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REVIEW

The Role of Cosmetology in an Effective Treatment of Rosacea: A Narrative Review

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Pages 1419-1430 | Received 16 Mar 2023, Accepted 17 May 2023, Published online: 05 Jun 2023

Abstract

Rosacea is a chronic inflammatory facial skin disease usually occurring in middle-aged patients. It manifests itself as an inflammatory condition with perivascular infiltrate, dilated blood vessels, lymphoedema, hyperplasia of sebaceous glands, and disorders of connective tissue structures brought on by fibrosis. Rosacea is characterized by multifactorial inflammatory mechanisms, and therefore it requires an interdisciplinary approach including adequate skin care, topical and/or systemic therapy, and physical modalities to successfully treat the various symptoms and disease subtypes. However, data regarding the possible role of cosmetologists in rosacea remains scanty and equivocal. The objectives of cosmetology therapy include restoration and regeneration, anti-inflammatory effects, the strengthening of blood vessels and regulation of their permeability, and the regulation of keratinization. Vascular abnormalities can be targeted with specific light and laser devices. Therefore, the present paper aims to review the latest advances and summarize different aspects concerning skin care in rosacea. Particular attention has been paid to the co-operation of cosmetologists with other specialists in order to bring about the interdisciplinary management of rosacea. It is also important to keep in mind that it is usually necessary to combine various methods of treatment, as this approach is more effective than monotherapy for attaining satisfactory cosmetic results in rosacea patients.

Introduction

Rosacea is a chronic skin disease usually occurring only in the facial area. Clinically, it manifests itself with an erythema, telangiectasias, and papules and pustules, while histopathologically – it is an inflammatory condition with a perivascular infiltrate, dilated blood vessels, lymphoedema, hyperplasia of sebaceous glands, and disorders of connective tissue structures brought on by fibrosis.Citation1 Vascular lesions appear in the central part of the face and gradually spread circumferentially, occasionally spreading to the skin of the neck and decolletage.Citation2 The typical location of the lesions, the accompanying inflammatory condition of the skin and the sensation of warmth and burning cause not only physical, but also mental discomfort to the patients, resulting in the lowering of their self-esteem.Citation3 Rosacea is usually diagnosed in adults aged 45–60.Citation2 It develops on the vascular skin, and the stage of prerosacea, which occurs in teenagers and young adults, precedes the appearance of the typical symptoms of the disease at the later stage of life.Citation4 Vascular skin may affect both women and men, and according to the Fitzpatrick scale, usually with skin phototypes I and II.Citation2

Pathological changes of rosacea occurring predominantly in the facial region are particularly exposed, often considered unesthetic not only by the patients themselves but also by others in their environment. It should be emphasized that the main reason for cosmetologic consultations in the event of rosacea is the aesthetic defect that causes stigmatization of patients followed by not so infrequent their social rejection. The facial and other changes that appear because of the disease may significantly affect the patients’ quality of life, self-esteem, and their mental health.Citation5,Citation6

Cosmetology has come to function as an essential complementary element of the treatment of diagnosed rosacea. Therefore, the cosmetic aspect of the therapy, based on the restoration of social confidence and self-esteem, may seem to function as a link between the physical beauty and the mental health of rosacea patients. Through this impact, cosmetology becomes an essential factor in the overall therapeutic process.

Methods

We conducted a review of the literature to provide an overview of the recent data concerning the role of cosmetology in rosacea treatment. The results are presented in the form of a topical review. Searches were conducted of the following databases: PubMed and the Google Scholar. Multiple search terms were used, including “skincare”, “cosmetics”, “rosacea” and “cosmetology”. Only English language papers published in peer-reviewed journals and book chapters have been included. Previously abstracts were read to assess their relevance. Then this method was used, 95 papers were identified and duly accessed. Each was subsequently read and analysed. This led to the identification of further relevant references, and further 68 relevant papers had been included in this paper.

