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ORIGINAL ARTICLE
Year : 2021  |  Volume : 66  |  Issue : 4  |  Page : 331-336
The Difference in Expression of Autophagy-Related Proteins in Lesional and Perilesional Skin in Adult Patients with Active and Stable Generalized Vitiligo—A Cross-Sectional Pilot Study


1 Department of Dermatology, Sir Run Run Shaw Hospital, Zhejiang University Medical College, 3 Qinchun Road East, Hangzhou, Zhejiang, China
2 Division of Dermatology and Venereology, Ryhov Hospital, Region Jönköping County, Jönköping; Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden

Date of Web Publication17-Sep-2021

Correspondence Address:
Haiyan Yu
Department of Dermatology, Sir Run Run Shaw Hospital, Zhejiang University Medical College, Hangzhou, Zhejiang 310016
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.IJD_774_19

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   Abstract 


Background: Autophagy plays an important role in maintaining intracellular homeostasis and is essential for cell survival and cell death. Dysfunction of autophagy has been described in many autoimmune diseases but data on vitiligo are scarce. Aims: The aim of this pilot study was to investigate the expression of autophagy-related proteins in patients with vitiligo. Methods: Western blotting was used to analyze the expression of microtubule-associated protein light chain 3 (LC3II/I), autophagy-related gene 5 (Agt5), mammalian target of rapamycin (mTOR) and p62 in lesional and perilesional vitiligo skin from seven patients with active generalized vitiligo and nine patients with stable generalized vitiligo compared to control skin from six healthy subjects. Results: Our data showed increased expression of the autophagy marker LC3II/I and decreased p62 protein expression in lesional skin of active and stable vitiligo compared to control skin (P < 0.01). No significant difference in the expression of LC3II/I and p62 was found in perilesional skin of active vitiligo patients (P > 0.05) compared to control skin. Expression of LC3II/I in stable vitiligo lesional skin was higher and p62 expression was lower compared to active vitiligo lesional skin (P < 0.01). Decreased p62 expression was shown in perilesional skin of stable vitiligo patients (P < 0.05). Agt5 protein in lesional and perilesional skin of both active and stable vitiligo patients were increased (P < 0.01 and P< 0.05) compared to control skin. The expression of mTOR protein in lesional and perilesional skin of active and stable vitiligo patients was significantly lower than in control skin (P < 0.01). Conclusions: The present study indicates increased autophagy in lesional skin in vitiligo patients. Stable vitiligo lesional skin showed increased autophagy compared to active vitiligo lesional skin. Missing activation of autophagy in active vitiligo perilesional skin suggests disturbed autophagy to be associated with vitiligo.


Keywords: Agt5, autophagy, LC3II/I, mTOR, p62, vitiligo


How to cite this article:
Yu H, Lin X, Huang Y, Cheng H, Seifert O. The Difference in Expression of Autophagy-Related Proteins in Lesional and Perilesional Skin in Adult Patients with Active and Stable Generalized Vitiligo—A Cross-Sectional Pilot Study. Indian J Dermatol 2021;66:331-6

How to cite this URL:
Yu H, Lin X, Huang Y, Cheng H, Seifert O. The Difference in Expression of Autophagy-Related Proteins in Lesional and Perilesional Skin in Adult Patients with Active and Stable Generalized Vitiligo—A Cross-Sectional Pilot Study. Indian J Dermatol [serial online] 2021 [cited 2021 Dec 2];66:331-6. Available from: https://www.e-ijd.org/text.asp?2021/66/4/331/326145





   Introduction Top


Vitiligo is an acquired skin disease characterized by localized or generalized pigment loss. The difficult treatment of vitiligo and the disfiguring appearance implies heavy psychological burden for the patients and seriously affects their quality of life.[1] Until now, the etiology and pathogenesis of vitiligo have not been fully understood. Several factors such as heredity, autoimmunity, oxidative stress as well as neurological and psychological causes may be associated with the pathogenesis of vitiligo.[2] Most researchers believe that vitiligo is an autoimmune disease triggered by various environmental factors resulting in the destruction and loss of melanocytes.[3]

Autophagy is a lysosome-dependent degradation pathway in eukaryotic cells. It is an important mechanism of maintaining intracellular homeostasis and ensuring self-protection. There is evidence emphasizing the role of autophagy in both, the innate and acquired immune response as well as in immune regulation.[4] Studies have shown that dysregulated autophagy is involved in the pathogenesis of autoimmune diseases such as lupus erythematosus[5] and inflammatory bowel diseases.[6]

Regulation of autophagy plays an important role in the physiological function of melanocytes.[7] Autophagy adjusts melanosome formation by regulating the UV resistance-related gene (UVRAG) complex.[8] The UVRAG complex itself can also activate and promote autophagy, and UVRAG gene polymorphisms are associated with increased susceptibility of vitiligo.[9] Further, inhibition of autophagy-related genes (BECN1) has shown to decline melanin aggregation.[10] Previous studies have shown that autophagy is essential in maintaining the homeostasis of melanocytes by protecting them from oxidative damage.[11],[12] Therefore, we hypothesize that autophagy and autophagy regulators are involved in the pathogenesis of vitiligo.

