The role of ceramides in skin homeostasis and inflammatory skin diseases

Journal Pre-proof The Role of Ceramides in Skin Homeostasis and Inflammatory Skin Diseases Qingyang Li, Hui Fang, Erle Dang, Gang Wang

PII:

S0923-1811(19)30370-6

DOI:

https://doi.org/10.1016/j.jdermsci.2019.12.002

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DESC 3543

To appear in:

Journal of Dermatological Science

Received Date:

26 November 2019

Accepted Date:

2 December 2019

Please cite this article as: Li Q, Fang H, Dang E, Wang G, The Role of Ceramides in Skin Homeostasis and Inflammatory Skin Diseases, Journal of Dermatological Science (2019), doi: https://doi.org/10.1016/j.jdermsci.2019.12.002

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.

The Role of Ceramides in Skin Homeostasis and Inflammatory Skin Diseases Qingyang Li, Hui Fang, Erle Dang, Gang Wang*

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi’an 710032, China

*Corresponding author: Professor Gang Wang, Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi’an 710032, China. E-mail: xjw-

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[email protected]. Tel: 86-29-84775401

Highlights

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• Ceramides are critical to skin barrier, epidermal self-renewal, and immune responses

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• Impaired ceramide metabolism is associated with several inflammatory dermatoses

ABSTRACT

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• Applying ceramides holds therapeutic promises in psoriasis and atopic dermatitis

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Ceramides, members of sphingolipid family, are not only the building blocks of epidermal barrier structure, but also bioactive metabolites involved in epidermal self-renewal and immune regulation. Hence, abnormal ceramide expression profile is recognized to defect extracellular lipid organization,

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disturb epidermal self-renewal, exacerbate skin immune response and actively participate in progression of several inflammatory dermatoses, exemplifying by psoriasis and atopic dermatitis. Here, we discuss recent advances in understanding skin ceramides and their regulatory roles in skin homeostasis and pathogenic roles of altered ceramide metabolism in inflammatory skin diseases. These insights provide new opportunities for therapeutic intervention in inflammatory dermatoses.

Keywords: Ceramides; Epidermal barrier; Inflammatory dermatoses; Psoriasis; Atopic dermatitis 1

Abbreviations1 1

Abbreviations:

Acylated ceramides (acylCer), atopic dermatitis (AD), C-X-C motif chemokine ligand 1 (CXCL1), ceramide synthase (CerS), corneocyte lipid envelope (CLE), dihydrosphingosine (DS), dihydroxysphinganine (T), elongase of long-chain fatty acids (ELOVL), esterified ω- hydroxy (EO), interferon (IFN) -γ, interleukin (IL), long chain (LC), long periodicity phase (LPP), natural moisturizing factor

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(NMF), non-hydroxy (N), nucleotide-binding domain and leucine-rich-repeat-containing family pyrin 3 (NLRP3), peroxisome proliferator-activated receptor (PPAR), phytosphingosine (P), phytosphingosine-carrying ceramides (phytoCer), Psoriasis Area Severity Index (PASI), Severity Scoring

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of Atopic Dermatitis (SCORAD), sphingomyelin (SM), sphingosine (S), sphingosine-1-phosphate

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(S1P), stratum corneum (SC), toll-like receptor (TLR), transepidermal water loss (TEWL), transient

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receptor potential ankyrin 1 (TRPA1), transient receptor potential vanilloid 1 (TRPV1), tumor ne-

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crosis factor (TNF), ultra-long chain (ULC), ultraviolet (UV), very long chain (VLC), α-hydroxy (A), β-glucocerebrosidase (GlcCerase), ω- hydroxy (O), 6-hydroxy-sphingosine (H).

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1.Introduction

Epidermal barrier, which mainly refers to the stratum corneum (SC), creates a first-line defense

against myriad potentially harmful invaders, diminishes transepidermal water loss (TEWL), and plays an essential role in maintaining skin homeostasis. Recognized as the "brick and mortar" model, epidermal barrier is constructed of 15 to 25 layers of anucleated corneocytes embedded in lamellar lipid matrix. Epidermal ceramides account for approximately 50% of total epidermal lipid by weight.

