasis

Abstract

Epithelial tissues are mainly composed of epithelial cells, covering both internal and external surfaces of our body. To maintain epithelial homeostasis, cellular functions, such as proliferation, migration, and differentiation, are flexibly regulated in response to changes in the cellular status, thereby contributing to barrier formation, immune reaction, and wound closure. Polyunsaturated fatty acids (PUFAs) are precursors of various lipid mediators that maintain tissue homeostasis by exerting characteristic bioactivities. This review aimed to summarize the role of PUFA-derived lipid mediators in epithelial cell functions, mainly focusing on the epidermis, cornea, and intestinal epithelium.

1. INTRODUCTION

Epithelial tissues cover the outer surface of all organs throughout the body, and play a variety of physiological roles, including barrier function, secretion, and absorption. Epithelial cells exhibit polarity, with structural and functional differences between the apical and basolateral sides, and are tightly packed together to form a large sheet of cells, protecting the organ from the external environment. Epithelial cells are present in various organs, including the epidermis, cornea, intestine, and respiratory tract, exerting unique functions in each tissue, thereby contributing to the maintenance of tissue homeostasis.¹⁾ For instance, epidermal keratinocytes in differentiated states constitute four layers, the stratum basale, stratum spinosum, stratum granulosum, and stratum corneum, forming stratified squamous.^2,3) Proliferation and differentiation of epidermal keratinocytes should be appropriately regulated for normal epidermal barrier function, turnover, and wound repairing. Similarly, corneal epithelial cells form stratified squamous on the ocular surface, and the normal process of turnover and wound healing is necessary for maintaining eye homeostasis.⁴⁾ Intestinal epithelial cells constitute simple columnar epithelium with characteristic roles, including selective absorption and barrier function.^5,6) Since epithelial cells are continuously exposed to external stresses, such as dryness, heat or cold stress, chemical and mechanical stimulation, and infection, regulatory machinery for responding to these stresses is indispensable for the maintenance of tissue homeostasis. Dysfunction of epithelial layer is involved in various disorders, such as inflammatory and allergic diseases.^7–16) Thus, chemical mediators and their receptors that orchestrate epithelial homeostasis have received great attention as potential therapeutic targets for epithelial diseases.

Fatty acids have structural variation in carbon chain-length, the number and position of double bonds, and the kind of modification groups, thereby generating diverse biological activities. Polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and linoleic acid (LA) are released by phospholipases and are actively converted to lipid mediators by a series of enzymes, including cyclooxygenases (COXs), lipoxygenases (LOXs), and CYPs, exerting bioactivities via their corresponding receptors^17–20) (Fig. 1). PUFAs are further classified into n-6 and n-3 series, based on the position of methyl-terminal double bonds. In general, n-6 PUFAs are known as precursors of inflammatory mediators, such as prostaglandins and leukotrienes, whereas the n-3 PUFA-derived mediators, such as resolvins, protectins, and maresins, play counterregulatory roles to regulate the local inflammatory responses appropriately. Therefore, understanding the global profile of lipid mediators and their corresponding receptors in each tissue or cell would be important to comprehend the molecular mechanism underlying the regulation of physiological and pathophysiological processes by PUFA-derived mediators. This review aimed to summarize the bioactivities of PUFA-derived mediators regulating epithelial cell functions, especially focusing on the epidermis, cornea, and intestinal epithelium.

Fig. 1. Production of Bioactive Lipid Mediators from PUFAs

PUFAs including AA, LA, DHA, and EPA are metabolized by COXs, LOXs, or CYPs to generate various lipid mediators such as prostanoids, hydroxides, or epoxides. Through the specific receptors, they exert characteristic bioactivities to regulate cellular proliferation, differentiation, migration, chemokine production, or barrier formation.

