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Abstract
Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily (TNFSF). It acts through its receptor fibroblast growth factor-inducible 14 (Fn14). Studies have indicated that TWEAK/Fn14 pathway activation controls multiple cellular responses, including proliferation, angiogenesis and induction of inflammatory cytokines. TWEAK/Fn14 is manifested in many tissues of our body and most importantly in the skin causing inflammation and many autoimmune and neoplastic cutaneous disorders. Evidence suggests that the TWEAK/Fn14 axis, the downstream signalling pathway and its inflammatory molecular expressions are involved in the pathogenesis of many cutaneous disorders such as psoriasis, atopic dermatitis (AD) vitiligo and melanoma. So, this literature review describes a brief introduction of TWEAK and TWEAK/Fn14 pathway and summarises the case-series and open-label studies performed in the field of dermatology and its potential therapeutic benefit.
Keywords: Inflammation, TWEAK, TWEAK/Fn14
Introduction of TWEAK 
Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) was initially described as a member of the TNF superfamily (SF) in 1997.[1] It binds to its receptor, fibroblast growth factor-inducible 14 (Fn14), participates in several biological activities and stimulation of cell growth and angiogenesis and stimulation of apoptosis and enhances multiple inflammatory effects of pro-inflammatory cytokines such as TNF-α, interleukin (IL)-1, IL-6 and interferon (IFN)-γ.[2]
Different literature studies have described the role of TWEAK and TWEAK/Fn14 pathway in different skin diseases such as psoriasis, atopic dermatitis (AD), bullous pemphigoid, vitiligo, acne vulgaris, melanoma and urticarial vasculitis. Studies are performed on both animal model and humans to rule out the exact role of TWEAK and TWEAK/Fn14 pathway in the pathogenesis of diseases in dermatology.
Discussion Serum TWEAK and psoriasis
Psoriasis vulgaris (PV) is a chronic inflammatory disease affecting the skin and joints. It approximately affects 2–3% of the world's population.[3] A study was performed to determine the serum levels of TWEAK in psoriasis patients and further assess whether TWEAK levels are associated with disease severity, duration of disease and expression of psoriasis-related cytokines including IL-6, IL-23 and TNF-α.
The study included forty-five patients with chronic plaque psoriasis and forty-three controls, and the severity of psoriasis was assessed by the Psoriasis Area and Severity Index (PASI).[4] Serum levels of cytokines were measured using enzyme-linked immunosorbent assay (ELISA) kits. The mean TWEAK, IL-6, IL-23 and TNF-α levels were significantly higher in psoriasis patients than in control subjects, but there were no significant correlations between the psoriasis severity, the disease duration and serum cytokine levels.[4]
Similarly, another study was performed, which included 20 patients with PV, eight patients with pustular psoriasis (PP), eight patients with erythrodermic psoriasis (EP) and 20 healthy controls (HCs).[5] This study showed that average levels of TWEAK were significantly higher in the psoriasis groups than in the HCs and suggest that TWEAK may have a role in the pathogenesis of different types of psoriasis via synergy with IL-17A, IFN-γ or IL-36-γ.[5]
TWEAK, psoriasis and AD
Atopic dermatitis is a chronic inflammatory disease of the skin, which clinically presents with pruritus (with periods of remission and recurrences) and is associated with other allergic conditions such as asthma and allergic conjunctivitis.[6] It affects up to 20% of children and up to 30% of adults, and recent studies show that its prevalence is increasing, particularly in low socioeconomic countries.[7]
A case–control study was conducted on total of ninety subjects, 30 patients with psoriasis, 30 patients with AD and 30 apparently HCs.[8] Skin biopsies were collected from lesions of patients and healthy individuals. TWEAK level was significantly higher in psoriasis than in AD patients and controls.[8] Also, there was a significant difference between AD patients and controls with a higher level of AD skin.[8] Therefore, TWEAK may have a role in the pathogenesis of psoriasis and AD.
