Human skin has a distinct profile of fatty acids and related bioactive lipid mediators that regulate many aspects of epidermal and dermal homeostasis, including immune and inflammatory reactions. Sebum lipids act as effective antimicrobial agents, shape immune cell communications and contribute to the epidermal lipidome. The essential fatty acid linoleic acid is crucial for the structure of the epidermal barrier, while polyunsaturated fatty acids act as precursors to eicosanoids, octadecanoids and docosanoids through cyclooxygenase, lipoxygenase and cytochrome P450 monooxygenase-mediated reactions, and endocannabinoids and N-acyl ethanolamines. Cross-communication between these families of bioactive lipids suggests that their cutaneous activities should be considered as part of a wider metabolic network that can be targeted to maintain skin health, control inflammation and improve skin pathologies.

Introduction

Fatty acids have long been recognised for their importance in skin health, and essential fatty acid deficiencies result in fatal epidermal barrier failure, characterised by desquamation and skin lesions [1,2]. Altering the cutaneous fatty acid profile through diet or nutritional supplementation has been reported to ameliorate inflammatory conditions (reviewed in refs [36]). As well as having direct effects on signalling pathways, gene transcription, inflammatory and immune responses, many of the fatty acid-mediated bioactivities are attributed, at least in part, to the formation of bioactive derivatives. These lipid mediators are produced via sequential enzymatic reactions that typically start with the liberation of the relevant fatty acid precursor from membrane phospholipids, following the action of inflammatory or other stimuli that activate the relevant phospholipases [79]. Once cleaved from the cellular membranes, free fatty acids can be converted into an array of bioactive mediators following the action of prostaglandin-endoperoxide synthases (cyclooxygenases; COX), lipoxygenases (LOXs) and cytochrome P450 monooxygenases (CYP), as well as transcellular and non-enzymatic reactions. Figure 1 shows a diagrammatic outline of the main biochemical reactions mediating the biotransformation of the key polyunsaturated fatty acid (PUFA) arachidonic acid (AA; C20:4n-6). The metabolism of various cutaneous PUFA occurs in a similar way and results in an array of eicosanoids, docosanoids, octadecanoids, endocannabinoids and N-acyl ethanolamines (NAEs) that have all been implicated in numerous aspects of cutaneous inflammation [3,5] (Table 1). This review article aims to give an overview of the most important fatty acids that are found in human skin, discuss their properties and introduce the biochemical pathways leading to the formation of bioactive lipid mediators involved in skin cell biology. A detailed appreciation of the profiles and balance of cutaneous fatty acids and related metabolites is important as this system can be targeted to maintain skin health, regulate inflammation and improve skin pathologies.

Figure 1.

Schematic outline of the main enzymatic reactions involved in the AA cascade, showing the conversion of this PUFA to various classes of bioactive lipid mediators potentially important in cutaneous biology. Although the relevant enzymes are expressed in skin cells, not all mediators have been identified in human skin to date. Abbreviations: AEA, arachidonoyl ethanolamine; COX, cyclooxygenase; CYP450, cytochrome P450; EET, epoxyeicosatrienoic acid; FAAH, fatty acid amide hydrolase; HETE, hydroxyeicosatetraenoic acid; 12-HETE-EA, 12-hydroxyeicosatetraenoic acid ethanolamine; LOX, lipoxygenase; LXA4, lipoxin A4; NAPE-PLD, N-acyl phosphatidylethanolamine phospholipase D; NArPE, N-arachidonoyl phosphatidylethanolamine; PC, phosphatidylcholine; PGE2, prostaglandin E2; PGE2-EA, prostaglandin E2 ethanolamine (prostamide); PLA2, phospholipase A2.

Figure 1.

Schematic outline of the main enzymatic reactions involved in the AA cascade, showing the conversion of this PUFA to various classes of bioactive lipid mediators potentially important in cutaneous biology. Although the relevant enzymes are expressed in skin cells, not all mediators have been identified in human skin to date. Abbreviations: AEA, arachidonoyl ethanolamine; COX, cyclooxygenase; CYP450, cytochrome P450; EET, epoxyeicosatrienoic acid; FAAH, fatty acid amide hydrolase; HETE, hydroxyeicosatetraenoic acid; 12-HETE-EA, 12-hydroxyeicosatetraenoic acid ethanolamine; LOX, lipoxygenase; LXA4, lipoxin A4; NAPE-PLD, N-acyl phosphatidylethanolamine phospholipase D; NArPE, N-arachidonoyl phosphatidylethanolamine; PC, phosphatidylcholine; PGE2, prostaglandin E2; PGE2-EA, prostaglandin E2 ethanolamine (prostamide); PLA2, phospholipase A2.

