"Uncovering the Intricate Role of Autophagy in Skin Health: From Cellular Homeostasis to Disease Pathogenesis"

Autophagy is a highly conserved process that involves the creation of autophagosomes, which ultimately fuse with lysosomes, enabling the breakdown of misfolded proteins and damaged organelles through the action of their enzymatic components. The fundamental role of autophagy lies in maintaining cellular homeostasis, both in normal physiological conditions and in pathological states. Moreover, it has been well-established that dysfunctions in autophagy contribute to the pathophysiology of various human diseases, underlining its critical significance in cellular health and disease processes [1, 2]. In the early 1960s, while studying lysosomes, Christian de Duve discovered autophagy, the process involving the formation of vesicles that engulf and digest cellular components, leading to the term "autophagy" or "self-eating."

Autophagy plays a vital role in maintaining skin health and is particularly important in the context of skin diseases. It helps remove damaged cellular components, such as misfolded proteins and organelles, preventing their accumulation, which can contribute to the development of skin disorders. Autophagy also protects skin cells from oxidative stress caused by environmental factors like UV radiation and pollution. Moreover, it regulates inflammation in the skin, a significant factor in conditions like psoriasis, eczema, and acne. Additionally, autophagy provides cellular energy and nutrients during periods of stress or nutrient deprivation. It influences epidermal cell differentiation, ensuring proper skin barrier function, and affects cell death processes [3]. Autophagy, acting as an adaptive response during stress, combats invading microorganisms and supplies nutrients, while the skin, the body's largest organ spanning 2m², serves as the primary defense against diverse environmental stressors like UV radiation, pathogens, mechanical forces, and toxins. Autophagy is believed to function as an endogenous defense mechanism against such environmental disturbances. As a result, autophagy is intricately linked to skin homeostasis and is likely to play a role in the pathogenesis and progression of skin diseases [6].

Autophagy in the immune response against viral infectious dermatoses and bacterial infections, acts as a double-edged sword in the skin's defense. In viral infections, autophagy can act as a protective mechanism by selectively degrading viral components and inhibiting viral replication. For instance, in herpes simplex virus (HSV) infections, autophagy has been shown to restrict viral spread and reduce viral titers. However, some viruses, like human papillomavirus (HPV), have evolved mechanisms to exploit autophagy for their benefit, promoting their replication. Similarly, in bacterial infections, autophagy can help eliminate invading bacteria and control infection [5]. Examples include Mycobacterium tuberculosis and Staphylococcus aureus, where autophagy aids in clearing intracellular bacteria and mitigating infection. However, certain bacterial pathogens, such as Salmonella, have developed strategies to evade autophagy, enabling their survival and proliferation within host cells. Understanding the delicate balance between autophagy's protective and exploitative roles in viral infectious dermatoses and bacterial infections holds promise for developing targeted therapeutic approaches to combat these challenging skin diseases [3].

Autophagy, as a cellular process, comprises several distinct mechanisms, with macroautophagy, microautophagy, and chaperone-mediated autophagy being the prominent types. Macroautophagy involves the formation of autophagosomes, double-membrane vesicles that sequester cytoplasmic components, and deliver them to lysosomes for degradation [1]. This process is vital for maintaining cellular homeostasis, as it allows for the recycling of cellular constituents and serves as a means of energy supply during stress conditions. In contrast, microautophagy entails direct engulfment of small portions of cytoplasm or organelles by lysosomes without vesicle formation. This rapid and selective process contributes to cellular clearance. Chaperone-mediated autophagy, on the other hand, targets specific proteins for degradation through chaperone recognition and delivery to lysosomes. Once inside the lysosomal lumen, the targeted proteins are broken down into amino acids for recycling [4]. Each type of autophagy plays a critical role in cellular health and is finely regulated to ensure proper functioning and maintenance of cellular integrity. Understanding the intricate interplay between these autophagic pathways is crucial for gaining insights into their implications in various physiological and pathological conditions [2, 3].