The aim of the present pilot study was to investigate the expression of autophagy markers related to different phases in the autophagy process. The microtubule-associated protein light chain 3 (LC3II/I) has been described as a useful indicator of autophagosome initiation. The autophagy-related protein Agt5 and mammalian target of rapamycin (mTOR) are both identified as important regulatory pathways for autophagy. P62 protein is an important protein in autophagy pathways and it interacts with LC3 protein and degrades through the autophagy-lysosome pathway. P62 expression is inversely correlated to the intensity of autophagy.[13] LC3II/I, Agt5, mTOR, and p62 protein were analyzed in lesional and perilesional skin of patients with generalized vitiligo.


   Materials and Methods Top


Patients

A total of 16 patients (6 men and 10 women) with generalized vitiligo were enrolled in this pilot cross-sectional study [Table 1]. Patients were consecutively recruited from the tertiary care outpatient clinic at the Department of Dermatology, Zhejiang University Hospital between February 2016 and October 2018. Patients enrolled were diagnosed with generalized vitiligo when presenting bilateral, depigmented macules or patches occurring in a random distribution over multiple areas of the body surface. Woods lamp was used as a diagnostic aid in all patients to ensure vitiligo diagnosis. Demographical data including age, sex, duration of vitiligo and previous treatment were collected. Disease activity was determined using the 6-point Vitiligo Index of Disease Activity (VIDA) score as described by Njoo et al.[14] According to this index, a VIDA score ≥1 defines active vitiligo, while a VIDA score ≤0 classifies stable vitiligo. In the present study, patients were selected and classified having active vitiligo when new lesions appeared within the last 3 months (VIDA score ≥3) and having stable vitiligo when no new lesions occurred within 1 year (VIDA score ≤0). Patients with mild active vitiligo (VIDA score ranging from 1 to 2) were not included. Based upon this classification, seven patients were classified as active and nine as stable vitiligo patients. Further exclusion criteria were other type of vitiligo than generalized, pregnancy, systemic diseases, and other inflammatory conditions including inflammatory skin diseases, systemic drug therapy or phototherapy within 3 months prior to the present study. Control skin tissue was obtained from six healthy subjects who underwent elective surgery for excision of benign nevi. This study was conducted in compliance with good clinical practice and according to the Declaration of Helsinki Principles. All participants gave their written informed consent prior to participation and the study procedure was approved by the Local Ethics Committee, Zhejiang University.
Table 1: Demographics and clinical characteristics of vitiligo patients and healthy controls

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Tissue samples

In each patient, two biopsies were taken by incisional biopsy from not sun-exposed lesional and perilesional normal skin near the edge of the lesion after local anesthesia using lidocaine 2%. Control skin samples were taken from healthy subjects immediately after surgical nevus excision from the surrounding skin. All tissue specimens were immediately stored at –80°C until further use.

Western-blot analysis

The skin tissue samples were cut into small pieces and homogenized at 4°C with 25,000 rpm for 5 min (DIAX 900, Heidolph, Schwabach, Germany) in lysis buffer containing 50 mmol/L Tris–HCl (pH 7.6), 20 mmol/L MgCl2, 150 mmol/L NaCl, 0.5% Triton-X, 5 units/mL aprotinin, 5 μg/mL leupeptin, 5 μg/mL pepstatin, 1 mmol/L benzamidine, and 1 mmol/L phenylmethylsulfonyl fluoride. The debris was removed by centrifugation, and the protein concentration in the lysates was determined by bicinchoninic acid protein assay kit (Pierce Biotechnology, Rockford, IL).

The proteins were separated by a 10% polyacrylamide gel, transferred to a polyvinylidene difluoride membrane. The membranes were blocked with skimmed milk for 2 h and then incubated with rabbit antibodies specific to LC3 (Proteintech, Chicago, USA), p62 (Proteintech, Chicago, USA), mTOR (Abcam, Cambridge, UK), Agt5 (Abcam, Cambridge, UK), and β-actin (Cell Signaling, Boston, USA) overnight, washed and incubated with Horseradish peroxidase-conjugated secondary antibodies. The signals were visualized using ECL kit. Band densities were quantified using a scanning densitometric analysis image software (National Institutes of Health, Bethesda, MD).

