The Journal of investigative dermatology最新文献

The contributions of specific growth factors (GFs) to hair follicle maintenance during aging remain poorly understood. The GF TGFα affects postnatal hair morphogenesis, and its loss leads to wavy hairs in young mice. Whether TGFα is required for proper hair follicle function during aging has not been explored. In this study, we find that loss of TGFα results in severe progressive alopecia, leading to an almost complete absence of back hairs in aged mice. Deep hair phenomics shows that the progressive hair loss is associated with a switch of hair-type proportions toward zigzag hairs, increased hair waviness, decreased hair length, and increased trichoptilosis with multiple hair breakage points. Hair loss is associated with a progressive dilatation of the upper hair follicle, which showed keratinocyte differentiation abnormalities. Metabolomic analyses of epidermal sheets identified diminished levels of prostaglandin H2 in Tgfa^-/- mice. Transcriptomic analyses linked the hair loss in aged Tgfa^-/- mice to upregulation of genes involved in retinyl ester synthesis in keratinocytes, which resulted in increased retinyl stearate in skin of aged Tgfa^-/- mice. Collectively, these findings identify TGFα as a critical regulator of hair follicles during aging, whose loss leads to progressive alopecia, associated with dysregulation of prostaglandin and retinoid metabolism.

Melanoma cells evade drug treatment by changing their phenotype from proliferative to migrative cells and vice versa in a process known as phenotype switching. The Microphthalmia-associated transcription factor (MITF) is a key regulator of phenotype switching in melanoma. Previous studies have shown that loss of MITF affects the expression of epithelial-to-mesenchymal transition marker genes such as E-cadherin (CDH1) and N-cadherin (CDH2). However, the specific roles of CDH1 and CDH2 in phenotype switching as well as their direct correlation with MITF remain unclear. This study aimed to investigate how MITF regulates CDH1 expression in melanoma. The results showed that a 1 kb intronic CDH1 fragment (CDH1-B) leads to MITF-dependent activation of CDH1 expression through specific binding sites. Although MITF represses the expression of the epithelial-to-mesenchymal transition transcription factors SNAIL, ZEB1, and TWIST1, knockdown of SNAI1 and TWIST1 did not affect CDH1 expression or expression from the CDH1-B element. In addition, ZEB1 did not affect expression from the CDH1-B element, suggesting that MITF activates CDH1 directly through this regulatory element. Our results show the direct role of MITF in regulating CDH1 expression in melanoma, highlighting an important step in the phenotype switching process.

Characterizing the transcriptome of defined human hair follicle (HF) compartments remains a fundamental hair research challenge. In this study, we have used laser-capture microdissection coupled with RNA sequencing to reveal gene expression profiles of 8 selected compartments of human anagen VI HFs. Principal component analysis identified a high degree of similarity in the distinct transcriptional profiles of each examined compartment as well as a sex-specific clustering. To validate our transcriptomic analysis, we demonstrated that well-known signature genes map to the correct HF compartment. Comparison with published microarray and single-cell RNA-sequencing data on human anagen VI HFs or selected cell populations showed that we were able to corroborate significant elements of their transcriptomic signatures, confirming the accuracy of our experimental pipeline. Furthermore, we identified, to our knowledge, previously unreported compartment-specific markers and confirmed the expression of selected ones, namely PAPPA2 for the dermal papilla, FOXM1 for the germinative hair matrix, APOD for the connective tissue sheath, and EHF for the bulge outer root sheath, by in situ hybridization. Finally, we conducted a CellChat analysis to uncover intercompartmental communication patterns and generated an-as yet unavailable-transcriptomic atlas of distinct human anagen VI HF compartments, which can be utilized to develop compartment-specific therapeutic interventions for the management of human HF disorders.

Altered epidermal lipid metabolism along with keratinocyte dysfunction is a characteristic feature of psoriasis. CD36, a key fatty acid translocase, has been implicated in various inflammatory diseases through its regulation of lipid metabolism, but its role in the keratinocytes of psoriasis remains unclear. In this study, we found that CD36 was significantly elevated in the lesional epidermis of patients with psoriasis and positively correlated with the disease severity. Mice with keratinocyte-specific CD36 knockout or sulfosuccinimidyl oleate (the blocker of CD36) ointment topical treatment exhibited relieved imiquimod-induced psoriasis-like inflammation visually and histologically. Furthermore, gas chromatography tandem mass spectrometry analysis revealed significant increase of CD36 ligands, particularly long-chain fatty acids, in lesional skin from both patients with psoriasis and mice with imiquimod-induced psoriasis. In vitro, CD36 facilitated long-chain fatty acids transport into keratinocytes, leading to lipid accumulation and elevated expression of chemokines, notably CXCL2 and CCL20, which recruit neutrophils and CCR6⁺ T cells, respectively. Mechanistically, CD36-mediated long-chain fatty acids uptake impaired mitochondrial function and induced mitochondrial ROS generation, thereby activating the NF-κB signaling pathway and promoting chemokine production. These findings demonstrate an essential role of CD36 in lipid metabolic‒inflammatory crosstalk in keratinocytes, suggesting that it could be a potentially effective therapeutic target in inflammatory skin diseases.

To address the need for rapid reduction of atopic dermatitis (AD) clinical manifestations, this study investigated the time course of the effects of ruxolitinib (selective JAK1/JAK2 inhibitor) cream on itch and associated changes in skin and serum biomarkers in adults with AD. In the open-label SCRATCH-AD study (NCT04839380), patients with AD, an Investigator's Global Assessment score ≥2, and a Peak Pruritus Numerical Rating Scale score ≥4 applied 1.5% ruxolitinib cream to all affected areas (except palms, soles, scalp, genitals, and folds; ≤20% body surface area) twice daily for 28 days. Among 46 patients, the mean change from baseline in Peak Pruritus Numerical Rating Scale was -3.4 on day 2 (worst itch, 24-hour recall; primary endpoint) and -5.7 on day 29. Mean change from baseline in modified Peak Pruritus Numerical Rating Scale (current itch) was -2.3 by 15 minutes. Skin (sampled with tape strips) and serum biomarkers associated with AD, such as CCL17 and matrix metalloproteinase 12, were downregulated with ruxolitinib cream and correlated with improvements in disease and symptom severity. There were no serious treatment-emergent adverse events. In summary, patients with AD who applied 1.5% ruxolitinib cream experienced rapid and sustained improvement in itch and clinical improvements that correlated with changes in AD biomarkers.