Characteristics of Rosacea

Rosacea – Aetiopathogenesis and Epidemiology

The cause of the disease is not completely understood. What is known though is that occurrence is influenced by both the endogenous and exogenous factors, while polymorphic skin lesions reflect the multifactorial background of rosacea.Citation1

A positive family history points to genetic predispositions. The study by Lynn et alCitation7 demonstrated a single nucleotide polymorphism (SNP) in the genes encoding butyrophilin-like protein 2 (BTNL 2) and in the human leucocyte antigen (HLA-DRA) gene. It is probable that three specific HLA alleles, proteins of the major histocompatibility complex (MHC) class II, ie, HLA-DRB1*03:01, HLA-DQB1*02:01 and HLA-DQA1*05:01, are significantly associated with rosacea,Citation7 which points to the role of the dysregulation of the immunological system in the pathogenesis of the disease.Citation1

The imbalances of the cutaneous microbiome are implicated in the pathogenesis of rosacea,Citation8,Citation9 whereby several microorganisms (Demodex folliculorum, Bacillus oleronius, Staphylococcus epidermidis, and Cutibacterium acnes) were postulated to have been used to as a key players.

Demodex folliculorum (D. folliculorum) mites are widespread on the skin of healthy people, however an excessive colonization of this microorganism plays a role in the pathogenesis of rosacea. A diagnosis of demodicosis in the presence of clinical symptoms, such as flushing, pruritus and a burning sensation of the skin, and also lacrimation and dryness of the conjunctiva accompanied by eyelid desquamation, is confirmed by microscopic examinations and the observation of more than 5 specimens/cm2.Citation10 Long-term enzymatic processes and burrowing into the skin by Demodex mites may lead to perifollicular inflammation. By releasing the products of their decomposition and leaving chitinous exoskeletons on the surface of human skin, dying mites trigger an immune response by influencing the secretion of inflammatory cytokines, such as interleukin (IL) 8, and tumour necrosis factor-alpha (TNF-alpha), and the expression of the Toll-like receptor (TLR) by interacting with cells from the pilosebaceous unit.Citation11 Clinical examinations have demonstrated an increased number of D. folliculorum on the skin of patients with rosacea in comparison with healthy individuals, and those with acne and seborrhoeic dermatitis.Citation11

Once Demodex die, internal microbes including Bacillus oleronius (B. oleronius), and toxins are released within the sebaceous glands of the face and eyelashes.Citation12,Citation13 B. oleronius triggers inflammatory pathways by producing antigenic proteins that potentially play a role in rosacea.Citation8 The two antigenic proteins from B. oleronius, sized 62kDa and 83kDa, have been found to react with the sera of rosacea patients.

It should be noted that microbiological changes do not occur on the skin only. Potential cutaneous effects of alterations have also been found in the gastrointestinal microbiome. It is therefore suggested that Helicobacter pylori (HP) infection may significantly influence the condition of rosacea skin. The data collected so far, however, are not homogenous, and sometimes even contradictory,Citation14–16 which renders their interpretation difficult. HP infection may cause inflammation and redness of the skin by releasing angiogenic and vasomotor agents, and there are studies with evidence that these bacteria increase concentrations of nitrous oxide, thereby leading to the dilation of blood vessels.Citation17,Citation18

Classification of Rosacea

Four clinical subtypes of the disease have been distinguished: erythematotelangiectatic rosacea (ETR), papulopustular rosacea (PPR), phymatous rosacea (PhR), and ocular rosacea.Citation19,Citation20 ETR is characterized by an erythema that covers the central part of the face, and by the evolution of lesions from a transient redness of the skin and single telangiectasias (prerosacea) to the full-blown form. Patients often complain of symptoms of skin hypersensitivity and intolerance to cosmetics. PPR is also referred to as “classic rosacea”, with papules and pustules dominant in its course, and sometimes accompanied by a delicate desquamation of the epidermis and thickening of the skin due to swelling. Inflammatory lesions are usually accompanied by dryness and a burning sensation of the skin. Chronic inflammatory lesions may lead to the development of solid facial oedema and hypertrophic lesions, referred to as phymatous rosacea. This rare manifestation of the disease can affect various parts of the face, and thus, depending on the location, we distinguish skin lesions of the nose (rhinophyma), chin (gnatophyma) and eyelids (blepharophyma). In the main, it affects Caucasian males aged over 40. It is characterized by hyperplasia and thickening of the skin, which becomes livid red in colour, with clearly marked, dilated sebaceous glands, increased fibrosis and the presence of nodular lesions. Ocular rosacea affects the eyes and eyelids.Citation20 The symptoms are not very specific, including photophobia, blurred vision, pain, swelling, fatigability of the eyelids, dryness of the eyes, foreign body sensation, burning and pruritus.Citation20,Citation21

