Interleukin-15 is a hair follicle immune privilege guardian.

The autoimmunity-promoting cytokine, Interleukin-15 (IL-15), is often claimed to be a key pathogenic cytokine in alopecia areata (AA). Yet, rhIL-15 promotes human hair follicle (HF) growth ex vivo. We have asked whether the expression of IL-15 and its receptor (IL-15R) isoforms is altered in human AA and how IL-15 impacts on human HF immune privilege (HF-IP) in the presence/absence of interferon-γ (IFNγ), the well-documented key AA-pathogenic cytokine, as well as on hair regrowth after experimental AA induction in vivo. Quantitative immunohistomorphometry showed the number of perifollicular IL-15+ T cells in AA skin biopsies to be significantly increased compared to healthy control skin, while IL-15, IL-15Rα, and IL-15Rγ protein expression within the hair bulb were significantly down-regulated in AA HFs. In organ-cultured human scalp HFs, rhIL-15 significantly reduced hair bulb expression of MICA, the key "danger" signal in AA pathogenesis, and increased production of the HF-IP guardian, α-MSH. Crucially, ex vivo, rhIL-15 prevented IFNγ-induced HF-IP collapse, restored a collapsed HF-IP by IL-15Rα-dependent signaling (as documented by IL-15Rα-silencing), and protected AA-preventive immunoinhibitory iNKT10 cells from IFNγ-induced apoptosis. rhIL-15 even promoted hair regrowth after experimental AA induction in human scalp skin xenotransplants on SCID/beige mice in vivo. Our data introduce IL-15 as a novel, functionally important HF-IP guardian whose signaling is constitutively defective in scalp HFs of AA patients. Our data suggest that selective stimulation of intrafollicular IL-15Rα signaling could become a novel therapeutic approach in AA management, while blocking it pharmacologically may hinder both HF-IP restoration and hair re-growth and may thus make HFs more vulnerable to AA relapse.

Melatonin Exerts Prominent, Differential Epidermal and Dermal Anti-Aging Properties in Aged Human Eyelid Skin Ex Vivo.

Human skin aging is associated with functional deterioration on multiple levels of physiology, necessitating the development of effective skin senotherapeutics. The well-tolerated neurohormone melatonin unfolds anti-aging properties in vitro and in vivo, but it remains unclear whether these effects translate to aged human skin ex vivo. We tested this in organ-cultured, full-thickness human eyelid skin (5-6 donors; 49-77 years) by adding melatonin to the culture medium, followed by the assessment of core aging biomarkers via quantitative immunohistochemistry. Over 6 days, 200 µM melatonin significantly downregulated the intraepidermal activity of the aging-promoting mTORC1 pathway (as visualized by reduced S6 phosphorylation) and MMP-1 protein expression in the epidermis compared to vehicle-treated control skin. Conversely, the transmembrane collagen 17A1, a key stem cell niche matrix molecule that declines with aging, and mitochondrial markers (e.g., TFAM, MTCO-1, and VDAC/porin) were significantly upregulated. Interestingly, 100 µM melatonin also significantly increased the epidermal expression of VEGF-A protein, which is required and sufficient for inducing human skin rejuvenation. In aged human dermis, melatonin significantly increased fibrillin-1 protein expression and improved fibrillin structural organization, indicating an improved collagen and elastic fiber network. In contrast, other key aging biomarkers (SIRT-1, lamin-B1, p16INK4, collagen I) remained unchanged. This ex vivo study provides proof of principle that melatonin indeed exerts long-suspected but never conclusively demonstrated and surprisingly differential anti-aging effects in aged human epidermis and dermis.

mTORC1 activity negatively regulates human hair follicle growth and pigmentation.

Dysregulation of the activity of the mechanistic target of rapamycin complex 1 (mTORC1) is commonly linked to aging, cancer, and genetic disorders such as tuberous sclerosis (TS), a rare neurodevelopmental multisystemic disease characterized by benign tumors, seizures, and intellectual disability. Although patches of white hair on the scalp (poliosis) are considered as early signs of TS, the underlying molecular mechanisms and potential involvement of mTORC1 in hair depigmentation remain unclear. Here, we have used healthy, organ-cultured human scalp hair follicles (HFs) to interrogate the role of mTORC1 in a prototypic human (mini-)organ. Gray/white HFs exhibit high mTORC1 activity, while mTORC1 inhibition by rapamycin stimulated HF growth and pigmentation, even in gray/white HFs that still contained some surviving melanocytes. Mechanistically, this occurred via increased intrafollicular production of the melanotropic hormone, α-MSH. In contrast, knockdown of intrafollicular TSC2, a negative regulator of mTORC1, significantly reduced HF pigmentation. Our findings introduce mTORC1 activity as an important negative regulator of human HF growth and pigmentation and suggest that pharmacological mTORC1 inhibition could become a novel strategy in the management of hair loss and depigmentation disorders.

Prevention and Treatment of Chemotherapy-Induced Alopecia: What Is Available and What Is Coming?

Millions of new cancer patients receive chemotherapy each year. In addition to killing cancer cells, chemotherapy is likely to damage rapidly proliferating healthy cells, including the hair follicle keratinocytes. Chemotherapy causes substantial thinning or loss of hair, termed chemotherapy-induced alopecia (CIA), in approximately 65% of patients. CIA is often ranked as one of the most distressing adverse effects of chemotherapy, but interventional options have been limited. To date, only scalp cooling has been cleared by the US Food and Drug Administration (FDA) to prevent CIA. However, several factors, including the high costs not always covered by insurance, preclude its broader use. Here we review the current options for CIA prevention and treatment and discuss new approaches being tested. CIA interventions include scalp cooling systems (both non-portable and portable) and topical agents to prevent hair loss, versus topical and oral minoxidil, photobiomodulation therapy (PBMT), and platelet-rich plasma (PRP) injections, among others, to stimulate hair regrowth after hair loss. Evidence-based studies are needed to develop and validate methods to prevent hair loss and/or accelerate hair regrowth in cancer patients receiving chemotherapy, which could significantly improve cancer patients' quality of life and may help improve compliance and consequently the outcome of cancer treatment.