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Along with free fatty acid and cholesterol, ceramides constitute a hydrophilic extracellular lipid matrix, which is indispensable for permeability barrier function [1]. In addition, ceramides also act as an active second messenger, regulate keratinocyte proliferation and differentiation, enhance proinflammatory cytokines production, and modulate immune responses. Aberrant metabolism and function of ceramides is involved in the pathogenesis of several inflammatory skin diseases, including psoriasis, atopic dermatitis (AD) and ichthyosis. In this review, we focus on the role of ceramides in the progression of inflammatory skin diseases that may provide a prospective for further depicting the path-

2. Expression and regulation of epidermal ceramide profile

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ogenesis and therapeutic strategies of inflammatory dermatoses.

Epidermal ceramides mainly reside in SC and exhibit great molecular heterogeneity, comprising

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18 classes. To discriminate ceramide classes, a nomenclature is used, which is based on the abbreviation of its fatty acid (N, non-hydroxy; A, α-hydroxy; O, ω- hydroxy; EO, esterified ω- hydroxy) and

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sphingoid base (DS, dihydrosphingosine; S, sphingosine; P, phytosphingosine; H, 6-hydroxy-sphingosine; T, dihydroxy-sphinganine). These ceramide classes each contain 300-1000 species based on

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their specific combination of fatty acids and base groups [2]. The most abundant ceramides in normal epidermis are Cer[NH], Cer[NP], Cer[AH] and Cer[AP], while Cer[EODS], Cer[ADS] and Cer[EOP]

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are among the least. In terms of their acyl chain length, ceramides are varied from having long chain (LC) (C14–C18), very long chain (VLC) (C20–C26), to ultra-long chain (ULC) (>C26). Acyl chain length in healthy skin mainly ranges from C16 to C36, mostly C24 [3]. Heterogeneity in ceramides

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molecular architecture enables significant disparity of ceramides functions among classes, suggesting their diverse roles in skin homeostasis. Epidermal ceramide expression profile is influenced by both internal and external factors. During

their de novo or salvage synthesis, ceramides mainly requires a same set of enzymes, except for ceramide synthases (CerSs), of which CerS3 is demonstrated to be exclusively required for ULC ceramides. Downregulating CerS3 activity leads to reduced proportion of ULC ceramides. Besides,

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it was reported that ZAG, an adipokine, could increase Cer[EOS], Cer[NP] and Cer[AS], and eventually restore skin barrier function in AD mice [4]. SC ceramide composition is altered by age. Children (<6 year-old) exhibit relatively more Cer[NH], and less α-hydroxy and esterified ω- hydroxy ceramides than adults [5]. Cer[EOS] is significantly reduced in seniors (>50s) compared to younger individuals (20-40s). Moreover, the degree of fatty acid chain saturation of Cer[EOS], which has marked effects on lamellar and lateral lipid organization, is decreased in autumn and winter, partially accounting for worse barrier function and higher reoccurrence rate of psoriasis in winter [6]. Ultraviolet (UV) irradiation exposure leads to an increase in ceramides and a decrease in sphingomyelin

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(SM) in HaCaT cells, possibly through promoting ceramide salvage pathway [7].Therefore, regulated by various factors, epidermal ceramides keep in dynamic equilibrium and play critical roles in skin

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homeostasis.