Cutaneous fatty acids

Sebum fatty acids

Human sebum has a unique fatty acid profile that contains the sebum-characteristic sapienic acid (C16:1n-10), as well as palmitic acid (PA; C16:0), palmitoleic acid (C16:1n-7) and oleic acid (OA; C18:1n-9) [1012]. Importantly, sebum-derived fatty acids have been shown to be effective antimicrobial agents for bacteria, such as Porphyromonas gingivalis, Staphylococcus aureus and Staphylococcus epidermidis, and play an active role in shaping the cutaneous microbiome [1116]. They are also actively involved in epidermal homeostasis and immune cell communications. It has been shown that OA can alter intracellular calcium in normal human keratinocytes and murine skin, leading to hyperproliferation and increased transepidermal water loss, while palmitoleic acid can cause keratinocyte hyperplasia in mouse skin [17,18]. Overall, sebum fatty acids contribute significantly to skin health and epidermal defence functions [16,19], directly affecting epidermal keratinocytes, informing the cutaneous immune barrier and protecting the surface of the skin from pathogenic microorganisms.

Fatty acids in epidermis and dermis

Cutaneous fatty acids found in the epidermis and dermis are key determinants of skin health. The epidermis is the outermost skin layer and comprises a basal layer of proliferating keratinocytes, which switch to differentiate and migrate upwards to form multiple stratified layers of denucleated cells at the surface [19]. The most abundant fatty acids in this layer are saturated fatty acids (SFA), i.e. PA and stearic acid, and monounsaturated fatty acids (MUFA), such as OA (∼23% each) [20]. The dermis contains high levels of unsaturated fatty acids, mostly OA (∼45%), as well as the SFA PA (∼20%) [20]. The ratio between SFA and MUFA represents the activity of Δ9 desaturase, an enzyme important for skin health: inhibition of Δ9 desaturase was shown to reduce proliferation of dermal fibroblasts and disturb the cellular response to growth factors, while deletion of the Δ9 desaturase gene in an animal model resulted in a ulcerative dermatitis, dry, flaky skin and severe alopecia [2123].

PUFA are found at lower levels than SFA or MUFA, e.g. linoleic acid (LA; C18:2n-6) and AA comprise ∼9–10 and 2–3% of the epidermal fatty acids, respectively. However, PUFA are very important for skin health (reviewed in ref. [20]). Linoleic acid is an essential fatty acid, an integral component of acylceramides, and insufficient levels result in impaired formation of the epidermal permeability barrier [24,25]. Indeed, genetic abnormalities in elongase enzymes (for example, ELOV4 deficiency) render the skin unable to produce long-chain fatty acids, and the barrier fails due to an absence of acylceramides [26]. Additionally, the epidermis relies on the dermis and systemic supplementation to provide long-chain PUFA such as AA, eicosapentaenoic acid (EPA; C20:5n-3) and docosahexaenoic acid (DHA; C22:6n-3), as it lacks the necessary Δ5 and Δ6 desaturases to form these long-chain PUFA from C18 fatty acid precursors [27]. Thus, the cutaneous profile of these fatty acids is greatly influenced by diet and responds to nutritional supplementation [4,5,28]. Animal and clinical studies, as well as work with preclinical models, have shown that PUFA supplementation can confer photoprotection, improve wound healing and reduce inflammatory markers [4,29,30]. Although the detailed molecular mechanisms of how fatty acids influence skin health are not always understood, often their effects can be attributed to formation of bioactive metabolites, as discussed below.

Fatty acid-derived lipid mediators

Prostanoids

The family of prostanoids includes various prostaglandins, thromboxanes and prostacyclin (PGI2), all formed from 20-carbon PUFA precursors [i.e. AA, dihomo-gamma linolenic acid (DGLA; C18:3n-6) and EPA], through the activities of constitutive COX-1 and/or inducible COX-2, and terminal prostanoid synthases (Figure 1). The bioactivities of prostanoids are mediated though a series of G-protein-coupled receptors that have been identified in many cell types, including skin cells (reviewed in refs [3,5,7]).

