Current insights into the role of human β‐defensins in atopic dermatitis

Summary

Anti‐microbial peptides or host defence peptides are small molecules that display both anti‐microbial activities and complex immunomodulatory functions to protect against various diseases. Among these peptides, the human β‐defensins (hBDs) are localized primarily in epithelial surfaces, including those of the skin, where they contribute to protective barriers. In atopic dermatitis skin lesions, altered skin barrier and immune dysregulation are believed to be responsible for reduced hBD synthesis. Impaired hBD expression in the skin is reportedly the leading cause of increased susceptibility to bacterial and viral infection in patients with atopic dermatitis. Although hBDs have considerable beneficial effects as anti‐microbial agents and immunomodulators and may ameliorate atopic dermatitis clinically, recent evidence has also suggested the negative effects of hBDs in atopic dermatitis development. In the current review, we provide an overview of the regulation of hBDs and their role in the pathogenesis of atopic dermatitis. The efforts to utilize these molecules in clinical applications are also described.

Introduction

Atopic dermatitis (AD) is a common inflammatory skin disease with a lifetime prevalence of approximately 20% 1. The hallmarks of AD are intense pruritus and chronic and relapsing skin inflammation. AD is associated strongly with immune dysregulation and epidermal barrier defects, resulting in allergic sensitization and increased susceptibility to skin infections 1.

The epidermis displays protective and defensive abilities, including radiation, anti‐oxidant, permeability barrier and anti‐microbial barrier protection 2. Skin‐produced anti‐microbial peptides (AMPs), also known as host defence peptides (HDPs), are key elements of innate immunity that play an essential role in the defence against microbial invasion 3, 4. HDPs also exhibit multi‐functional effects on the host immune system by inducing both pro‐ and anti‐inflammatory responses as well as promoting cell migration, cell proliferation, angiogenesis and wound healing 3.

In humans, one of the best‐characterized HDP families is the defensins. Human defensins are small (3·5–6 kDa) cationic peptides and can be subdivided into α‐ and β‐defensins based on the expression pattern and position of the three intramolecular disulfide linkages 3. Human α‐defensins are found primarily in neutrophils and the Paneth cells of the small intestine, whereas human β‐defensins (hBDs) are localized in epithelial surfaces, including the skin 3, 4, 5. Although the expression of hBDs increases substantially upon infection, inflammation or the presence of wounds 3, 6, several reports have revealed that inflammation in the skin of AD patients resulted in impaired hBD expression, leading to perturbed innate immunity and susceptibility to skin infections 4, 6, 7, 8.

Many reports have examined AD skin to elucidate the complex hBD regulation, which is influenced by immunological disturbances, skin barrier defects and infection. The multiple functions of hBDs, including broad‐spectrum anti‐microbial and immunoregulatory activities, may have future pharmaceutical applications in AD. This review focuses on the current knowledge of hBDs with an emphasis on their regulatory mechanisms in AD, their roles in AD pathogenesis and their applicability as therapeutic agents for AD.