3. Ceramides -- key regulators in maintaining skin homeostasis

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3.1. Ceramides maintain epidermal barrier function

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Ceramides, fatty acid and cholesterol constitute the extracellular lipid matrix of epidermal barrier in an approximately equimolar ratio and are assembled in a dense orthorhombic lateral packing within

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SC interstices. Among them, ceramides are central to the permeability barrier structure and function. Replacing C24 Cer[NS] by C16 Cer[NS] in a SC lipid membrane model augments hexagonal lateral packing, lipid membrane destabilization and phase separation, which results in increased permeability to water, theophylline and indomethacin [8]. Acylated ceramides (acylCer), such as Cer[EOS], cova-

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lently bind to envoplakin and involucrin and form corneocyte lipid envelope (CLE), which acts as a scaffold linking hydrophilic corneocytes and lipophilic extracellular lipids [9]. AcylCer is required for the formation of the long periodicity phase (LPP) and the orthorhombic lateral packing of lipids, which are considered to be essential in maintaining the skin lipid lamellae structure [10]. Reduced acylCer can lead to a "leaky" permeability barrier and often exhibit xerotic and scaly appearance as seen in ichthyosis and AD. Therefore, a balanced expression of ceramide classes is required for stable and dense organization of SC lipids and a well-functioning epidermal barrier. 4

3.2. Ceramides promote epidermal self-renewal In addition, ceramides have been reported as an active second messenger with pro-apoptosis function in several tissues and cells. In skin, although in lack of direct evidence, ceramides were speculated to regulate keratinocyte proliferation/differentiation balance by exerting anti-proliferative and pro-apoptotic effects. Ceramide synthesis is enhanced along with the rate of keratinocyte differentiation both in vitro and in vivo [11]. Ceramides inhibit cell growth in human skin squamous cell carcinoma and are involved in both death receptors- and mitochondria-related apoptosis [12]. Interest-

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ingly, application of stable ceramide analogs causes downregulation of selenoproteins and glutathione peroxidase 4, which could promote ferroptosis [13]. Although ceramides are indispensable in epidermis, excessive ceramides may cause irreversible cell death and inflammation, as seen in UV-

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induced skin damage [14]. Hence, the equilibrium between ceramide synthesis and degradation is essential for maintaining epidermal renewal and normal homeostasis.

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3.3. Ceramides regulate skin immune response

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Ceramides and their derivatives have been largely investigated in their roles in modulating immune system and inflammation. By promoting the stabilization of Toll-like receptor (TLR) 4, ceramides

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were shown to enhance LPS-induced proinflammatory signaling [15]. Studies in microglia have discovered that ceramides function as intracellular modulators of nucleotide-binding domain and leucine-rich-repeat-containing family pyrin 3 (NLRP3) inflammasome assembly and induce the secretion of interleukin (IL) -1β [16]. Sphingosine-1-phosphate (S1P), a ceramide metabolite, upregulates

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cathelicidin antimicrobial peptide expression in keratinocytes and activates innate immunity [17]. Thus, ceramides are regarded as bioactive transmitter involved in various inflammatory signaling pathways. Further studies need to focus on whether extracellular ceramides stacked in the lipid matrix in SC also hold multifunctional properties in inflammation and immune response. 4. Ceramides in inflammatory skin diseases 4.1. Psoriasis 5

Psoriasis is a T cell mediated inflammatory skin disease, characterized by attenuated epidermal barrier function. Koebner phenomenon and efficacy of occlusion in clinical practice, offer eloquent examples of how psoriasis could be provoked by disruption of epidermal permeability barrier. Genome-wide association studies in both European and Chinese populations have identified skin barrier regulatory genes of the late cornified envelope as new susceptibility genes for psoriasis [18]. Recently, our group has demonstrated that disruption of epidermal barrier, by increasing mechanical stress, could exacerbate psoriasis phenotype via inducing keratinocyte proliferation and overexpression of C-X-C motif chemokine ligand 1 (CXCL1), S100A8, S100A9, lipocalin 2, β-defensin, and

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IL-6 in mice [19]. Taken together, these findings indicate that psoriasis could be driven by a primary defect in epidermal barrier function.

It has long been reported that psoriatic skin exhibits malfunctioned epidermal barrier integrity

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along with disturbed ceramides metabolism. Although it was once considered that total ceramide

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level was not altered in psoriasis epidermis, recent studies with improved measurement methods and larger and more strictly controlled sample size have shown that significantly decreased total

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ceramides are inversely correlated with Psoriasis Area Severity Index (PASI) score [20]. VLC ceramides are increased in psoriatic lesions, while ULC ceramides are significantly decreased [21].