The classification of rosacea had been updated based on new insight into the pathophysiology of the disease.Citation20,Citation21 Persistent centrofacial erythema and phymatous changes have been recognised as the diagnostic phenotype of rosacea. Major phenotypes include: flushing, papules and pustules, telangiectasia, ocular manifestations such as lid margin telangiectasia, interpalpebral conjunctival injection, spade-shaped infiltrates in the cornea, scleritis, and sclerokeratitis. Meeting two or more of these criteria may be considered diagnostic. Secondary signs and symptoms, such as a burning and/or stinging sensation of the skin, skin dryness, oedema and ocular manifestations (“honey crust” and collarette accumulation at the base of the lashes, irregularity of the lid margin, evaporative tear dysfunction), may appear with one or more diagnostic or major phenotypes.Citation21

Various clinical types of rosacea are presented in .

Figure 1 Clinical presentation of various clinical type of rosacea: (A) papules, (B) papules and telangiectases, (C) erythema and telangiectases, (D) erythema, telangiectases, and papules. Property of the author.

Figure 1 Clinical presentation of various clinical type of rosacea: (A) papules, (B) papules and telangiectases, (C) erythema and telangiectases, (D) erythema, telangiectases, and papules. Property of the author.

Rosacea as an Interdisciplinary Problem

Rosacea is characterized by multifactorial, inflammatory mechanisms, therefore it requires an interdisciplinary approach including adequate skin care, topical and systemic pharmacotherapy, and physical modalities to successfully treat the various symptoms and disease subtypes.Citation19–21

The association of gastrointestinal and neuropsychiatric disorders supports the concept of a gut-brain-skin interaction in rosacea.

The association with the gut-brain axis has also been established via multiple parallel pathways between them, including the autonomic nervous system and the pituitary-hypothalamus-adrenal axis.Citation22,Citation23 A schematic view of possible factors belonging to this axis and contributing to the molecular mechanisms of rosacea is presented in .

Figure 2 Schematic view of possible factors belonging to the gut-brain-skin axis and contributing to the molecular mechanisms of rosacea. Property of the author.

Figure 2 Schematic view of possible factors belonging to the gut-brain-skin axis and contributing to the molecular mechanisms of rosacea. Property of the author.

The Role of the Gut-Skin Axis

The gut-skin axis plays an important role in the pathophysiology of rosacea, with diseases from the inflammatory bowel diseases (IBD) group having been identified as the most significant. The high risk of occurrence of IBD disorders and rosacea is most probably due to the genetic factors.Citation14,Citation24 Numerous studies have revealed the relationship between rosacea and SIBO (small intestinal bacterial overgrowth),Citation25–28 and it has been postulated that SIBO-positive patients are more often representative of the papulopustular type of rosacea.Citation25 It has been demonstrated that diarrhoea chylosa, too, causes a disturbance of the gut-skin axis and impacts the course of the disease.Citation14,Citation29 Altered gastrointestinal and skin microbiome of patients with rosacea may also play a role in the etiopathogenesis.Citation1

Neurogenic Inflammatory Factors

Sunlight, changes in temperature, spicy food, alcohol and physical activity are all triggers for erythema, for these stimuli can activate sensory nerve endings in the skin, resulting in the emergence of inflammation. Keratinocytes stimulated by neuropeptides release pro-inflammatory cytokines, ie, IL-1α, IL-6 and IL-8.Citation30 Another neuropeptide, substance P (SP), affects the Langerhans cells, intensifying their migration and bringing about the mast cell degranulation and increased histamine activity, which has a vasodilating effect. SP also induces the release of the vascular endothelial growth factor (VEGF) from mast cells, which, by increasing the vascularization and proliferation of endothelial cells, contributes to the worsening of the inflammatory condition and erythema.Citation30 The skin of patients with rosacea shows a greater density of sensory neurons involved in the release of neuropeptides. An important role (the sensation of heat, nociception, activation by capsaicin) is also played by transient receptor potential (TRP) cation channels, which are present, among others, at sensory nerve endings.Citation30 Stimulated TRP channels release SP and the calcitonin gene-related peptide (CGRP), which has a strong vasodilating effect, affecting the smooth muscle cells of arterioles.Citation31 Rosacea is also characterized by an increased secretion of vasoactive intestinal peptide (VIP), which is able to stimulate the degranulation of mast cells, leading to the increased secretion of histamine and the dilation of blood vessels.Citation31 The mechanism of neurogenic inflammation explains the impact of triggers on the skin, primarily due to its ultimate vasodilating and pro-inflammatory action through neuropeptides.