 

Fig. 1. Schematic diagram of autophagic process. Upon stimulation, the cytosolic double-membrane vesicles are formed, termed as autophagosomes. Then fusion of the completed autophagosomes with the lysosome results in the delivery of an inner vesicle (autophagic body) into the lumen of the degradative compartment. Subsequent breakdown of the vesicle membrane allows the degradation of its cargo and eventual recycling of the amino acids.

Autophagy in skin diseases

To maintain cellular homeostasis, cells use a process called autophagy to recycle and destroy damaged or defective parts, such as proteins, organelles, and infected cells.  It is essential for several physiological activities, such as immunity, metabolism, and cellular development. However, when the autophagy procedure is misconfigured, it may affect the start and growth of several skin conditions. Epstein-Barr virus is type 4 of human herpes virus and it is related to cutaneous lymphoma. Due to its presentation on Major Histocompatibility Complex MHC class II molecules, EBV nuclear antigen 1 (EBNA1, the main CD4+ T-cell antigen of latent EBV infection) is recognized by CD4+ T cells. According to Casper's research, this process can be inhibited by using the autophagy suppressor 3-methyladenine (3-MA) or by silencing the autophagy-related gene (Atg) 12 (autophagy-associated gene) [1]. The double-stranded DNA virus known as the herpes simplex virus (HSV) often leads to infections of the skin and mucous membranes. HSV comes in two varieties: HSV-1 and HSV-2. Autophagy acts as an HSV antiviral. The presentation of the HSV-1 antigens on MHC class I molecules is made easier by autophagy that is activated during HSV-1 infection. HSV-1, however, has developed methods that inhibit the regulation of autophagy. For instance, the  PKR ( Protein Kinase R) and eIF2 (E74-like factor 2) phosphorylation that are necessary for the induction of autophagy are disrupted when the HSV-1 neurovirulence protein ICP34.5 interacts with Beclin 1 to prevent autophagy. Additionally, a recent study showed that ATG5 gene knockdown increases vulnerability to HSV-2 infection in vivo and decreases HSV-2 antigen processing and presentation on MHC class II molecules. Small, non-enveloped human papillomaviruses (HPVs) infect humans. Human tumours and pimples are both brought on by HPVs. Autophagy caused by HPV16 virions reduces infections in primary human keratinocytes exposed to the virus by promoting the breakdown of viral capsid proteins [3, 5].

 

Conclusion:

 Autophagy is critical for maintaining healthy skin and is especially significant when it comes to skin problems. It aids in the removal of damaged cellular components, shields skin cells from oxidative stress, controls inflammation, supplies nutrition and energy to cells, promotes cell development, and modulates the processes involved in cell death. The immune response to bacterial and viral skin diseases involves autophagy as well. It is crucial for understanding the complex processes and interactions of various forms of autophagy to design specialized therapeutic strategies to treat skin diseases.

 

 By:  Sareeta Baig & Anas Iqbal

 

References:

[1] Klapan, K., Simon, D., Karaulov, A., Gomzikova, M., Rizvanov, A., Yousefi, S., & Simon, H. U. (2022). Autophagy and skin diseases. Frontiers in Pharmacology, 13, 844756.

[2] Guo, Y., Zhang, X., Wu, T., Hu, X., Su, J., & Chen, X. (2019). Autophagy in skin diseases. Dermatology, 235(5), 380-389.

[3] Yu, T., Zuber, J., & Li, J. (2015). Targeting autophagy in skin diseases. Journal of Molecular Medicine, 93, 31-38.

[4] Chen, R. J., Lee, Y. H., Yeh, Y. L., Wang, Y. J., & Wang, B. J. (2016). The roles of autophagy and the inflammasome during environmental stress-triggered skin inflammation. International journal of molecular sciences, 17(12), 2063.

 

[5] Nagar, R. (2017). Autophagy: A brief overview in perspective of dermatology. Indian Journal of Dermatology, Venereology and Leprology, 83, 290.

 

[6] Kim, H. J., Park, J., Kim, S. K., Park, H., Kim, J. E., & Lee, S. (2022). Autophagy: guardian of skin barrier. Biomedicines, 10(8), 1817.