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This bias towards shorter ceramides contributes to hexagonal lipid organization and phase separation in extracellular lipid membranes. Cer[NS] is elevated in psoriatic lesions, whereas phytosphingosinecarrying ceramides (phytoCer, such as Cer[NP] and Cer[AP]) and acylCer are both reduced in psoriatic lesions and correlate with increased TEWL and inferior water retention capacity [2]. PhytoCer

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enhances SC barrier structure by forming strong hydrogen bonds and highly thermostable domains in the extracellular lipid matrix [22]. Thus, decreased phytoCer and acylCer, which are critical for epidermal lipid lamellae structure and keratinocyte differentiation, act as a causal role in permeability barrier dysfunction and hyperproliferation in psoriasis. Furthermore, circulating levels of total ceramides are decreased in psoriasis patients, while serum S1P increased [23]. Presumably, decreased serum ceramides can be ascribed to enhanced ceramide degradation, since S1P is a derivative from 6

ceramide hydrolysis. S1P promotes Th17 cell development, IL-17 generation, trans-endothelial T cell migration, and angiogenesis [24]. Hence, ceramides and their metabolites may exacerbate immune response in psoriatic pathogenesis. To investigate the mechanisms underlying the altered ceramide expression profile in psoriasis, researchers have focused on the enzymes in ceramide metabolism. SPT, the rate-limiting enzyme in ceramide de novo synthesis, is decreased in psoriatic epidermis. A study in SPT-cKO mice showed that a marked reduction of ceramides in the epidermis leads to barrier dysfunction, upregulation of IL-17 and γδ T cell expansion in the psoriasiform lesions [20]. β-glucocerebrosidase (GlcCerase),

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CerS3, and elongase of long-chain fatty acids (ELOVL) 1 are also downregulated in psoriatic lesions, which can partially explain the decrease in acylCers and alteration of permeability barrier function

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(Fig. 1) [25]. 4.2. Atopic dermatitis

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Epidermal barrier dysfunction has been observed in both lesional and non-lesional skin sites of AD, manifested as enhanced TEWL, raised skin pH, altered surface microbiota colonization pattern,

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and disturbed ceramide profile. With regards to the total level of SC ceramides, studies have reported a significant decrease in lesional AD skin [26]. Yet, the composition rather than the amount of

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ceramides is more strongly associated with disturbed skin barrier function in AD. Studies have also found increased relative levels of Cer[AS], Cer[AH], Cer[AP], Cer[ADS], and Cer[NS] in AD lesions compared to healthy subjects, whereas decreased levels of Cer[NP], Cer[NH], and acylCer [27]. Sim-

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ilar to the changes of ceramide acyl chain length in psoriasis, AD skin also exhibits an elevation in LC and VLC ceramides, particularly C18 ceramides, but a reduction in ULC ceramides [28]. This altered composition of epidermal ceramides correlate with downregulated levels of natural moisturizing factor (NMF), enhanced TEWL, and increased Severity Scoring of Atopic Dermatitis (SCORAD) index [5]. The underlying attenuated barrier function in AD results in continuous generation of cytokines and chemokines, a proinflammatory cytokine cascade, and unimpeded intrusions of allergens and antigens, which contributes to the "atopic march" [29]. Cer[EOS]/Cer[NS] ratio is 7

significantly lower in AD patients with food allergy than those without food allergy [30]. These results indicate that altered ceramide composition not only contributes to disrupted barrier function but also inflammatory and allergic properties in AD individuals. Studies have reported raised SM deacylase and declined sphingomyelinase in AD, which may cause a decrease in total ceramides, Cer[NS], and Cer[AS] [27]. High levels of CerS4 in AD contribute to the enhanced synthesis of the short-chain ceramides [31]. P. aeruginosa and S. aureus, present in microflora of AD skin, could produce ceramidase activated by sphingosine derived from the host [32]. However, it is intriguing to explain the causal link between the reduced ceramides and altered