2. PUFA-DERIVED MEDIATORS THAT REGULATE EPITHELIAL HOMEOSTASIS

2.1. COX Metabolites

COXs are rate-limiting enzymes in the production of prostanoids, such as prostaglandins and thromboxanes from AA. COX has two isozymes, COX1 and COX2. COX1 is referred to as a “constitutive isozyme” that is distributed widely in the body while COX2 is an “inducible isozyme,” which is rapidly upregulated in response to stimuli.^21,22) Each prostanoid exhibits a characteristic function for regulating epithelial homeostasis (Table 1). Prostaglandin E₂ (PGE₂) is locally produced by COXs and PGE₂ synthase (mPGES), and acts on specific G protein-coupled receptors designated as EP1, EP2, EP3, and EP4.²³⁾ Pharmacological inhibition of COXs by non-steroidal anti-inflammatory drugs (NSAIDs) exacerbated skin inflammation in mice, and topical application of EP2 agonist selectively suppressed thymic stromal lymphopoietin (TSLP) production from epidermal keratinocytes, caused by NSAIDs, in protein kinase A (PKA)-dependent manner.^24,25) In lesional regions of patients with atopic dermatitis, TSLP was highly expressed in the apical side of the epidermis, where differentiated keratinocytes were present,²⁶⁾ whereas EP2 was expressed throughout the epidermis,²⁷⁾ suggesting that suprabasal keratinocytes could be targets of PGE₂ in the epidermal tissue. Although EP4 signal is coupled to adenylate cyclase and increase cAMP production, followed by activation of PKA as well as EP2, EP4 is barely expressed in the epidermis while EP2 is highly expressed^27,28); this might explain the large contribution of EP2. On the other hand, epidermal keratinocytes in stratum basale express EP3, which is a Gi-coupled receptor, and the PGE₂–EP3 axis suppresses skin inflammation by suppressing the induction of chemokine CXCL1, which is the chemoattractant for neutrophils.²⁹⁾ Moreover, immune cells contribute to the pathogenesis of skin inflammation. PGE₂ triggers mast cell activation via EP3, inducing skin inflammation,³⁰⁾ whereas PGE₂–EP3 signaling in dendritic cells is essential for fine-tuning excessive skin inflammation.³¹⁾ Furthermore, PGE₂ regulated T cell differentiation and expansion via EP2/EP4 activation, contributing to the pathogenesis of allergic contact dermatitis and psoriatic dermatitis.^32–35) In colonic inflammation, mPGES-1 expression in colon was enhanced in mucosal epithelial cells and infiltrated inflammatory cells, which was associated with PGE₂ upregulation, mediating intestinal inflammation negatively as well as epidermis by inhibiting necroptosis of intestinal epithelial cells via EP4 signaling and inducing resolution of colitis.^36–38) PGE₂ downregulated epithelial Na-K-ATPase activity by transcriptional suppression of α1 and β1 subunits of Na-K-ATPase via EP2/EP4 and PKA activation, which suggested the involvement of PGE₂ in the malabsorption of essential nutrients in chronic enteritis.³⁹⁾ prostaglandin D₂ (PGD₂) negatively regulated the T-helper 2 (Th2) inflammatory responses in intestinal epithelial cells through its receptor CRTH2 expressed in the intestinal stem, goblet, and tuft cells.⁴⁰⁾ Furthermore, prostaglandin I₂ (PGI₂)-IP signaling in intestinal epithelial cells suppressed epithelial permeability, maintained occludin expression, and inhibited epithelial apoptosis.⁴¹⁾

Table 1. Structure and Function of COX Metabolites in Epithelial Tissues

Name	Structure	Tissue	Functions
PGE2		Epidermis	・Enhances TSLP production24,25)
			・Suppresses CXCL1 induction29)
			・Promotes wound healing49)
			・Activates mast cells30)
			・Mediates dendritic cells31)
			・Regulates T cell differentiation32–35)
		Intestine	・Inhibits necroptosis37)
			・Causes malabsorption39)
PGD2		Intestine	・Suppresses IL13Rα expression40)
PGI2		Intestine	・Inhibits permeability41)
15d-PGJ2		Breast epithelium	・Induces apoptosis50)
TXA2		Epidermis	・Induces pruritus42,51)
			・Mediates γδT cell43)
12-HHT		Epidermis	・Promotes migration45)
			・Mediates barrier function46)
		Cornea	・Promotes migration47)
		Intestine	・Mediates barrier function48)
			・Enhances proliferation52)