Statistical analysis

All values were calculated as mean and standard deviation. Student's paired t-test was used to analyze the results obtained from lesional and perilesional vitiligo skin. Unpaired t-test was used to compare vitiligo and normal skin. All statistical analysis was performed using GraphPad Prism 5 software (GraphPad Software Inc., San Diego, CA). All results given a P value of <0.05 were considered significant.

Ethics committee

The study was assessed and approved by the Institutional Ethics Committee, Sir Run Run Shaw hospital, Zhejiang university.


   Results Top


Increased expression of autophagy-related protein LC3II/I and Atg5 in vitiligo lesional and perilesional skin

Microtubule-associated protein-1 light chain 3 (LC3) is a marker of autophagy. The level of LC3 I transformed into LC3 II indicates the degree of autophagy activation.[15] Hence, an increased ratio of LC3II/I expression is pointing toward stimulated autophagy. Therefore, the ratio of LC3II/I protein in lesional and perilesional vitiligo skin was determined and compared to control skin by western-blot analysis. As shown in [Figure 1]a and [Figure 1]c, LC3II/I protein expression was increased in active and stable vitiligo lesional skin and stable vitiligo perilesional skin compared to control skin (P < 0.01). In addition, LC3II/I protein expression in stable vitiligo lesional skin is significantly increased compared to active vitiligo lesional skin and stable peri-vitiligo skin (P < 0.01). However, there was no significant difference in the expression of LC3II/I protein between active vitiligo perilesional skin and control skin (P > 0.05).
Figure 1: Expression of autophagy proteins in vitiligo patients and controls: (a) Western blot protein bands, (b) Atg5 protein is significantly increased in active and stable vitiligo compared to active and stable perilesional skin, (c) LC3II/I is significantly increased in active and stable vitiligo compared to active and stable peri-vitiligo samples, (d) p62 is significantly decreased in active and stable vitiligo skin as well as stable vitiligo perilesional skin, and (e) mTOR is significantly decreased in active and stable vitiligo lesional skin (**P < 0.01, *P < 0.05; control, n = 6, active, n = 7 and stable vitiligo n = 9)

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Autophagy-related protein Atg5 expression was found to be significantly increased in active and stable vitiligo lesional (P < 0.01) and perilesional skin (P < 0.05) compared to control skin. The expression of Atg5 in stable vitiligo lesional skin was significantly higher than in active vitiligo lesional skin (P < 0.05) [Figure 1]b.

Decreased expression of mTOR and p62 protein in lesional and perilesional vitiligo skin tissue

p62 is an important protein in autophagy pathways. p62 interacts with LC3 protein and degrades through the autophagy-lysosome pathway. p62 expression is inversely correlated to the intensity of autophagy.[16] As shown in [Figure 1]d, our results revealed significantly lower expression of p62 protein in lesional skin of both active and stable vitiligo (P < 0.01) and in perilesional skin of stable vitiligo patients (P < 0.05) compared to control skin. No difference in p62 expression was found between active vitiligo perilesional skin and control skin (P > 0.05).

mTOR is an important regulatory protein for autophagy. Our data showed significantly lower expression of mTOR protein in lesional and perilesional skin of both active and stable vitiligo patients (P < 0.01) compared with control skin [Figure 1]e.


   Discussion Top


There is evidence for LC3 being a reliable autophagy marker.[15] The ratio of LC3II to LC3I is positively correlated with increasing autophagy activity. The adaptor protein p62/SQSTM1 is consumed in the process of autophagy. Thus, increasing expression of LC3II/LC3I is accompanied by decreasing abundance of p62 protein and increased autophagy flux.[16] Since our results showed an increased LC3II/I ratio and decreased p62 expression in lesional skin in both active and stable vitiligo, we suggest an increased autophagy activity in vitiligo lesional skin in vivo.

Interestingly, our data revealed enhanced autophagy in stable vitiligo lesions compared to active lesions proposing that the activation of autophagy might play a protective or restorative role preventing vitiligo progression. Moreover, no autophagy activation in perilesional skin of active vitiligo was found in the present study. These results may be interpreted as if there is impaired autophagy activation in the adjacent skin of active vitiligo lesions. However, a previous study showed that impairment of autophagy in cells usually goes along with p62 protein accumulation,[17] which was not found in the present study. It is difficult to explain these different results, but one can hypothesize on the presence of an inhibitory factor suppressing autophagy and facilitating vitiligo development. Still, our data indicated an imbalance in the activation of autophagy in vitiligo which might be correlated with the development of vitiligo.