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microflora, since a depletion in ceramides was reported to enable S. aureus growth [33]. Interestingly, it was uncovered that Th2 cytokines, interferon (IFN) -γ, and tumor necrosis factor (TNF) -α induce a decrease in ULC ceramides and an increase in LC ceramides (
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between epidermal barrier dysfunction and cytokines generation in AD pathogenesis (Fig. 2) [25,34].

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4.3. Ichthyoses

Ichthyoses, a group set of hereditary diseases, display an epidermal barrier abnormality, which

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parallels the severity of the clinical phenotype. Most of causative genes are associated with ceramide synthesis, especially acylCer, and CLE formation. For example, patients who carry a mutation in

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PNPLA1 (patatin-like phospholipase domain-containing protein 1), ELOVL1, or CERS3, which are all directly involved in acylCer synthesis, result in reduced ULC ceramides and impaired CLE structure [35]. Mutations in ABHD5 (α/β hydrolase domain containing 5), which enhances acylCer pro-

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duction, are involved in ichthyosis symptoms of Chanarin-Dorfman syndrome. In Neu-Laxova syndrome, patients also exhibit reduced SC ceramides due to phosphoglycerate dehydrogenase deficiency [36]. Regardless of the diverse etiology of these inherited disorders, almost all of the ichthyoses ultimately end up with reduced total ceramide and acylCer amount, and defects in the extracellular lipid matrix, which drives epidermal hyperproliferation and keratinization. 4.4. Netherton syndrome

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Netherton syndrome, resulting from recessive mutations in SPINK5 (serine protease inhibitor Kazal‐ type 5), is characterized by the triad of congenital ichthyosis, hair shaft anomalies and severe atopic diathesis. The total amount of SC ceramides in patients with Netherton syndrome is reduced, with significantly decreased Cer[NP] and acylCer. Cer[AS], Cer[NS] and Cer[AH] show little difference compared to the healthy skin. C14-C20 ceramides are raised, particularly C34, which leads to reduced LPP and augmented hexagonal packing. A study has revealed that in Netherton syndrome, the expression of the β-glucocerebrosidase and acid sphingomyelinase, enzymes involved in ceramide salvage pathway, is much lower and more diffuse throughout the epidermis [37]. This al-

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tered enzyme activity may be resulted from increased pH in the SC or unregulated kallikrein activity. 4.5. Acne

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Average ceramide chain length is significantly decreased in acne lesions, contributing to dryness and irritation in acne patients. Applying external ceramides within moisturizers among 29 acne pa-

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tients presents significantly reduced lesions, increased amount and chain length of SC ceramides, and alleviated skin barrier with reduced TEWL [38]. Besides, circulating levels of ceramide chain length

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are reduced, while C16 SM and ceramide-1-phosphate levels are elevated in acne patients compared to healthy controls, indicating a systemic disturbed ceramide metabolism [39]. Studies have revealed

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the properties of ceramide composition governing S. aureus growth on SC, yet little has been known about effects of ceramide profile on P. acnes and its pathogenic roles in acne [33]. 4.6. Skin aging

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Skin aging is characterized by flattening of the dermal-epidermal junction, decreasing and disorganization of the extracellular matrix. SC ceramide content and Cer[EOS] decline significantly with age [2]. Interestingly, the rate of altered ceramides is almost the same for both sun-exposed skin and sun-protected skin, which indicates an intrinsic alteration of ceramide metabolism in skin aging [40]. Topical supplementation of ceramides inhibited wrinkle formation and reduced TEWL in aged skin,

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suggesting a critical role of ceramides in delaying skin aging [41]. Further studies need to clarify the mechanism by which ceramides exert anti-aging effects. 4.7. Pruritus Pruritus is associated with many chronic skin disorders and are commonly seen in elderly individuals. The sensation of itch can arise from the activation of epidermal nerve fibers, which requires exogenous penetrating pruritogens or endogenous mediators activating protease-activated receptor and transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively).