Thromboxanes, another prostanoid produced by COXs, are involved in the regulation of epithelial homeostasis via TP receptor. In the skin, TP is expressed in epidermal keratinocytes and dorsal root ganglion (DRG) neurons. Thromboxane A₂ (TXA₂) synthase is selectively and highly expressed in epidermal keratinocytes, and its expression was further enhanced in the affected epidermis of mouse atopic dermatitis-like conditions.⁴²⁾ TXA₂ induced itch, either by directly acting on the TP receptors of DRG neurons or by promoting the production of other itch mediators from keratinocytes by acting on their own TP in the autocrine system.⁴²⁾ TXA₂ also regulated skin homeostasis by facilitating interleukin-17A (IL-17A) production from γδT cells, thereby promoting psoriatic dermatitis.⁴³⁾ Besides TXA₂, 12-hydroxyheptadecatrienoic acid (12-HHT), another product of TXA₂ synthase, acted as a mediator to regulate epithelial cell function; 12-HHT functioned as a potent endogenous ligand for BLT2,⁴⁴⁾ and contributed to skin wound healing via BLT2 signaling.⁴⁵⁾ BLT2 is highly expressed in epidermal keratinocytes, and in BLT2-deficient mice, re-epithelialization associated with epidermal keratinocyte migration was suppressed, with virtually no effect on immune cell accumulation or myofibroblast-contributed wound size. Similarly, delayed wound healing was observed in TXA₂ synthase-deficient mice. The 12-HHT-BLT2 axis upregulated the expression of claudin-4, a major constituent of epithelial tight junction, and enhanced IL-6 production upon UVB irradiation.⁴⁶⁾ In addition, 12-HHT promotes corneal wound healing in a BLT2-dependent manner.⁴⁷⁾ In BLT2-deficient mice, dextran sodium sulfate-induced intestinal inflammation was more severe than in wild-type mice, due to impaired intestinal epithelial cell barrier function.⁴⁸⁾

2.2. LOX Metabolites

PUFAs have highly reactive methylene hydrogens flanked by multiple cis-double bonds and are converted to highly reactive hydroperoxy fatty acids by LOXs, which are then converted to leukotrienes and various hydroxide-type mediators via a series of subsequent reactions.⁵³⁾ There are several LOX enzymes with different reaction regioselectivities, contributing to the production of a wide variety of fatty acid metabolites responsible for epithelial homeostasis (Table 2). AA is converted to leukotriene A₄ (LTA₄) by 5-LOX via 5-hydroperoxyeicosatetraenoic acid (HpETE), followed by hydrolysis dependent on LTA₄ hydrolase activity to produce LTB₄; addition of glutathione by LTC₄ synthase produces LTC₄, which is then converted to LTD₄ and LTE₄. LTC₄, LTD₄, and LTE₄ have glutathione-derived cysteines and are collectively referred to as CysLTs. LTB₄ exhibits a chemotactic effect on granulocytes via BLT1. LTB₄ promoted skin homing of neutrophils and CD8⁺ T cells, contributing to pathogenesis of dermatitis.^54–56) LTB₄ also mediated tumor necrosis factor α-induced CCL27 production from epidermal keratinocytes.⁵⁷⁾ LTD.₄ was produced in cultured intestinal epithelial cells and has been shown to regulate cell survival and proliferation in a CysLT1 receptor-dependent manner by autocrine action.⁵⁸⁾ In irritant-induced asthma model, upregulation of CysLT1 signaling protected epithelial cells from oxidative stress.⁵⁹⁾ While CysLT1 is expressed in epithelial cells,⁶⁰⁾ CysLT biosynthetic enzymes were upregulated in eosinophils in allergic diseases, such as asthma,^61–64) suggesting that eosinophil-derived CysLTs acted on epithelial CysLT1. LTE₄ has been shown to mediate mucin secretion and submucosal swelling by acting on GPR99 expressed in airway epithelial cells.⁶⁵⁾

Table 2. Structure and Function of LOX Metabolites in Epithelial Tissues

Name	Structure	Tissue	Functions
LTB4		Epidermis	・Enhances CCL27 production57)
			・Promotes homing of immune cells54–56)
LTD4		Intestine	・Promotes cell survival58)
		Respiratory tract	・Enhances oxidative stress response59)
LTE4		Intestine	・Mediates mucin secretion65)
8-HETE		Epidermis	・Induces keratin1 expression70)
9-HODE		Epidermis	・Inhibits proliferation74)
12-HETE		Epidermis	・Promotes proliferation76)
		Intestine	・Promotes proliferation77)
		Respiratory tract	・Induces cell death78)
		Cornea	・Promotes proliferation79)
12-HEPE		Epidermis	・Suppresses CXCL1/2 expression80)
15-HETE		Epidermis	・Inhibits proliferation92)
		Intestine	・Mediates permeability93)
		Cornea	・Mediates mucin production94)
LXA4		Epidermis	・Inhibits cytokine production84)
			・Inhibits proliferation84)
		Cornea	・Promotes re-epithelialization85,86)
PD1		Cornea	・Promotes re-epithelialization86)
17-HDHA		Cornea	・Promotes re-epithelialization86,87)
RvE1		Epidermis	・Inhibits dendritic cell migration89,90)
		Cornea	・Promotes migration88)
RvD1		Epidermis	・Promotes migration91)
RvD2
RvD4