Disorders of the Connective Tissue Structure and the Process of Fibrosis

Studies have shown a significantly increased expression of extracellular matrix metalloproteinase (MMP), mainly MMP-9, in skin with rosacea (granulomatous subtype),Citation32 which leads to the damage of the collagen and elastin fibres within the extracellular matrix and to fibrosis.Citation33 It has also been documented that elastin fibres are thicker and more amorphous than tissue samples from the control group.Citation32 This leads to skin remodelling and an increased influx of inflammatory cells.Citation32,Citation33

The Impact of Hormones on Vascular Endothelium

Oestrogens intensify the release of nitric oxide, which is responsible for the dilation of blood vessels that negatively affects the condition of vascular skin. Vasodilation is a feature of the skin ageing process, observed in particular in post-menopausal women.Citation34 The risk of rosacea increases for women taking menopausal hormone therapy and hormonal contraception.Citation35

Opportunities for Co-Operation Between Cosmetologists and Other Specialists

Rosacea is a dermatosis that is difficult to treat and frequently originates from systemic disorders. Therefore it requires close co-operation between dermatologists, cosmetologists, other physicians of different specialties, and dieticians. There are also specific products that will negatively affect the condition of the skin by causing paroxysmal flushing, namely, alcohol, hot foods and beverages, spicy dishes (especially those rich in capsaicin), and cinnamon.Citation36

The selection of pharmacological and instrumental treatment depends on the phenotype of the disease.Citation37 To date, it has been impossible to cure the disease completely, however properly selected topical and systemic pharmacotherapy, the use of instrumental methods, appropriate skin care and a change of lifestyle may all help to control it.

Therapy for Rosacea

The therapy depends on the phenotype of the disease and the topical as well as systemic medications are used. The most common topical medications include: alpha-adrenergic brimonidine gel, 0.33%, oxymetazoline hydrochloride cream, 1%, an alpha1A-adrenoceptor agonist, Ivermectin, azelaic acid, metronidazole, and retinoids.Citation37,Citation38 The beneficial impact of dermal injections of botulinum toxin has also been described.Citation39

Doxycycline (subantimicrobial), Doxycycline, Minocycline, Tetracycline, Azithromycin, Trimethoprim/Sulfamethoxazole, Clindamycin and Isotretinoin – as well as Carvedilol, Clonidine and Propranolol – are applied orally.Citation37

The action of individual light devices is presented in .

Table 1 Indications and Safety of Light Devices Used for the Treatment of Rosacea

Rosacea therapy uses lasers for which haemoglobin and oxyhaemoglobin are the target chromophore. The energy absorbed by the target chromophore is converted into heat, which brings about the coagulation of blood vessels walls and their closure. PDL with a wavelength of 585/595 nm is considered as the “gold standard” in rosacea therapy due to its high efficacy and long-lasting effects, coupled with a good safety profile.Citation41,Citation42 The PTP laser with a wavelength of 532 nm is used less frequently due to shallow beam penetration. Neodymium-Doped Yttrium Aluminium Garnet (Nd:YAG) is used in the treatment of purple and blue vascular lesions. A Q-switched 595-nm Nd:YAG laser with low non-purpuragenic fluence proved to be safe and effective in treating early-stage erythematotelangiectatic lesions.Citation45 It is less effective, however, in treating diffuse erythema.Citation41–45 Carbon dioxide and erbium are used to remove phymas.Citation40,Citation45

Skin Care and Cosmetological Procedures in Rosacea

When deciding upon a most relevant cosmetological support for the treatment of rosacea, it is vital to take into account the clinical stage of the disease and a given patient’s expectations. A holistic therapeutic approach should always be determined on a case-by-case basis.

The objectives of cosmetology therapy are presented diagrammatically in .

Figure 3 Pyramid of cosmetological effects on rosacea skin. Property of the author.

Figure 3 Pyramid of cosmetological effects on rosacea skin. Property of the author.