Atg5 is an essential protein for autophagosome formation.[18] During this process, Atg12 links first to Atg5, then to Atg16, and finally constitute the Atg12, Atg5, and Atg16 complex which initiates the phagophore elongation. In contrast, mTOR is an important regulatory protein.[18] Accordingly, the activation of autophagy pathways is often correlated with increased expression of Atg5 protein and decreased mTOR protein. Our results showed increased expression of autophagy-related protein Atg5 and decreased expression of mTOR protein in lesional skin of vitiligo patients suggesting increased autophagy activation in vitiligo skin lesions in vivo.

In contrast to LC3II/I and p62, which indicated no autophagy activation in perilesional skin in active vitiligo, increased Atg5 concentrations were found in perilesional skin of both active and stable vitiligo. These results suggest that there might be inhibitors suppressing the activation of autophagy pathway during the development of vitiligo. These inhibitors may disrupt the protective function of autophagy against harmful insults, such as oxidative damage, resulting in tissue damage and the progression of the disease. It has been proven that inflammatory cytokines can disturb the balance of autophagy in affected organs.[19] Further studies are needed to clarify these findings. There is additional evidence that Atg5 has autophagy-independent functions as a proapoptotic molecule triggering mitochondrial outer membrane permeabilization.[20] Hence, increased expression of Atg5 might induce apoptosis in perilesional skin of active vitiligo patients leading to the progression of vitiligo.

Autophagy is a key factor in maintaining intracellular homeostasis, thereby protecting the organism from a variety of diseases, including infections, neurodegeneration, aging, and autoimmune diseases.[21] Defects or imbalances in autophagy are associated with several diseases, such as neurodegenerative diseases,[21] lupus erythematosus,[5] and inflammatory bowel disease.[6] Data describing the relationship between autophagy and vitiligo development are scarce. Previous research[10],[22],[23] showed that autophagy is involved in the regulation of melanocyte function. Deletion of autophagy-related genes (BECN1) led to the decline of melanin aggregation[23] and melanin levels in human skin cultured ex vivo were diminished by autophagy activators and enhanced by autophagy inhibitors.[22] Mouse melanocytes with a deletion of autophagy protein Atg7 developed premature senescence and accumulated products of oxidative damage.[24] Although many factors are associated with the pathogenesis of vitiligo, oxidative stress has recently been recognized as the most important concomitant factor in the pathogenesis of vitiligo.[23] Oxidative stress induces melanocyte cell death and has a direct effect on the gene expression of melanocytes involved in apoptosis, inflammation, and autophagy.[11],[25] Imbalance of autophagy has been supposed as a mechanism involved in the pathogenesis of vitiligo by breaking the redox balance of melanocytes and autophagy plays a protective role against the damage of melanocytes induced by oxidative stress insults.[11] In line with these findings, our data showed enhanced autophagy in stable vitiligo lesions compared to active vitiligo. The activation of autophagy in stable lesions suggests that activated autophagy might be a self-protective or restorative mechanism preventing from vitiligo development. We found no activation of autophagy in active vitiligo perilesional skin compared to stable vitiligo perilesional skin. These data indicate an imbalance in autophagy in active vitiligo which might be correlated with the pathogenesis of vitiligo.

Since the management of vitiligo remains challenging, new treatment options are highly needed. Autophagy might be a new potential therapeutic target for vitiligo. Compounds activating autophagy via Atg5 or LC3II/I may have beneficial effects on vitiligo lesions as it has been shown for tacrolimus which activates autophagy via the mTOR pathway.[26],[27] However, the dual functions of autophagy in autoimmune diseases have to be considered since treating autophagy might even deteriorate chronic inflammatory diseases.[19] α-Melanocyte-stimulating hormone, used as vitiligo treatment,[28] has been shown to induce mTOR reducing autophagy and enhancing the survival of melanocytes under oxidative stress.[29] Recent studies suggest basic fibroblast growth factor (bFGF) and statins as treatment alternatives.[30],[31] Both, bFGF and statins, exert therapeutic effects mediated via autophagy regulation.[32],[33]

Study limitations

A limitation in the present study is the small sample size and larger studies on autophagy markers in vitiligo are needed to verify the present results. However, the current study was designed as a pilot study testing the hypothesis of dysfunctional autophagy in vitiligo. Future studies might even include other relevant autophagy markers and investigate the effect of vitiligo treatment on their expression.


   Conclusion Top


The results in the present study suggest an increased autophagy flux in the lesional skin of patients with vitiligo. Lesional skin from patients with stable vitiligo showed more autophagy activation than active vitiligo lesional skin. Imbalance of the autophagy in active vitiligo perilesional skin might result in the development of vitiligo. The role of activation of autophagy might be a self-protection or restoration mechanism in vitiligo development. Hence, compounds activating autophagy or modulating autophagy by targeting involved proteins could offer new therapeutic options for vitiligo in the future.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

This project was supported by grants of Natural Science Foundation of Zhejiang Province.

Conflicts of interest

There are no conflicts of interest.



 
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