The regulation and biological functions of hBDs

hBD‐1 was first isolated from the plasma of patients with renal disease in 1995 9. It is expressed constitutively in various epithelial tissues, including suprabasal keratinocytes, sweat glands and the sebaceous glands of the skin 10. Furthermore, hBD‐1 is up‐regulated by lipopolysaccharide, peptidoglycan and interferon (IFN)‐γ 3, 6. The second hBD, hBD‐2, was identified originally in psoriatic scales 11, and its expression is inducible upon stimulation with tumour necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐17, IL‐22 and various bacteria and yeasts 3, 11, 12. Among the above proinflammatory cytokines, IL‐17 has been reported to be one of most potent inducers of hBD‐2 in various epithelial cells 13, 14. Although hBD‐2 is primarily inducible, it can also be detected in normal skin with site‐specific differences related to its anatomical position 10. Under stimulatory conditions, hBD‐2 appears in the differentiated suprabasal layers and stratum corneum of the skin 15. These findings are consistent with a report showing that hBD‐2 is stored in lamellar bodies (LBs) in the spinous layer and is released into the intercellular space during the formation of the cornified envelope 16. In addition to epithelial cells, both hBD‐1 and hBD‐2 are detected in monocytes and macrophages, indicating their roles in the interface between the innate and adaptive immune systems 17. hBD‐3 is found in different tissues, including the skin, lung epithelial tissue and non‐epithelial tissues 18. Similar to hBD‐2, hBD‐3 is also located predominantly in the upper epidermis, and its secretion occurs during LB content extrusion at the interface of the stratum granulosum and stratum corneum 19. hBD‐3 expression stimulators in keratinocytes include TNF‐α, IL‐1β, IL‐22, bacteria and various growth factors 3, 4, 12. hBD‐4 mRNA is expressed highly in the testis and is up‐regulated in keratinocytes upon challenge with bacteria and phorbol 12‐myristate 13‐acetate (PMA) 20, 21. However, isolation of the natural hBD‐4 peptide has not yet been described. hBDs have anti‐bacterial activities against many microorganisms, including both Gram‐positive and ‐negative bacteria, fungi and viruses 3, 4, 15. Decreased hBD expression correlates with high susceptibility to skin infections 22. However, the effectiveness of anti‐microbial activities varies for each hBD. For example, hBD‐3 is salt‐insensitive and displays strong microbicidal activity against yeasts as well as Gram‐negative and ‐positive bacteria, including multi‐resistant bacteria at low micromolecular concentrations 23. In contrast, hBD‐1 and hBD‐2 are less potent antibiotics and are predominantly active against Gram‐negative bacteria and yeasts, especially when tested under low ionic strength conditions 5. hBDs also induce the production of several cytokines/chemokines and inflammatory mediators. Additionally, they enhance chemotaxis of various cell types, including dendritic cells, neutrophils, mast cells and T lymphocytes, suggesting an association between hBDs and cellular infiltration to sites of inflammation and/or infection 3, 4, 6. Furthermore, up‐regulation of hBD‐2 and hBD‐3 at wound sites and the ability of hBDs to promote keratinocyte migration and proliferation demonstrate the roles of these peptides in the re‐epithelialization process of healing skin epithelium 24, 25. In addition to its wound‐healing properties, hBD‐3 enhances and maintains skin barrier integrity by inducing tight junction (TJ) proteins 26. Together, these functions suggest that, in addition to being microbicidal agents only, hBDs also have an extensive range of immunomodulatory properties.

hBD expression in AD

Although the microbiota that normally inhabit the skin, such as Staphylococcus epidermidis, have been shown to induce hBD‐2 and hBD‐3 expression, thus enhancing skin protection against pathogens 27, 28, the expression of both hBD‐2 and hBD‐3 in normal skin is low. However, this expression is increased substantially upon infection or during chronic inflammatory skin diseases such as psoriasis 11, 15, 18. Approximately 6·7% of psoriatic patients suffer from either bacterial or viral infections; in contrast, this incidence is increased by four‐ to fivefold in AD patients 29. In the early 2000s, Ong et al. 30 and Nomura et al. 8 first identified lower concentrations of hBD‐2 and hBD‐3 in AD skin lesions compared with those in psoriatic skin. As both hBD‐2 and hBD‐3 exhibit anti‐bacterial activities against Staphylococcus aureus, herpes simplex virus (HSV) and vaccinia virus, which frequently colonize AD skin 4, 6, decreased hBD expression is believed to contribute to increased susceptibility to bacterial and viral infections in AD.

As the pathogenesis of AD includes the complex relationship between epidermal barriers and immune responses, which are associated with genetic and environmental factors 1, identifying a clear mechanism for hBD regulation in AD has been challenging. Although many publications have reported several mechanisms of hBD regulation, it remains debatable whether it is immune dysfunction or skin barrier defects that trigger hBD expression. Here, we aimed to investigate the possible factors contributing to hBD regulation in AD.