Keratinocytes and fibroblasts, as well as skin-resident immune cells, produce many prostanoids including PGE2, PGE1, PGE3, PGD2, PGF, PGI2 and TXB2 [3133]. One of the best studied species is PGE2, which regulates keratinocyte and fibroblast growth and proliferation through production of growth factors and cytokines, including fibroblast growth factor, epidermal growth factor (EGF), tumour necrosis factor-α, interleukin (IL)-1, IL-6 and IL-8 [3439]. PGE2 also acts as a potent immunomodulatory stimulus, triggering recruitment of T lymphocytes and maturation of dendritic cells, both important for skin immunity [4042]. These changes are associated with vasodilation and further recruitment of immune cells, as demonstrated by the increased accumulation of neutrophils and oedema in rodent skin following a local injection of PGE1 and PGE2 [43,44]. Conversely, PGE3 was not mitogenic in murine epidermal cultures or a dermal fibroblast cell line, and it has been suggested to play an anti-inflammatory role [4547].

PGD2 can also stimulate T-cell and eosinophil migration [48]. In skin, it is produced mainly by Langerhans cells and dermal mast cells, and high levels of PGD2 have been linked to hair loss and androgenetic alopecia [49]. The inhibition of hair growth involves a potent apoptotic action of PGD2 on follicular keratinocytes, although it has also been shown that PGD2 may also act as an anti-inflammatory mediator, depending on the cell type and time of its production [50].

Multiple studies have shown increased production of cutaneous prostanoids following the up-regulation of COX-2 in response to inflammatory stimuli, as observed in the sunburn reaction and wound healing [33,51,52]. Interestingly, COX-2 inhibitors were found to cause a significant delay to wound healing, with wounds showing significant reduction in PGE2 levels, epidermal proliferation, angiogenesis and extracellular matrix [53,54]. However, mice showed accelerated wound healing when catabolism of PGE2 was inhibited [55,56]. This finding highlights the role of skin prostaglandins in regulating the early phases of inflammation, which are crucial for efficient resolution and tissue remodelling. Non-steroidal anti-inflammatory drugs inhibit COX-1 and -2 activity, and therefore prostanoid production, which may reduce skin inflammation. However, free fatty acids are then metabolised through other enzyme pathways. Indeed, when cutaneous COX-derived prostaglandin production was blocked by indomethacin, LOX metabolism dominated and an increase in 12-hydroxyeicosatetraenoic acid (HETE) was observed, so although erythema was reduced, there was a greater inflammatory infiltrate in the skin [57]. Interestingly, PGE2 has recently been shown to mediate a phase of post-inflammatory immune suppression, believed to be important for prevention of an autoimmune response, highlighting its importance past the initial inflammatory phase [58].

Hydroxy fatty acids

LOXs produce a series of hydroxy fatty acids and leukotrienes (LTs) [59,60]. Human and animal skin express many LOX isoforms, e.g. 5-, 8-, 12- and 15-LOX, that can utilise a range of fatty acid substrates, including AA, LA, EPA, DGLA and DHA (reviewed in refs [3,5,7]) (Figure 1). The 12R-LOX is unique to mammalian skin cells and has been purported to be involved in cutaneous inflammation, given observations of 12R-HETE in psoriasis skin. Its main role, however, is believed to be linked to the formation of the epidermal lipid barrier, in conjunction with the epidermis-type eLOX-3. These two enzymes perform consecutive oxidisations of the linoleic acid in acylceramides, enabling its linkage to cornified envelope proteins, which are crucial for an effective epidermal barrier [6063]. Indeed, congenital ichthyosis has been linked to mutations in 12R-LOX and eLOX-3 [64,65]. LOX reactions are also involved in the transcellular metabolism of PUFA to generate lipoxins from AA, resolvins and protectins from EPA and DHA, and maresins from DHA, collectively known as specialised pro-resolving mediators (SPMs) for their anti-inflammatory functions [66]. Although many their hydroxy fatty acid precursors have been found in skin, before and after PUFA supplementation, the SPMs themselves have not been identified in skin to date, and their importance in cutaneous health and disease remains unclear [29,67,68].