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Ceramides can maintain epidermal barrier integrity, reduce penetration of pruritogens, provide itch relief and improve quality of life [42]. Sphingomyelinase, an enzyme that produce ceramides, was shown to inhibit TRPV1 and TRPA1 induced Ca2+ and calcitonin gene related peptide release, while

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ceramides exhibited little influence on TRPA1 and TRPV1 activation in trigeminal neurons and TRPV1-expressing CHO cell line [43]. Nevertheless, functions of ceramides toward TRPV1 and

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TRPA1 may show a different picture in itch-associated unmyelinated C fibers and requires investi-

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gation in future studies. Altogether, these studies provide evidence for the multifunctional role of ceramides in the pathogenesis of various inflammatory dermatoses (Table 1).

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5. Ceramides in the treatment of psoriasis and AD

Recent studies have discovered decreased SC ceramide content and SC hydration as contributors of inflammation in aging, obesity, and other systemic disorders. Man et al. have pointed out that aberrant epidermal permeability barrier provokes an elevation in both cutaneous and circulating cy-

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tokine levels, independent of hepatic or T cell involvement [44]. Improving epidermal barrier function alone, by topical application of an emollient, could reduce circulating levels of proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α [45]. Hence, maintaining epidermal homeostasis may possess therapeutic promises for dermatoses with systemic inflammation, such as psoriasis and AD. Previous studies have shown that topical application of phytoCer or its analogues (phytosphingosine maleic and fumaric acid amides) increases NMF and skin hydration, decreases skin inflammation 10

in keratinocytes, and ameliorates IL-23-induced psoriasiform dermatitis in mouse ears [3]. A recent study among 106 psoriasis vulgaris patients implicated that topical application of linoleic acidceramide moisturizer is effective for both treatment and prevention of psoriasis [46]. Worthy to note that ceramides must be delivered with cholesterol and fatty acids in an appropriate ratio and sufficient amount to impart barrier improvements, otherwise barrier function would be deteriorated [29]. Therapeutic effects of ceramides are also frequently studied in AD. Ceramides were shown to prevent the downregulation of filaggrin and disorganization of keratin 10 and β4-integrin in an AD-like 3D human skin model [47]. Topical application of linoleic acid-ceramide moisturizer also show

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promising effects in AD patients, by significantly improving skin capacitance, TEWL, Eczema Assessment Severity Index (EASI) and pruritus scores [48]. Moreover, ceramide-containing moisturizers can minimize corticosteroid exposure, prevent corticosteroid side-effects and reduce AD flares,

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via stimulating peroxisome proliferator-activated receptor (PPAR) α expression, reducing inflamma-

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tion, and enhancing antimicrobial peptides expression [49]. A randomized trial in infants with high risk of AD proved that topical application of ceramide dominant emollient prevents development of

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AD and food sensitization [50]. Thus, application of ceramides offers more than a therapeutic relief of symptoms, but also preventive measures in the development of psoriasis and AD.

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6.Conclusion

Ceramides, the main element of extracellular lipid in SC, exert various roles in skin homeostasis,

including epidermal barrier maintenance, epidermal self-renewal, and immune modulation. Ceramide

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expression varies among classes in both normal and diseased skin. Impaired ceramide expression profile is associated with increased TEWL, inferior water capacity of SC, and enhanced inflammation. Evidence from both in vivo and in vitro studies have uncovered promising effects of ceramides in enhancing permeability barrier and alleviating skin inflammatory and immune responses. The challenge for future studies is to understand the precise mechanism of epidermal ceramides in inflamma-

tory cytokines cascade and immune cells infiltration to the skin, which further facilitates new therapeutic strategies in inflammatory skin diseases. 11