Immune dysregulation in AD impacts hBD expression

Immune abnormality in AD is characterized classically by T helper type 2 (Th2)‐mediated disease. Activated Th2 lymphocytes produce predominantly IL‐4, IL‐5, IL‐10, IL‐13 and IL‐31 cytokines, which can also be secreted by mast cells, eosinophils and basophils 31, 32. Although Th2 activation is a hallmark of AD, several recent studies have also suggested the role of Th17 and Th22 responses in various stages of the disease 31, 33. Interestingly, Th2‐derived cytokines have been related to reduced hBD expression (Fig. 1). Ong et al. 30 demonstrated that IL‐4 and IL‐13 suppressed TNF‐α‐induced hBD‐2 expression in human keratinocytes. Subsequently, other studies confirmed that TNF‐α‐ and IFN‐γ‐induced hBD‐2 and hBD‐3 expression was inhibited by IL‐4 and IL‐13 8, 34. Furthermore, Howell et al. 35 showed that over‐expression of IL‐10 down‐regulated hBD‐2 expression in keratinocytes through suppression of proinflammatory cytokines, including TNF‐α and IFN‐γ. Th2 cytokines inhibited signal transducer and activator of transcription (STAT)‐1‐mediated and nuclear factor‐κB‐mediated hBD‐2 and hBD‐3 expression through the activation of STAT‐6 and the suppressors of cytokine signalling (SOCS)‐1 and −3, indicating suppressive mechanisms of hBDs by Th2 cytokines 8, 34.

Figure 1.

Schematic representation of human β‐defensin (hBD) regulation in atopic dermatitis (AD). Altered skin barrier function involves both non‐lesional and lesional AD skin. The disturbed skin barrier potentiates immune reactivity through allergen and/or irritant penetration, which involves Langerhans cells (LC) and dendritic cells (DC), and induces T helper type 2 (Th2) polarization. While the skin microbiota, including Staphylococcus epidermidis, can limit pathogen colonization by enhancing hBD expression, over‐production of Th2 cytokines, such as interleukin (IL)‐4, IL‐10, IL‐13 and IL‐31, inhibits hBD expression. IL‐17‐producing T helper (Th17) cells and mast cells produce IL‐17 and histamine, respectively, which contribute to protective immunity by inducing hBD expression, but simultaneously exacerbate AD by inducing itching.

Notably, the Th2 cytokines IL‐4, IL‐13 and IL‐31 suppress the expression of skin barrier‐related proteins, which are critical in AD pathogenesis 31, 33, 36. In this context, IL‐4 and IL‐13 not only down‐regulate S100A11‐induced hBD‐3 and filaggrin expression 37, but they also inhibit the compensatory up‐regulation of TJ proteins and hBD‐2 38. Furthermore, the inhibitory effects of IL‐31 on S. aureus‐induced hBD‐2 and hBD‐3 have been reported in filaggrin knock‐down skin 39. Together, these findings suggest that Th2 cytokines weaken both skin barrier integrity and the innate immune response with increased susceptibility to allergens and infections.

Interestingly, compared with chronic AD skin lesions, which displayed low IL‐4 expression levels 40, acute AD skin lesions expressed relatively high hBD‐2 levels 41. Additionally, nearly 80% of AD skin lesions with increased hBD‐3 levels occurred in acute AD 41. Based on these data, increased Th2 cytokine levels are insufficient to inhibit hBD expression in acute AD lesions. Notably, hBD expression was higher in both acute and chronic AD skin lesions compared with healthy control skin, suggesting that hBD induction is not generally impaired in AD patients 41.

IL‐17‐ and IL‐22‐producing cells are abundant in inflammatory skin diseases, including AD, indicating that these cytokines might play key roles in AD pathogenesis 31, 33. Numerous studies have reported that increased numbers of IL‐17‐producing cells in both skin lesions and the peripheral blood of AD patients are correlated with acute phase and severity of AD 42, 43. Furthermore, studies in murine AD models demonstrated that IL‐17 levels were elevated initially, followed by increases in Th2 cytokines in progressive skin lesions. These findings indicate that IL‐17 is an initial cytokine in the development of AD 44, 45. Of particular interest are the effects of IL‐22 on keratinocytes. IL‐22 induced keratinocyte proliferation with epidermal hyperplasia as well as abnormal terminal differentiation of the epidermis 33, which may be a possible explanation for the lichenification in AD skin development. Both IL‐17 and IL‐22 are strong inducers of hBD‐2 and hBD‐3 in keratinocytes 12, 14. Furthermore, a positive correlation between IL‐22 and hBD expression in AD skin lesions has also been reported 12, 46.