In mice, Alox8 encodes 8-LOX, which is highly expressed in the epidermis.⁶⁶⁾ Strong induction of 8-LOX expression in the skin of mouse model of imiquimod-induced psoriasis (with skin barrier dysfunction) and that of inhibitor of kappaB (IκB)-deficient mice suggests that 8-LOX may be involved in the response against pathogenic stress, such as inflammation or barrier defect.^67–69) 8-Hydroxyeicosatetraenoic acid (HETE) activates peroxisome proliferator-activated receptor α (PPARα) in epidermal keratinocytes, induces keratin 1 expression, and regulates differentiation.⁷⁰⁾ Besides, 8-hydroxyeicosapentaenoic acid (HEPE) produced from EPA also has PPARα agonist activity, approximately 10 times that of EPA, and has been reported to suppress triglyceride accumulation in high fat diet-induced obese mice.^71–73) Moreover, linoleic acid is converted to 9-hydroxyoctadecadienoic acid (HODE) by 8-LOX, which inhibits the proliferation of epidermal keratinocytes via GPR132.⁷⁴⁾

12-Hydroxy fatty acids, including 12-HETE and 12-HEPE, are produced by 12-LOX. Murine 12/15-LOX, an ortholog of human 15-LOX, also contributes to the production of 12-HETE from AA. 12-HETE is produced in the upper epidermal layer, where differentiated keratinocytes are present, and are highly accumulated in the skin of patients with psoriasis. Intradermal injection of 12-HETE induced skin pruritus via BLT2 expressed in neuronal sensors and was suspected to be associated with itching in various dermatitis.⁷⁵⁾ Insulin-like growth factor II stimulation induced 12-LOX expression in the epidermis and cultured keratinocytes, and 12-HETE stimulated keratinocyte DNA synthesis and mitogenesis in MAP kinase- and PI3 kinase-dependent manner.⁷⁶⁾ 12-HETE promoted the proliferation of Caco-2 cells, an intestinal epithelial cell line,⁷⁷⁾ but inhibited proliferation of airway epithelial cells by promoting cytochrome C release and inducing cell death.⁷⁸⁾ In the corneal epithelium, 12-LOX expression and 12-HETE production were induced by epidermal growth factor (EGF) stimulation, and 12-HETE induced the proliferation of corneal epithelial cells.⁷⁹⁾ EPA-derived 12-HEPE was dominantly produced in the skin of mice fed n-3 PUFA-enriched diet, and suppressed the expression of the neutrophil chemotactic factor CXCL1/2 via the epidermal keratinocyte nuclear receptor RXR, thereby inhibiting neutrophil infiltration into the skin, and improving the symptoms of allergic contact dermatitis.⁸⁰⁾

Human 15-LOX and its murine orthologue 12/15-LOX are expressed in immune cells, such as eosinophils, monocytes, macrophages, and dendritic cells, as well as in epithelial cells, and produce anti-inflammatory lipid mediators, including lipoxins, resolvins, and protectins.^81–83) Lipoxin A₄ (LXA₄) functions via ALX receptor and directly acts on epithelial cells to regulate their functions. The LXA₄-ALX axis inhibited the production of IL-6 and IL-8 in keratinocytes in vitro and to inhibit the proliferation of keratinocytes by arresting the cell cycle at G0/G1.⁸⁴⁾ LXA₄ and DHA-derived protectin D₁ (PD₁) and 17-hydroxydocosahexaenoic acid (HDHA) are locally produced in mouse cornea, and deletion of 12/15-LOX delayed corneal wound healing.^85,86) Topical application of LXA₄, PD₁, or 17-HDHA promoted corneal re-epithelialization, indicating the contribution of 12/15-LOX-derived metabolites to the corneal wound healing process. 12/15-LOX is expressed in corneal epithelial cells and in eosinophils, which were accumulated during corneal wound healing. In eosinophil-specific 12/15-LOX-deficient mice, proliferation of corneal epithelial cells was reduced during corneal re-epithelialization, suggesting that 12/15-LOX-expressing eosinophils contribute to corneal wound healing via the local production of pro-resolving mediators.⁸⁷⁾