Funding This work was supported by the National Natural Science Foundation of China (no. 81673051 and 81872519). Conflict of interest The authors have no conflict of interest to declare. Text word count: 3050; Number of references: 50; Table: 1; Figures: 2

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[49] S.E. Lee, M.K. Jung, S.J. Oh, et al., Pseudoceramide stimulates peroxisome proliferator-activated receptor-alpha expression in a murine model of atopic dermatitis: molecular basis underlying the anti-inflammatory effect and the preventive effect against steroid-induced barrier impairment, Arch Dermatol Res, 307, (2015) 781-792. [50] A.J. Lowe, J.C. Su, K.J. Allen, et al., A randomized trial of a barrier lipid replacement strategy for the prevention of atopic dermatitis and allergic sensitization: the PEBBLES pilot study, Br J Der-

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Biography of first author Qingyang Li is an M.D. student at Fourth Military Medical University, China. She works in the team of Prof. Gang Wang in the Department of Dermatology, Xijing Hospital, Fourth Military Medical University. She specializes in cell biology, mitochondria function, and lipid metabolism. Her research interest focuses on epidermal barrier, ceramides, and vascular endothelial cells in the

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pathogenesis of psoriasis.

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Legends Fig 1. Altered ceramide profile mediates the progress of psoriasis. Reduced activity of ceramide synthesis enzymes, including GlcCerase, CerS3 and ELOVL1, leads to decreased acylCer and phytoCer, and increased Cer[NS] and short chain ceramides(
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mune response in psoriatic skin.

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Fig 2. Alteratered ceramide profile is actively involved in the pathogenesis of AD. Increased ceramidase, SM deacylase, and CerS4 account for the reduction of total ceramide amount and increased short chain ceramides (<24C) in lamellar bodies. Besides, Cer[AS] and Cer[NS] are elevated, whereas Cer[NP], Cer[NH], and acylCer are reduced. The altered ceramide profile leads to a less dense extracellular lipid matrix and increased risks for external intrusions, which stimulates

Th2/Th22 inflammation. Besides, disturbed ceramide profile and impaired barrier function itself can

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lead to continuous generation of cytokines and chemokines, such as IL-1α, TNF-α, and β-defensin,

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exacerbating inflammation in AD.

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Table 1. Expression profile and function of epidermal ceramides in inflammatory dermatoses

[NP], [AP], acylCer, long chain ceramides Cer[AS], Cer[AH], Cer[AP], Cer[ADS], and Cer[NS], short chain ceramides

AD

Cer[NP], Cer[NH], and acylCer, long chain ceramides

Ichthyoses

Netherton syndrome

CER [EOS], [NP], CER[AP], and CER[AH]

short chain ceramides, unsaturated ceramides, glucosylceramides

maintain extracellular lipid packing structure, reduce TEWL

ceramide chain length

total ceramides and Cer[EOS]

inhibit wrinkle formation, hold SC hydration capacity

Unknown

maintain barrier integrity, reduce pruritogens penetration preventing TRPV1 or TRPA1 activation?

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Skin aging

Pruritus

maintain epidermal CLE structure, reduce TEWL, restrain keratinocyte proliferation

maintain epidermal barrier function, increase SC hydration influencing growth of P. acnes?

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Acne

reduce TEWL, prevent barrier-induced proinflammatory cytokine cascade, protect against intrusions of allergens and antigens

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Cer[NP] and acylCer

enhance barrier function, restrict keratinocyte pro[21] ; liferation, prevent barrier- Tawada et al. 2014 [23] Mysliwiec et al. 2017 induced inflammation response

van Smeden et al. 2014 ; Elias et al. 2019 [30]

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Psoriasis

References

Mueller et al. 2019 [35]

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Cer[NS], [AS], short chain ceramides

Roles and functions

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Inflammatory Ceramide expression prodermatoses file

van Smeden et al. 2014 [37]

Isoda et al. 2015 [38]

Lueangarun et al. 2019 [41]

Zirwas et al. 2017 [42]

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