The Journal of investigative dermatology最新文献

Skin is constantly exposed to environmental and iatrogenic stressors, and its response varies depending on the type of stress. Responses from these stressors include acute local and systemic multiorgan inflammation and delayed immunosuppression. Unfortunately, the mechanisms behind these effects regarding effectors remain unclear. In this review, we provide evidence for a pathway in which the damaged skin keratinocyte responds through formation of effector platelet-activating factor within microvesicle particles. This paper highlights the therapeutic potential of blocking this process through pharmacologic inhibition of the enzyme acid sphingomyelinase needed for microvesicle particle biogenesis.

The most common subtype of cutaneous T-cell lymphoma, mycosis fungoides (MF), is characterized by proliferation of malignant T cells in the skin. In the more clinically aggressive folliculotropic MF (FMF), malignant T cells localize to follicular epithelium, whereas in classic MF, they infiltrate the dermis and epidermis. How the localization of neoplastic T cells to the follicular niche contributes to the clinical aggression in FMF is unclear. To uncover the tumor microenvironmental differences between perifollicular FMF and dermal classic MF regions, we analyzed patient samples using spatial transcriptomics. Transcripts were collected from specific cell subsets within follicular (FMF) and dermal (classic MF) regions of interest to compare gene expression, spatial deconvolution, and pathway activity. Our work revealed that the neoplastic CD4 T cells around the hair follicles in FMF had a highly inflammatory phenotype, better adaptation to cellular starvation, higher metabolic activity, and enhanced antigen presentation. In contrast, cutaneous T-cell lymphoma-associated macrophages in FMF exhibited an immunosuppressive phenotype with decreased IL-2 and IFN signaling. These findings suggest that the follicular microenvironment may provide survival advantages to malignant T cells while promoting a dysregulated antitumor immune response. These observations provide insight into the mechanisms underlying the more aggressive clinical features of FMF versus classic MF.

Nagashima-type palmoplantar keratosis (also referred to as SERPINB7-related palmoplantar epidermal differentiation disorder) is the most common form of palmoplantar keratoderma in East Asia. It is characterized by erythematous hyperkeratosis, palmoplantar hyperhidrosis, and a distinctive foot odor that significantly impairs QOL. In this study, we aimed to clarify the etiology of this odor by investigating the plantar microbiome and evaluating the therapeutic effects of topical benzoyl peroxide. Compared with healthy controls, individuals with Nagashima-type palmoplantar keratosis exhibited significantly higher objective odor scores; increased bacterial load, especially in the intertoe area; and reduced microbial diversity. Corynebacterium and Staphylococcus were the predominant dysbiotic flora species. The topical application of benzoyl peroxide significantly reduced foot odor and bacterial load; increased microbial diversity; and selectively decreased Corynebacterium abundance, particularly that of C tuberculostearicum. These changes correlate with the species-specific susceptibility of skin-resident bacteria to benzoyl peroxide. Our findings suggest that microbial dysbiosis, especially the overgrowth of Corynebacterium species, is central to the pathogenesis of foot odor in Nagashima-type palmoplantar keratosis. Topical benzoyl peroxide is a promising therapeutic intervention for mitigating dysbiosis and its associated foot odor. This study highlights the potential of microbiome-targeted therapies for symptom relief in inherited skin disorders such as Nagashima-type palmoplantar keratosis.

Chronic pruritus of unknown origin is a debilitating condition characterized by persistent itch without an identifiable cause, yet its underlying mechanisms remain elusive. Using single-cell RNA sequencing, we identified systemic immune dysregulation in patients with chronic pruritus of unknown origin, characterized by upregulated CCL3 expression in monocytes and NK cells. Plasma CCL3 levels effectively distinguished patients with chronic pruritus of unknown origin from healthy controls and strongly correlated with itch severity. Although CCL3 did not function as a direct pruritogen in mice, it enhanced sensory neuron sensitivity through CCR1, thereby amplifying scratching responses to diverse pruritogens. Furthermore, cutaneous CCL3 was markedly upregulated in a chronic dry-skin itch model. Inhibition of CCR1 or neutralization of CCL3 significantly suppressed scratching behavior in this model. Together, these findings identify CCL3 as a potential diagnostic biomarker for chronic pruritus of unknown origin and highlight the CCL3-CCR1 axis as a critical neuroimmune pathway underlying chronic itch. This CCL3-CCR1 signaling pathway may represent a promising therapeutic target for refractory pruritic disorders.

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.