Resolvins derived from EPA and DHA constitute the resolvin E (RvE) and resolvin D (RvD) series, respectively. RvE₁ enhanced the migration of corneal epithelial cells through matrix metalloproteinase and sheddase-mediated EGF receptor (EGFR) transactivation.⁸⁸⁾ Moreover, RvE1 inhibited the migration of dendritic cells and attenuates dermatitis by blocking BLT1 signaling.^89,90) RvD₁, RvD₂, and RvD₄ were produced at skin wound sites, and topical application of those mediators promoted skin wound healing. RvD₁ and RvD₂ promoted wound healing in an ALX receptor-dependent and GPR18-dependent manner, respectively, by selectively promoting migration, but not proliferation, of epidermal keratinocytes.⁹¹⁾ Epidermal keratinocytes express 12/15-LOX and are a potential source of RvD production during wound repair.

2.3. Epoxy Fatty Acids

CYP isozymes mediate the production of epoxyeicosatrienoic acids (EETs) from AA, epoxyeicosatetraenoic acids (EpETEs) from EPA, epoxydocosapentaenoic acids (EpDPEs) from DHA, and epoxyoctadecamonoenoic acids (EpOMEs) from LA, regulating epithelial homeostasis (Table 3). These fatty acid epoxides are hydrolized by soluble epoxide hydrolase (sEH) to produce bicinal diol. Arachidonic acid-derived 5,6-EET and 8,9-EET increased intracellular calcium ions by activating TRPV4 in intestinal epithelial cells, thereby increasing intestinal paracellular permeability.^95–97) 11,12-EET promoted skin wound healing in diabetic mice due to modulation of inflammation and angiogenesis.^98,99) In ischemia, 14,15-EET rescued deteriorated wound healing by enhancing neovascularization and altering inflammatory response in wound as in 11,12-EET.¹⁰⁰⁾ 14,15-EET, on the other hand, also acts directly on epidermal keratinocytes and contributes to epidermal barrier formation by promoting involucrin expression and keratinization.¹⁰¹⁾ EPA-derived 17,18-EpETE was abundant in the intestinal tract of mice fed n-3 PUFA-enriched diet, and exerted anti-allergic effect by suppressing mast cell degranulation in vivo.¹⁰²⁾ Moreover, 17,18-EpETE suppressed allergic contact dermatitis by inhibiting neutrophil infiltration via GPR40.¹⁰³⁾ Also, 17,18-EpETE acted directly on airway epithelial cells, and inhibited IL-6 and IL-8 production, thereby contributing to the suppression of airway inflammation through GPR40 expressed in airway epithelial cells.¹⁰⁴⁾

Table 3. Structure and Function of Epoxides in Epithelial Tissues

Name	Structure	Tissue	Functions
5,6-EET		Intestine	・Enhances permeability95–97)
8,9-EET		Intestine	・Enhances permeability96)
11,12-EET		Epidermis	・Promotes wound healing98,99)
14,15-EET		Epidermis	・Promotes wound healing100)
			・Promotes barrier formation100)
17,18-EpETE		Epidermis	・Inhibits neutrophil homing103)
		Intestine	・Inhibits mast cell activation102)
		Respiratory tract	・Inhibits cytokine production104)

3. CONCLUSION

Dysregulated epithelial cell homeostasis leads to epithelial inflammation, injury, and abnormal secretion and absorption, resulting in the development of various epithelial diseases. Dysregulated balance of lipid mediators has been reported in various epithelial diseases,^{41,105–110)} claiming great attention as targets for the potential therapeutics. Epithelial tissues have heterogeneous cell population, and the actions of lipid mediators are determined by the combination of precursor fatty acids, metabolic enzymes and their corresponding receptors, which intricately and skillfully regulate epithelial cell homeostasis (Fig. 2). Further studies of the temporal and spatial regulation of lipid mediator production and their receptor expressions will lead to a global understanding of the role of PUFA-derived lipid mediators in epithelial tissue homeostasis.

Fig. 2. PUFA-Derived Lipid Mediatorts in Skin Homeostasis

PUFA-derived mediators regulate epithelial cell functions via corresponding receptors expressed in epithelial cells or infiltrated immune cells, orchestrating epithelial homeostasis.

Acknowledgments

This study was supported by JSPS KAKENHI 20H00495 and RIKEN Pioneering Project “Glyco-Lipidologue Initiative.”

Conflict of Interest

The authors declare no conflict of interest.

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