Skin barrier dysfunction in AD disturbs hBD expression

A relationship between physical and anti‐microbial skin barriers has been documented 47. hBD‐2 and hBD‐3 up‐regulation has been found in keratinocytes following epithelial lining disruption of the skin 41, 48, 49 and during the epithelial differentiation process through specific signalling mechanisms, including TNF‐α, IL‐1β and growth factors 15, 21, 49. In contrast, constitutive hBD‐1 levels, which are expressed constantly in suprabasal keratinocytes 10, were reduced significantly in AD lesions compared with healthy skin. These levels become normalized after skin barrier status improvements 50. These observations indicate that skin barrier dysfunction is an important factor in intrinsic hBD regulation.

In terms of skin barrier dysfunction in AD, filaggrin loss‐of‐function mutations played a major pathogenic role in AD 1, 51. Furthermore, filaggrin is an important protein that is terminally differentiated in keratinocytes, and its breakdown products, which are natural moisturizing factors, are essential for appropriate skin hydration, pH maintenance and barrier homeostasis 51. Filaggrin down‐regulation also affects LB formation 51, 52. In addition to filaggrin deficiency, the disturbance of maturation and delivery of the lamellar granules as well as TJ defects also contributed to AD pathogenesis 53.

Although many studies have investigated the role of filaggrin in hBD expression, the results are conflicting. For example, Clausen et al. 54 and van Drongelen et al. 39 suggested that hBD‐2 and hBD‐3 expression is not related to filaggrin mutations, while flaky‐tail mice, which exhibit filaggrin deficiency, displayed reduced hBD‐2 expression levels 52. Furthermore, the impact of filaggrin‐deficient epidermis on the impaired LB secretory system, leading to abnormal expression of HDPs, has been described 53. Nonetheless, a recent study observed that hBD‐2 and hBD‐3 expression was increased significantly in filaggrin deficiency 38. Based on these findings, the impact of filaggrin on hBD expression is controversial and requires further investigation.

In addition to containing hBDs, LBs are also an important source of lipids, ceramides and hydrolytic enzymes, which are primarily responsible for the epidermal permeability barrier 2, 53. Compared with healthy individuals, the skin of AD patients displays abnormalities in both epidermal lipid metabolism and the extruding mechanism of LBs 53. The co‐regulation of hBD‐2 expression and barrier lipid production has been reported 48, providing additional evidence of the relationship between permeability and anti‐microbial barriers in the epidermis. Therefore, abnormalities in LB formation, secretion and post‐secretory processing in atopic patients could account for the abnormal hBD expression levels 53.

Non‐lesional AD skin has been demonstrated to share characteristics with lesional AD, including immunological abnormalities, broad epidermal differentiation defects and impaired skin permeability barrier functions 55, 56. There was no significant difference in the amounts of hBDs between non‐lesional AD skin and the skin of healthy individuals 41, while skin perturbation, either induced mechanically or via direct contact with irritants, enhanced epidermal hBD‐2 levels 57. These findings further support the hypothesis that hBDs are up‐regulated upon skin injury in response to epidermal barrier loss, which in turn evokes inflammatory responses and intrinsic anti‐microbial mechanisms 47, 48.

Scratching behaviour regulates hBD expression

One of the general principles for AD treatment is to limit itching 58, 59. The release of pruritogens, such as histamine, prostaglandins, IL‐31 and thymic stromal lymphopoietin (TSLP), triggers pruritic sensation 58, 60, 61. In addition to mast cells, histamine is produced by basophils, macrophages, T cells, dendritic cells and neurones 62, and its receptors can be detected in various cell types, including epidermal keratinocytes 62. In AD skin, histamine is a harmful trigger of skin inflammation by induction of proinflammatory cytokines and suppression of skin barrier functions 62. However, histamine contributes to immune protection against bacterial and viral infections 63, 64. Moreover, in‐vitro studies have demonstrated that histamine elevates hBD‐2 and hBD‐3 production by keratinocytes 65, 66 and in‐vivo application of topical histamine‐induced hBD‐3 expression 65. Therefore, in addition to its role in itch induction, histamine is implicated in host defence by promoting anti‐microbial activities in AD.

Epidermal damage by mechanical insults induces TSLP, a pruritogen and a proallergic cytokine 61. TSLP over‐expression, which is observed frequently in AD skin 60, induces Th2 polarization and promotes robust scratching behaviours 31, 61. In contrast to histamine, TSLP inhibited hBD‐2 production by keratinocytes through the Janus kinase (JAK)2/STAT‐3‐dependent signalling pathway 67. Furthermore, TSLP down‐regulates IL‐17‐induced hBD‐2 production, indicating another biological effect of TSLP in AD 67.

