Ryeim ansaf
Skin aging can be attributed to many factors such as cellular damage accumulation, systemic inflammation, metabolism, and the environment. Over the past decade, there have been many significant advances in the field of skin aging, including studies that explore the clearance of senescent (growth-arrested) cells in skin, regenerative therapeutics, and even 3D bioprinting of skin. One of the latest discoveries showed that blocking Interleukin 17 (IL-17) signaling leads to delays in the skin aging process. But how does IL-17, a pro-inflammatory cytokine, delay what has been known as the inevitable hallmarks of skin aging?
IL-17 is a type of pro-inflammatory cytokine (a protein secreted by the immune system to affect other cells) that is involved in skin inflammation and immune responses. In skin, it has several functions, including the promotion of wound healing, modulation of immune cells, and resistance against infections. Previously, there was a scarce amount of research on how these age-associated inflammatory cues affect skin aging.
Aiming to explore this area of science, a research group from Spain published a manuscript in the journal Nature Aging titled “Targeting lymphoid-derived IL-17 signaling to delay skin aging”. Inspired by the lack of research associated with this topic, the researchers used single-cell RNA (scRNA-seq) sequencing to analyze various types of immune cells present in the dermis skin layer of an ultraviolet irradiated skin aging mouse model. From this, they were able to analyze gene expression profiles for cells at 6, 12, 24, and 36 months of age. Additionally, immunofluorescence and flow cytometry were used to quantify IL-17 expression in different immune cells. This resulted in the observation that aged skin cells have a higher expression of IL-17, which may lead to chronic inflammation and increased oxidative stress through the production of pro-inflammatory cytokines and chemokines.
To investigate this further, the researchers injected anti-IL-17 antibodies to block the signaling of IL-17 in vivo. This led to the reduction of various histological skin aging hallmarks such as thinning epidermis, poor wound regeneration, and impaired hair follicle growth. For example, with IL-17 signal blocking, hair follicles grew at a faster pace in the anagen (“growth”) phase; the dermal papilla fibroblast cells expressing factors for hair follicle anagen entry suggest that these could be more prone to hair follicle regeneration after being treated with anti-IL17 antibodies. Researchers also performed function assays, like wound healing, to measure the effects of anti-IL-17 antibodies on epidermal stem cell proliferation, differentiation, and regeneration. The results from this study suggested that the in vivo blocking of IL-17 signaling reduces the proinflammatory state of the skin, resulting in delayed aging hallmarks through the reduction of inflammation and oxidative stress.
Image sourced from: Solá P, Mereu E, Bonjoch J. et al. Targeting lymphoid-derived IL-17 signaling to delay skin aging. Nat Aging 3, 688–704 (2023). https://doi.org/10.1038/s43587-023-00431-z
Despite these discoveries, there are still some challenges and limitations to fully understanding the impacts of IL-17 on aging skin. For example, the molecular mechanism by which IL-17 signaling impairs homeostasis and inflammation in skin is unknown, as well as any adverse effects associated with blocking IL-17 signaling in vivo. This is particularly important for patients with autoimmune diseases, as they would be more prone to infections and side effects.
The significance of this work mainly revolves around the discovery that IL-17 signaling could be used as a potential strategy to delay or even prevent age-associated skin disease. Clinical applications of this work include the development of skin regenerative therapeutics to treat age-associated ailments like excessive dryness or poor tissue repair. Interestingly, these potential therapeutics can be developed based on pre-existing anti-IL-17 therapies already approved for treatments of inflammatory associated diseases like psoriasis. Currently, there are four anti-IL-17 agents that have been approved by the FDA for this, including secukinumab, ixkizumab, brodalumab, and bimekizumab. It is unclear whether these agents also impact skin aging, however, as the field of regenerative medicine continues to expand, we can expect to see more therapeutic companies encompassing anti-aging themes within their pre-existing products.
References:
Ansaf RB, Ziebart R, Gudapati H, Simoes Torigoe MR, Victorelli S, Passos J, Wyles SP, 3D bioprinting—a model for skin aging, Regenerative Biomaterials, Volume 10, 2023, rbad060, https://doi.org/10.1093/rb/rbad060
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Solá P, Mereu E, Bonjoch J. et al. Targeting lymphoid-derived IL-17 signaling to delay skin aging. Nat Aging 3, 688–704 (2023). https://doi.org/10.1038/s43587-023-00431-z
Gotesman RD, Vender R. Bimekizumab for Moderate-to-Severe Plaque Psoriasis. Skin Therapy Lett. 2021 May;26(3):1-4. PMID: 34077151.
Puig L, Bakulev AL, Kokhan MM, Samtsov AV, Khairutdinov VR, Morozova MA, Zolkin NA, Kuryshev IV, Petrov AN, Artemeva AV, Zinkina-Orikhan AV. Efficacy and Safety of Netakimab, A Novel Anti-IL-17 Monoclonal Antibody, in Patients with Moderate to Severe Plaque Psoriasis. Results of A 54-Week Randomized Double-Blind Placebo-Controlled PLANETA Clinical Trial. Dermatol Ther (Heidelb). 2021 Aug;11(4):1319-1332. doi: 10.1007/s13555-021-00554-4. Epub 2021 May 31. PMID: 34060012; PMCID: PMC8322379.