Because of the damaged hydrolipid barrier, rosacea skin is usually dry, rarely seborrhoeic, and the epidermal hydration levels are uniformly low.Citation46

Due to the strong reactivity of the skin to temperature changes, it is advisable to avoid warming products, lipid winter creams and algae masks that strengthen the skin barrier. Thus, hydrophilic formulations such as hydrogels, O/W creams with a low lipid content and lamellar products are preferred. Waterproof make-up cosmetics, the removal of which entails more intensive rubbing, should be avoided.Citation47

Basic Principles for Rosacea Skin Care and Hygiene

Proper skin care can significantly improve the effects of pharmacotherapy and reduce subjective symptoms, such as pruritus, burning, and tightening of the skin.

The skin of persons suffering from rosacea is highly reactive and easily irritated, which forces the use of mild washing emulsions with a slightly acidic pH. Water temperature is also important – it should be lukewarm, so as not to additionally irritate the skin with another physical factor and not to cause vascular reactions.Citation47 Mechanical peeling agents should be abandoned in favour of enzymatic peelings or delicate peelings based on polyhydroxy acids.Citation48 It is advisable to use care products which are free from alcohol, essential oils, waxes and mineral oils. Men should also give up alcohol-based after-shaves due to the irritating effect of menthol.Citation47 The impact of temperature changes on the condition of rosacea skin in winter may be to a certain extent mitigated by the use of cold creams.

It is recommended to gently remove make-up with the hands, using oil products containing emulsifiersCitation49 so as not to remove lipids from the corneal layer of the epidermis and reduce the sensation of “skin tightening”.Citation49,Citation50

The composition and properties of skin care products applied in the treatment of rosacea must be properly adapted to the needs of the affected skin. The use in cosmetics of active substances – which have primarily a skin-calming, anti-inflammatory, or vessel-stabilizing effect – is of limited importance in rosacea. Moisturizing and regenerating cosmetics should be light preparations and rich in anti-inflammatory substances, for example, Centella asiatica extract. It is important that they additionally contain compounds which help restore the skin’s lipid barrier. Ingredients occurring naturally in the intercellular cement and their derivatives – ceramides, fatty acids and sterols – will work well.Citation51 If the skin is irritated and strongly reactive, active ingredients should not be used specifically for vascular lesions. First of all, it will be necessary to strengthen the hydrolipid barrier. It is not recommended to apply cosmetic preparations that increase flow through skin blood vessels or those with an anti-ageing effect.Citation47

Despite the presence of papules and pustules, active products should not contain ingredients typically used in acne skin therapy or stem cells. The desired ingredients include kinetin, retinaldehyde, Licochalcon A, tranexamic acid, azelaic acid and extracts from plants rich in polyphenols, eg red clover herb extract or Chinese tea leaf extract.Citation47,Citation52–58 Cosmetics should utilise natural raw materials with anti-inflammatory, soothing, moisturizing, antioxidant, radiation protective and blood vessel sealing properties. These make it possible to enhance therapeutic effects or prevent undesirable effects.

The topical use of vitamins and antioxidants in cosmetics can protect and correct skin damage in rosacea. It has been documented,Citation59 that topical vitamin K provides rapid improvement in the flushing, non-transient erythema, telangiectasia, burning and dryness with mild and tolerable side effects. Vitamin PP presents a multidirectional action on cosmetics: (i) inhibition of histamine secretion associated with the intensification of erythema, (ii) reduction of inflammatory processes, (iii) an anti-swelling effect.Citation6 Moreover, some antioxidant agents, such as topical vitamin C or vitamin E, are already used in skin care products. Vitamin C has been shown to repair and replenish barrier function in rosacea-prone skin.Citation1

Raw materials proven to locally alleviate the symptoms of rosacea have been presented in .

Table 2 Effects of Selected Natural Raw Materials Used in the Treatment of RosaceaCitation56–58,Citation60–62

The skin of patients with rosacea is very sensitive to solar radiation, which is one of the environmental factors inducing and exacerbating skin lesions.Citation47 Protection against the sun should be based primarily on the avoidance of exposure. The daily use of photoprotective products with an SPF≥30 and their reapplication every two hours is a fundamental element of care. Reinholz et alCitation62 recommend that these should be formulations containing physical filters, that is, zinc oxide or titanium dioxide, however there are no studies comparing the tolerance of different filters in individuals affected with rosacea.Citation47 A study by Cole et alCitation63 invalidated the established belief that a majority of physical filters reflect light, and thereby allegedly do not cause the skin to warm up. Zinc oxide and titanium oxide act primarily as ultraviolet (UV) absorbers. Achieving adequate protection against UVA and UVB rays by using physical filters alone carries with it the risk of skin whitening. Thus, it is the skin’s reaction to specific filters that should be the decisive indicator of whether or not a product is suitable.