Similarly, another study was performed where skin tissue and sera were collected from patients with AD (age = 18–60 years) who had not received any topical or systemic therapies within recent 4 weeks.[9] Normal skin tissue and sera were collected from healthy donor. Regulated upon activation normal T cell expressed and secreted. MCP-1:monocyte chemoattractant protein-1 MRL/lpr: The mouse MRL lymphoproliferation strain(a.k.a MRL/lpr) SLE:systemic lupus erythematosus CCL2:c-c Motif chemokine ligand 2 BP:bullous pemphogoid Nuclear factor kappa B,Tumour necosis factor like weak inducer of apoptosis receptor.[9] Furthermore, the levels of TWEAK, RANTES, MCP-1 and IP-10 were also determined in the serum samples by ELISA but found no significant difference in these cytokines between patients and HCs.[9]
TWEAK and vitiligo
Vitiligo is an acquired cutaneous disorder characterised by the development of white macules due to selective loss of melanocytes, approximately affecting 0.5% of the population worldwide.[10]
A case–control study was performed at Benha University, which included 100 subjects (50 vitiligo patients and 50 control subjects).[11] All patients were subjected to complete cutaneous examination to evaluate the clinical type, distribution and severity of vitiligo using Vitiligo Area Scoring Index.[11] Tweak serum levels were higher in patients than in control subjects. Besides the above, serum levels were significantly higher in segmental vitiligo than in nonsegmental vitiligo.[11] So, TWEAK may play a potential role in the pathogenesis of vitiligo and aid in differentiating between segmental vitiligo and nonsegmental vitiligo.
TWEAK and acne vulgaris
Acne vulgaris is a chronic inflammatory disease of the pilosebaceous unit due to increased sebum production, altered keratinisation, inflammation and bacterial colonisation of hair follicles by Propionibacterium acne.[12]
A case-controlled study included 100 acne vulgaris patients divided into two groups: 25 patients with moderate and remaining 25 patients with severe acne; another group consisted of 50 acne-free control subjects.[13] This study revealed acne patients had elevated TWEAK serum levels when compared to the control subjects (p = less than 0.005), and serum TWEAK levels did not show any difference regarding disease grade, post-acne scar and hyperpigmentation.[13] It seems that serum TWEAK also may be involved in inflammatory cutaneous disorders, but more studies are needed to clarify its exact role.
TWEAK and cutaneous lupus
Cutaneous lupus erythematosus covers a wide range of dermatologic manifestations, which may or may not be associated with systemic disease.[14]
It is found that TWEAK signalling via Fn14 has an important role in the pathogenesis of cutaneous disease in the MRL/lpr lupus strain. Animal models have been used in investigating many crucial aspects of SLE. Doerner performed a study in which TWEAK treatment of murine PAM212 keratinocytes stimulated the secretion of RANTES through Fn14. MRL/lpr Fn14 knockout (KO) lupus mice were compared with MRL/lpr Fn14 wild-type (WT) mice to evaluate for any differences in the severity of cutaneous lesions and the presence of infiltrating immune cells.[15] Fn14 KO mice had a significant cutaneous disease as compared with MRL/lpr Fn14 WT mice and markedly decreased skin infiltration of T cells and macrophages, which strongly implicates the role of TWEAK/Fn14 signalling in the pathogenesis of cutaneous manifestation in the MRL/lpr model of spontaneous lupus.[15]
TWEAK and HSP
Henoch–Schonlein purpura (HSP) is the most common vasculitis disease of childhood with an incidence of about 10 cases per 100000 a year, with boys being more affected than girls affecting skin, joints, gastrointestinal tract and kidneys.[16]
A study was performed in the Hospital of Sichuan University, Chengdu, and 34 patients with HSP (16 males and 18 females) who met the diagnostic criteria for HSP, 19 patients with PV and 20 patients with AD together with 29 age- and sex-matched controls were enrolled.[17] Serum levels of TWEAK were elevated significantly in patients with the acute stage of HSP but not in patients with PV or AD compared with those in HCs. Serum TWEAK levels in patients with or without internal organ involvement were higher than those in the control group.[17] So, TWEAK is supposed to act as an important mediator of endothelial inflammation, which is associated with the pathogenesis of HSP.