Linoleic acid-derived hydroxyoctadecadienoic acids (HODEs) are the most abundant hydroxy fatty acids found in human skin [20]. Both 9- and 13-HODE are potent chemotactic agents and cause increased infiltration and migration of neutrophils and macrophages, as well as regulating the proliferation and differentiation of epidermal keratinocytes [6972]. Recently, HODEs have been considered as important mediators in inflammatory pain, although evidence for their role in cutaneous pain is limited [73,74].

LTs are 5-LOX derivatives of AA with potent chemotactic properties and induce neutrophil infiltration in inflamed skin. However, the cutaneous activity of 5-LOX is relatively low, and increased formation of LT has been attributed to infiltrating immune cells and not resident skin cells [75,76]. 12-HETE and 15-HETE are the main LOX-derived products of AA in skin [20]. 12-HETE is considered pro-inflammatory and has been associated with increased infiltration of leukocytes [57,77,78]. 15-HETE has been shown to decrease levels of LTB4 and 12-HETE, and stimulate the remodelling of injury sites and production of EGF in endothelial cells, a property important in the later stages of inflammation [7982]. Both 12-LOX and 15-LOX protein expression has been found up-regulated in human skin following exposure to UVR (ultraviolet radiation), with concomitant increases in 12- and 15-HETE [33], while increased 15-LOX gene expression in the human skin has been associated with a reduction in pro-inflammatory IL-6 and TNF-α, epidermal thickness and epidermal cell migration [83]. Interestingly, a study on mice lacking the 12/15LOX gene showed a reduced number of mesenchymal stem cells with disturbed kinetics in the wounded dermis, which has implications for tissue remodelling [84]. Additionally, the 12-LOX DHA product, 14-HDHA (hydroxydocosahexaenoic acid), improved all stages of the wound healing process in mice, via enhanced re-epithelisation, granulation and angiogenesis [85]. Hence, these findings confirm a strong involvement of LOX-derived PUFA mediators in sustaining the later stages of inflammation, when COX-mediated production of prostaglandins has decreased [33].

Epoxy fatty acids

The CYP isozymes CYP2C and CYP2J are epoxygenases that mediate the production of epoxyeicosatrienoic acids (EETs) from AA (Figure 1). These epoxides are rapidly transformed by the soluble epoxide hydrolase (sEH) to dihydroeicosatetraenoic acids (DHETs) that exhibit much reduced bioactivities. Furthermore, CYP-mediated oxidations can produce a range of HETE similar to the ones formed by LOX. Other PUFA substrates for CYP reactions include LA, EPA and DHA [8688].

While the role of DHET in skin inflammation is unclear, cutaneous functions of EET are emerging. Increasing endogenous levels of EET via inhibition of sEH improved vascularisation in an engineered skin substitute [89]. Additionally, topical application of EET accelerated epithelialisation in the hairless mouse, while CYP inhibitors significantly delayed wound closure [90,91]. Analysis of individual EET has revealed that 11,12 EET increases angiogenesis and improves wound healing in diabetic mice, while 14,15-EET is directly involved in epidermal barrier function through regulation of involucrin and promotion of the cornification of human and murine keratinocytes [92,93]. The non-epoxy CYP product 20-HETE appears to have a role in angiogenesis, as it leads to increased proliferation and migration of endothelial cells [94,95]. Despite a limited understanding of the role of CYP reactions and resulting epoxy fatty acids in skin health, these compounds appear to be important during later stages of inflammation and wound healing, and further research to elucidate EET and DHET function in skin is required [9698].

Endocannabinoids and NAE

Human skin produces the classic endocannabinoids arachidonoyl ethanolamine (anandamide; AEA) and 2-arachidonoyl glycerol (2-AG), as well as a range of NAE [20] (Figure 1). AEA and 2-AG are known ligands for the cannabinoid receptors CB1 and CB2, the expression of which has been reported in the epidermis, dermo-epidermal junction and dermis [20,99]. AEA and 2-AG derive from phospholipid-esterified AA and can be further metabolised by COX, LOX and CYP enzymes; however, the prevalence of these species in human skin has not been confirmed [9]. Many of the fatty acid-derived NAE present very low or no affinity to CB1 or CB2 and are believed to act through other receptors such as vanilloid receptor 1 (TRPV1) and PPARα [100,101].