Masks, which soothe and calm skin redness, are an excellent ad hoc alleviating solution. Anti-redness masks usually have the form of gels and contain ingredients which reduce skin reactivity, and have a moisturizing and refreshing effect. It is recommended to select dermocosmetics that are intended for rosacea and therefore have a lower allergenic potential.Citation62,Citation63

Make-Up

For most patients, and especially those with self-perceived severe erythema and no inflammatory lesions, the erythema associated with rosacea brings with it a significant decrease in the health-related quality of life, and should therefore be treated as an important medical problem requiring medical intervention.Citation64 Make-up can help immediately cover skin imperfections and improve one’s self-evaluation, however it should not aggravate the underlying dermatosis. It should therefore be considered as a useful adjuvant, the advantage of which is its immediate effectiveness in the absence of significant adverse effects.Citation65–67 Skin redness can be camouflaged with care creams or light green or yellow coloured make-up. The base of these products should be adapted to the condition of the skin and must be free of mineral oils, fragrances and preservatives. Coloured skin care products or make-up should be applied at least 10 minutes after the administration of topical medications.Citation47,Citation65,Citation67 High-coverage products are less suitable for use in rosacea due to their content of pigments, fats and waxes.Citation47

A multicentre retrospective study concerning daily care showed that the use of traditional make-up (more than 6 times a week) and the excessive use of facial cleansers (twice or more times daily) were closely correlated with the development of rosacea.Citation67 If make-up is necessary, a simple medical make-up with mineral products should be recommended in order to minimize the risk of developing rosacea.Citation63 Mineral make-up provides excellent coverage and is easy to use, protects against UV radiation, and is non-comedogenic and anti-inflammatory. It is presently considered that mineral make-up should be free of talc and consist mainly of a combination of titanium dioxide (TiO2), zinc oxide (ZnO), iron oxides, mica, bismuth oxychloride (BiOCl), or boron nitride (BN) Mineral powders require the skin to be clean and prepared with a moisturizing cream, and thus it is necessary to wait until the cream is fully absorbed before their application.Citation68 The personal skincare procedures recommended in rosacea are presented in .

Table 3 Most Commonly Recommended Cosmetic Procedures in the Treatment of Rosacea

Conclusion

The role of a cosmetological procedure may be seen as an essential complement to the treatment of rosacea. The implementation of an appropriate treatment and proper skincare brings about positive outcomes and improves the rosacea patients’ quality of life. What should be remembered though is that usually a combination of various treatments rather than monotherapy is more effective and leads to satisfactory results. Combining pharmacological and cosmetic procedures successfully - requires, however, an individual approach to every patient whose particular needs should be fostered as best as possible. This is more likely to be achieved when the cosmetological treatment proposed is consulted with a dermatologist.

Abbreviations

BTNL 2, Butyrophilin-Like Protein 2; CGRP, calcitonin gene-related peptide; ETR, erythematotelangiectatic rosacea; FDA, Food and Drug Administration; HLA-DRA, Major Histocompatibility Complex, Class II, DR Alpha; HP, Helicobacter pylori; IBD, inflammatory bowel disease; IL, interleukin; IPL, intensive pulsed light; KTP, potassium-titanyl-phosphate laser; MMP, matrix metalloproteinase; ND:YAG, Neodymium-Doped Yttrium Aluminium Garnet; PDL, pulsed dye laser; PHA, polyhydroxy acids; PhR, phymatous rosacea; PPR, papulopustular rosacea; PTP, potassium titanyl phosphate; SIBO, small intestinal bacterial overgrowth; SNP, single nucleotide polymorphism; SP, substance P; TLR, Toll-like receptor; TNF-alpha, tumor necrosis factor-alpha; TRP, transient receptor potential cation; UV, ultraviolet; VEGF, vascular endothelial growth factor; VIP, vasoactive intestinal peptide.

Disclosure

The authors report no conflicts of interest in this work.

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