Additionally, repeated scratching in response to allergens or inflammation leads to skin damage and release of IL‐33, another epithelial‐derived cytokine 68. This cytokine stimulates Th2 immune responses and activates mast cells and basophils 31, 68, which promote AD pathogenesis. Recently, Alase and co‐workers 69 demonstrated that incubation of human keratinocytes with IL‐33 suppressed hBD‐2 up‐regulation in acute eczematous lesions, although its capacity was weaker than the inhibitory effect of IL‐4. Overall, the compensatory hBD expression, which is up‐regulated to balance the damage to epidermal keratinocytes, in AD might be disturbed by Th2‐derived cytokines as well as pro‐Th2 cytokines (Figs 1 and 2).

Figure 2.

Scratching behaviour is involved in the regulation of human β‐defensin (hBD) expression. Pruritogenic mediators such as histamine and interleukin (IL)‐31 induce robust itch sensation in lesional skin of atopic dermatitis (AD) patients, followed by scratching and the subsequent creation of open wounds that become infected. The production of hBDs is induced by skin injury and infected wounds with Staphylococcus aureus. However, the damaged epidermis also triggers the keratinocyte production of pro‐T helper type 2 (Th2) cytokines such as thymic stromal lymphopoietin (TSLP) and IL‐33 which, in turn, down‐regulate the expression of hBDs. TSLP also suppresses IL‐17‐induced hBD expression and acts as a pruritogenic mediator. Constant scratching leads to skin thickening, which can also be driven by IL‐22. Increased expression of IL‐22 suppresses Th2 activation and promotes hBD expression in AD.

Topical therapy and phototherapy in AD mediate hBD expression

Barrier‐restoring therapies on hBD expression

Restoration of the epidermal barrier is achieved following application of emollients, which recover water and lipids in the skin 59. Decreased ceramide levels in the epidermis are responsible for impaired skin barrier function 53, 59, and treatment with emollients that contain ceramide improves skin barrier integrity and relieves AD symptoms 59, 70. Moreover, ceramide‐dominant emollient application also improved the anti‐microbial barrier by inducing hBD‐2 expression 71. In addition to ceramide‐based emollients, the moisturizing action of urea has been demonstrated in the treatment of AD 59. A recent report showed that topical urea improved permeability barrier function significantly by reducing transepidermal water loss 72. Treatment with urea cream also enhanced epidermal differentiation makers, such as filaggrin, involucrin, loricrin and transglutaminase‐1, and it elevated hBD‐2, confirming the benefits of barrier repair treatment in AD on anti‐microbial barriers 72.

Topical calcineurin inhibitors on hBD expression

Topical therapies, including steroid or calcineurin inhibitors, such as tacrolimus, are effective at stabilizing AD symptoms 59, 73. To date, topical tacrolimus in AD patients appears to be safe and is more effective than low‐potency corticosteroids 73. In addition to its immunomodulatory effects, tacrolimus improves skin hydration and barrier functions in AD patients 74. A previous clinical trial reported that following application of tacrolimus ointment, the hBD‐2 expression levels increased with a concurrent decrease in IL‐4 levels 71. Thus, topical treatment with tacrolimus is not limited to improvements in skin hydration or inflammation suppression but also contributes to permeability and anti‐microbial barrier function normalization in AD. A schematic representation of the effects of topical therapy on hBD regulation is shown in Fig. 3.

Figure 3.

Schematic representation of the effects of topical therapy and phototherapy in atopic dermatitis (AD) on human β‐defensin (hBD) expression. Emollient application is the mainstay of AD treatment. In addition to improving the skin barrier integrity, emollient promotes anti‐microbial barrier function by inducing hBD expression. Furthermore, topical immunomodulators, such as tacrolimus, and ultraviolet B (UVB) phototherapy not only suppress inflammatory responses but also normalize the skin barrier function and induce hBD expression.