Endocannabinoids and NAE are involved in various cutaneous functions, including keratinocyte differentiation [102,103]. AEA inhibits the proliferation of human epidermal keratinocytes and dermal fibroblasts via induction of apoptosis [103,104]. This apoptotic function of AEA was also observed in human sebocytes, where both AEA and 2-AG stimulated differentiation, maturation and lipogenesis via CB2-mediated signalling [105,106]. Furthermore, AEA limits excessive mast cell activation in hair follicles, highlighting its function in the regulation of dermal inflammation [107]. Palmitoyl ethanolamine (PEA) and oleoyl ethanolamine (OEA) have anti-inflammatory and analgesic effects, and PEA has been shown to reduce itching in a murine allergic dermatitis model, while linoleoyl ethanolamine (LEA) reduced lipopolysaccharide-induced inflammation in macrophages, thereby improving contact dermatitis [108111]. The n-3 PUFA-derived eicosapentaenoyl ethanolamine (EPEA) and docosahexaenoyl ethanolamine (DHEA) have been shown to mediate anti-inflammatory protective mechanisms and reduction in itching and pain, suggesting a potentially important role in skin [112114].

Endocannabinoids and NAE may also serve as immunomodulatory mediators in the skin and have been found to be up-regulated during various types of skin inflammation [99,115]. AEA and 2-AG levels were increased after UVR treatment of HaCaT keratinocytes [116], while in study involving different keratinocyte and fibroblast cell lines, AEA, 2-AG and CB1 and CB2 expression were found to decrease following UVR irradiation [117,118]. A clinical study [119] reported increased 2-AG, but stable levels of AEA, OEA and PEA in the serum of human volunteers subjected to a repetitive cutaneous exposure to simulated solar UVR [119]. Similarly, the skin of human volunteers irradiated with low-dose UVR did not show any changes in levels of endocannabinoids and NAE species, although there was an increase in stearoyl ethanolamine, LEA, OEA and PEA following sodium lauryl sulfate application [120]. Mustard vesicants also increased levels of AEA and 2-AG, and increased expression of CB receptors, in murine skin in vivo, although only several days after stimulation [121].

Overall, it is believed that endocannabinoids and NAE may act to quench inflammation, and their production may prevent an excessive inflammatory response in the skin. Up-regulation of CB1/CB2 receptor expression was observed in fibroblasts and macrophage-like cells during wound healing in rats [104], while 2-AG and CB1 activation are associated with reduced immune infiltration, scarring and accelerated wound closure in epithelial cells. However, CB1 activation in the dermis slowed wound healing, suggesting different roles for endocannabinoids in the different skin compartments [104,122].

Conclusion

Fatty acids are crucial for skin health, as they contribute to the structural and functional integrity of the epidermis. Additionally, their metabolism into a range of bioactive mediators that regulate various aspects of epidermal and dermal homeostasis, including immune and inflammatory reactions, shows their importance for cutaneous health and disease. The availability of precursor fatty acids, coupled to the expression and activity of lipid metabolising enzymes, determines the profile of cutaneous lipid mediators. COX-derived prostaglandins and LOX-derived hydroxy fatty acids respond to most inflammatory stimuli; the properties of these mediators are continually being elucidated. CYP-derived lipid mediators have not been extensively studied in the skin, but there is evidence supporting their involvement in tissue remodelling. Finally, endocannabinoids and NAE appear to support homeostasis and transcellular signalling during cutaneous inflammation, and may prevent excessive immune responses. The cross-communication between these families of fatty acid-derived lipids suggests that their properties should not be studied in isolation, and their prevalence should be considered as part of a wider metabolic network that regulates cutaneous reactions.