TWEAK and bullous pemphigoid
Bullous pemphigoid is an autoimmune disease, which is characterised by the presence of subepidermal blisters, which clinically present as tense bullae and characteristically affect the elderly population. The annual incidence of bullous pemphigoid has been estimated to be between 2.4 and 23 cases per million in the general population and 190–312 cases per million in individuals older than 80 years.[18]
Liu performed a study where TWEAK levels in sera and blister fluid of patients with bullous pemphigoid and sera of normal control subjects were measured.[19] Skin tissues were collected from patients with BP. Both TWEAK and Fn14 were highly expressed in skin lesions of bullous pemphigoid.[19] The serum TWEAK levels along with the downstream proteins of RANTES, MCP-1 and IP-10 in patients were significantly higher than those in normal control subjects, and more of it, a positive correlation was found between the serum levels of TWEAK and anti-BP IgG.[19] This study concludes that TWEAK may act as a therapeutic target for patients with bullous pemphigoid.
TWEAK and urticarial vasculitis
Urticarial vasculitis is a subset of vasculitis, which is characterised clinically by urticarial skin lesions and histologically by necrotising vasculitis.[20]
A study was performed in the West China Hospital of Sichuan University, blood samples were obtained from 23 HC subjects, 30 patients with urticarial vasculitis in the acute stage, 14 patients with urticarial vasculitis (UV) in the convalescent stage and 11 patients with cutaneous leukocytoclastic angiitis and skin biopsies were also taken.[21] The high expression of TWEAK/Fn14 was expressed in the dermal vessel wall of skin lesions in patients with UV. Similarly, elevated serum TWEAK levels were observed in patients with UV in the acute stage.[21] These findings suggested that TWEAK may be a potential marker for evaluating the severity of this disease.
TWEAK and systemic sclerosis
Systemic sclerosis (SSc) is an immune-mediated rheumatic disease, which is characterised by fibrosis of the skin, internal organs and vasculopathy.[22]
In a study, to determine the serum level of TWEAK and its clinical association in patients with SSc, serum TWEAK levels from 70 patients with SSc were examined and further in a retrospective longitudinal study sera from 23 patients with SSc were analysed.[23] Serum TWEAK levels were increased in patients with SSc and were associated with a lower frequency of pulmonary fibrosis, and also, there was no difference in TWEAK level between limited cutaneous SSc and diffuse cutaneous SSc.[23] So, TWEAK could be a protective factor against the development of pulmonary fibrosis in SSc.
TWEAK and melanoma
Melanoma, also known as malignant melanoma, is a type of skin cancer, which develops from melanocytes. Although melanoma accounts for only 4% of all dermatologic cancers, it is responsible for 80% of deaths from skin cancer only.[24]
Studies have shown that TWEAK and Fn14 have been detected in human cancer tissue. A study was performed where murine B16 melanoma cells were engineered to secrete high levels of soluble TWEAK, and their properties were examined.[25] The TWEAK-mediated reduction in B16 cell invasive capacity was dependent on the activation of the non-canonical NF-kB signalling pathway. It was found that TWEAK/Fn14 binding activates canonical NF-kB signalling in both melanoma and prostate cancer cells.[25]
Kang and his colleagues performed a research study by culturing human melanoma cells.[11] This study showed increased TWEAKR expression through blocking Notch downstream transcriptional repressor HEY1 and amplified TWEAK-TWEAKR interaction to induce CCL2 production in melanoma cells suggesting a significant role of TWEAK in tumour cells and immunological microenvironment.[11]
Conclusion TWEAK is a cytokine that synchronises cellular proliferation, inflammation, differentiation, angiogenesis and apoptosis. TWEAK/Fn14, its biological activities, downstream signalling pathway and the expression and function of related inflammatory molecules have been involved in the pathogenesis of different cutaneous and autoimmune disorders. Also, some of the data with respect to therapeutic implications of TWEAK/Fn14 in cutaneous disorders are from animal models. So, more studies, especially in humans, are needed to further clarify the exact role of TWEAK and its exact pathogenesis in different diseases in dermatology so that we can comprehensively discuss the effect of targeting this molecule therapeutically.
Characteristics included in the study
NR—not reportedAD—atopic dermatitisSSc—systemic sclerosisUV—urticarial vasculitisCLA—cutaneous leukocytoclastic angiitis.Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
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