Vitamin D supplements and phototherapy affect hBD expression in AD

The active metabolite of vitamin D, 1,25‐(OH)₂D₃, is obtained from exposure to solar ultraviolet B (UVB) radiation and from limited dietary sources 75. A recent meta‐analysis reported that AD patients, especially paediatric AD patients, have lower serum vitamin D levels compared with healthy controls 76. Several reports have also demonstrated that vitamin D deficiency correlates with AD prevalence and severity 77, 78, as well as risk of bacterial colonization, especially methicillin‐resistant S. aureus 79. In addition to calcium homeostasis, vitamin D also regulates the immune system, terminal keratinocyte differentiation and the epidermal permeability barrier 75, 80. Furthermore, vitamin D receptor (VDR) expression was decreased in AD skin compared with normal skin 81, and alterations in VDR expression profiles were associated with AD severity 82.

hBD‐2 and VDR down‐regulation correlated with vitamin D insufficiency 81. Furthermore, VDR activation induced filaggrin, hBD‐2 and hBD‐3 expression in the skin lesions of AD mice, together with an improvement in the affected skin 83. Wang et al. 84 also demonstrated that vitamin D directly stimulated hBD‐2 expression in keratinocytes through vitamin D response elements located in the hBD‐2 promoters, indicating that the vitamin D pathway could be a target for hBD‐2 regulation. Subsequently, another group reported that hBD‐2 up‐regulation via the Toll‐like receptor (TLR)‐2/1 pathway required IL‐1β induction in co‐operation with vitamin D activation 85.

Therapeutic targeting of vitamin D production by vitamin D supplements or ultraviolet (UV) phototherapy has shown beneficial effects in the course of AD 76. UVB‐induced vitamin D improved the skin barrier in AD mice models by enhancing keratinocyte differentiation marker expression in parallel with hBD‐2 and hBD‐3 up‐regulation 86. Additionally, hBD‐2 and hBD‐3 were enhanced in normal keratinocytes following UVB radiation 87. Furthermore, Gambichler et al. 50 reported that hBD‐2 over‐expression in AD skin lesions returned to normal after UVB radiation and was accompanied by AD skin resolution. The authors suggested that the restoration of the skin barrier and suppression of bacterial colonization and inflammation by phototherapy were causes of the normalized hBD‐2 levels. Interestingly, UVB radiation induces keratinocyte hBD‐1 expression, which is normally constitutive 50. These findings indicate the beneficial effects of phototherapy in AD by enhancing the anti‐microbial defence barrier in the skin (Fig. 3).

The roles of hBDs in AD

Positive roles of hBDs in AD pathogenesis

Secondary skin infections, particularly S. aureus and HSV infections, are observed frequently in AD patients 88. S. aureus colonization is increased approximately 20‐fold on AD skin compared with healthy skin and probably correlates with disease severity 89. In addition to the compromised physical and immune skin barriers, it has been suggested that altered HDP expression, especially hBDs, also predisposes AD individuals to recurrent skin infections 88. Given that hBDs display potent killing activities against S. aureus 4, 5, these peptides are indispensable to protect against bacterial infections in AD patients. In addition to their anti‐bacterial activity, hBDs exhibit anti‐viral activities against HSV 6, 90. Decreased expression of hBDs in the skin from AD patients with a history of eczema herpeticum may, in part, explain the recurrent HSV infections in AD skin 7. Meyer‐Hoffert et al. 91 also suggested a role of hBD‐3 against the molluscum contagiosum virus, another frequent complication in AD.

As the skin of AD patients is very sensitive and vulnerable to allergens and irritants, the yeasts Candida and Malassezia may aggravate AD due to allergic reactions 92. There is evidence that hBDs have potent fungicidal activity against C. albicans in the skin and mucosa 3, 5, 93. Additionally, exposure of human skin keratinocytes to M. furfur triggered hBD‐2 production to protect against invading microbes 94. These observations suggest that decreases in hBD expression in atopic skin facilitate the colonization of pathogenic organisms and increase susceptibility to recurrent skin infections in AD patients. Thus, restoration of hBD production in AD skin is necessary to combat bacterial, viral and fungal infections.

Additionally, a body of evidence suggests that epidermal TJs contribute to permeability barriers 53, 95 and are related to LB secretory system regulation 96. TJ protein down‐regulation is observed in both lesional and non‐lesional AD skin, indicating a role for TJs in AD pathogenesis 97. As hBD‐1 and hBD‐3 have been shown to improve TJ barrier function 26, 98, this implies that increasing hBD generation in AD skin may not only protect against infections but also contribute to skin barrier maintenance and improvement in this skin condition (Fig. 4).