Table 1
Examples of lipids and some of their roles in skin
Lipid Biological role 
Sapienic acid Antimicrobial [13,14
Oleic acid Promotes keratinocyte proliferation [17
Palmitoleic acid Promotes keratinocyte proliferation [18
Linoleic acid Essential component of epidermal acylceramides [24
PGE2 Regulates fibroblast and keratinocyte growth [34,36,37]; recruitment of immune cells [40,41]; vasodilation [43]; wound healing [5456]; post-inflammatory immune suppression [58
PGE1 Recruitment of immune cells [43
PGD2 Stimulates immune cell migration [48]; hair loss [49
9-HODE Immune cell recruitment; pain [74
13-HODE Immune cell recruitment; pain [74
LTB4 Immune cell recruitment [76
12-HETE Immune cell recruitment [57
15-HETE Suppresses inflammatory cytokine and lipid mediator production [79,81,83]; vascular remodelling [82
14-HDHA Reepithelialisation [85]; granulation [85]; angiogenesis [85
EETs Vascularisation [89]; epithelialisation [90,91]; angiogenesis [92]; keratinocyte cornification [93
AEA Inhibits fibroblast and keratinocyte proliferation [103,104]; suppresses mast cell activation [107
PEA Reduces itch [108]; analgesic [108
OEA Analgesic [109
LEA Suppresses macrophage activation [111
EPEA Reduces itch [112]; analgesic [113
DHEA Reduces itch [112]; analgesic [113
Lipid Biological role 
Sapienic acid Antimicrobial [13,14
Oleic acid Promotes keratinocyte proliferation [17
Palmitoleic acid Promotes keratinocyte proliferation [18
Linoleic acid Essential component of epidermal acylceramides [24
PGE2 Regulates fibroblast and keratinocyte growth [34,36,37]; recruitment of immune cells [40,41]; vasodilation [43]; wound healing [5456]; post-inflammatory immune suppression [58
PGE1 Recruitment of immune cells [43
PGD2 Stimulates immune cell migration [48]; hair loss [49
9-HODE Immune cell recruitment; pain [74
13-HODE Immune cell recruitment; pain [74
LTB4 Immune cell recruitment [76
12-HETE Immune cell recruitment [57
15-HETE Suppresses inflammatory cytokine and lipid mediator production [79,81,83]; vascular remodelling [82
14-HDHA Reepithelialisation [85]; granulation [85]; angiogenesis [85
EETs Vascularisation [89]; epithelialisation [90,91]; angiogenesis [92]; keratinocyte cornification [93
AEA Inhibits fibroblast and keratinocyte proliferation [103,104]; suppresses mast cell activation [107
PEA Reduces itch [108]; analgesic [108
OEA Analgesic [109
LEA Suppresses macrophage activation [111
EPEA Reduces itch [112]; analgesic [113
DHEA Reduces itch [112]; analgesic [113

Abbreviations

     
  • 2-AG

    2-arachidonoyl glycerol

  •  
  • AA

    arachidonic acid

  •  
  • AEA

    arachidonoyl ethanolamine

  •  
  • CB

    cannabinoid receptor

  •  
  • COX

    cyclooxygenase

  •  
  • CYP

    cytochrome P450

  •  
  • DGLA

    dihomo-gamma linolenic acid

  •  
  • DHA

    docosahexaenoic acid

  •  
  • DHEA

    docosahexaenoyl ethanolamine

  •  
  • DHET

    dihydroxyeicosatrienoic acid

  •  
  • EET

    epoxyeicosatetrienoic acid

  •  
  • EGF

    epidermal growth factor

  •  
  • EPA

    eicosapentaenoic acid

  •  
  • EPEA

    eicosapentaenoyl ethanolamine

  •  
  • HDHA

    hydroxydocosahexaenoic acid

  •  
  • HETE

    hydroxyeicosatetraenoic acid

  •  
  • HODE

    hydroxyoctadecadienoic acid

  •  
  • IL

    interleukin

  •  
  • LA

    linoleic acid

  •  
  • LEA

    linoleoyl ethanolamine

  •  
  • LOX

    lipoxygenase

  •  
  • LT

    leukotriene

  •  
  • MUFA

    monounsaturated fatty acid(s)

  •  
  • NAE

    N-acyl ethanolamine(s)

  •  
  • OA

    oleic acid

  •  
  • OEA

    oleoyl ethanolamine

  •  
  • PA

    palmitic acid

  •  
  • PEA

    palmitoyl ethanolamine

  •  
  • PGI2

    prostacyclin

  •  
  • PUFA

    polyunsaturated fatty acid(s)

  •  
  • sEH

    soluble epoxide hydrolase

  •  
  • SFA

    saturated fatty acid(s)

  •  
  • SPM

    specialised pro-resolving mediator

  •  
  • UVR

    ultraviolet radiation

Author Contribution

All authors contributed equally to the work.

Funding

A.N. is supported by the NIHR Manchester Biomedical Research Centre as a Dermatology Theme Key Researcher. A.C.K. was supported by the Medical Research Council [grant no. MC_PC_15058].

Acknowledgments

The support of NIHR Manchester Biomedical Research Centre and MRC (MC_PC_15058) is gratefully acknowledged.

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

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