Figure 4.

Schematic representation of the roles of human β‐defensins (hBDs) in atopic dermatitis (AD) pathogenesis. In addition to their anti‐microbial activities against pathogenic microorganisms, hBDs strengthen the tight junction (TJ) barrier function, resulting in improved permeability barrier. In contrast, over‐expression of hBDs may contribute to the pathogenesis of AD by attracting and activating immune/inflammatory cells, including mast cells and dendritic cells (DC). hBD‐mediated release of histamine, prostaglandin D₂ (PGD₂) and interleukin (IL)‐31 increases skin vascular permeability and provokes the sensation of itch. hBDs also induce the secretion of inflammatory cytokines, including IL‐4, IL‐13, IL‐31 and IL‐22 by T cells, which are involved in AD pathogenesis.

Negative roles of hBDs in AD pathogenesis

Several studies have suggested that disturbed HDP expression, including hBDs, is a cause of recurrent skin infections in AD 4, 8. Increasing evidence suggests that hBDs may also contribute to AD pathogenesis (Fig. 4). For example, DEFB1, which encodes hBD‐1, was identified as an AD‐associated gene 99. Furthermore, the presence of hBD‐2 in AD skin was correlated positively with both epidermal barrier impairment and AD severity 54. Moreover, hBDs are known to attract and activate inflammatory/immune cells, including mast cells and T cells, which are involved in AD pathogenesis 4, 6. Mast cells are critical for AD pathogenesis, as their activation results in histamine and prostaglandin release, which are pruritogenic mediators, and cause an immediate increase in vascular permeability 32, 58. Because hBDs attract and activate mast cells to degranulate, produce lipid mediators, enhance pruritogenic factor secretion such as IL‐31 and nerve growth factor, and increase vascular permeability 4, 6, these peptides may contribute actively to AD symptom exacerbation. Intriguingly, both hBD‐2 and hBD‐3 also cause the release of Th2 cytokines (IL‐4, IL‐13, IL‐31) and IL‐22 from human T cells 46, which are involved in AD pathogenesis.

Potential clinical applications of hBDs in AD

While the increasing prevalence of antibiotic resistance represents a significant problem in infectious diseases, HDPs have retained their anti‐microbial activities and have attracted widespread attention as potential pharmaceuticals 6. Elucidation of the wide variety of HDP functions has led to the development of these peptides as anti‐infectives, immunomodulators and immunosuppressors 6, 100. Scudiero et al. 101 recently developed an anti‐microbial cyclic peptide carrying regions of hBD‐1 and hBD‐3. This peptide is not cytotoxic, is stable and exerted enhanced anti‐microbial activity. Furthermore, hBD‐1 modifications resulted in improved anti‐microbial activities against opportunistic pathogens, including C. albicans and anaerobic bacteria 102. Additionally, as hBDs strengthen anti‐microbial and skin permeability barriers 6, 25, 98, these molecules might be useful when applied locally onto infected skin lesions in AD and concurrently aid in the recovery of skin barrier functions. Unfortunately, the development of these peptides as drugs for clinical use has been very limited due to their susceptibility to proteolytic cleavage, induction of inflammation and high manufacturing costs.

Conclusions

Skin barrier dysfunctions combined with abnormal immune responses in AD allow the penetration of potential allergens and pathogens that worsen AD symptoms. Additionally, AD skin shows altered HDP expression levels, including hBDs. Because hBDs exhibit anti‐microbial and immunomodulatory activities, alterations in hBD expression are believed to increase skin infection susceptibility, resulting in AD exacerbation. The current AD therapies consist of immunological status normalization in parallel with both permeability and anti‐microbial barrier functions. Although recent evidence has suggested roles for hBDs in AD pathogenesis, many efforts have been devoted recently to developing these peptides for therapeutic applications. Therefore, further investigations are needed to uncover the roles of hBDs in AD pathogenesis and to assess their clinical potential, which would clearly benefit from new therapeutic approaches.

Disclosure

All authors have no disclosures to declare.

Author Contributions

P. C. and F. N. outlined, drafted and completed the review; P. C. designed and prepared figures; F. N. and H. O. coordinated the project and provided critical comments on the manuscript.