Interleukin-6 (IL-6) and the neuropeptide calcitonin gene-related peptide (CGRP) promote the generation of T helper 17 (Th17) cells. Th17-type immunity is involved in several autoimmune disorders, including psoriasis. Also, there is evidence that sensory nerves play a role in Th17-type immunity, including in psoriasis. Vitamin D (VD) blood levels vary inversely with the severity of psoriasis, and topical VD analogs are effective treatments for this disease. We have now asked whether 25-dihydroxyvitamin D3 [25(OH)D3] and the more potent, active analog 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] inhibit IL-6 and/or α-CGRP production by transformed mouse embryonic dorsal root ganglion (DRG) neurons (MED17.11 cells), which serve as a surrogate for primary DRG neurons. After culture in differentiation medium, MED17.11 cells express markers of mature DRG neurons. Lymph nodes are innervated, so IL-6 and CGRP released from nerves are anatomically situated to influence Th17 cell generation. MED17.11 cells were cultured in differentiation medium for 48-h to induce differentiation; then, medium in each well was replaced with fresh differentiation medium containing a range of concentrations of 25(OH)D3 or 1α,25(OH)2D3. Twenty-four and 48-h later, supernatants were collected, and cells were harvested and lysed. IL-6 and α-CGRP content of supernatants and lysates were assessed by ELISA. Both 25(OH)D3 and 1α,25(OH)2D3 significantly inhibited IL-6 content of supernatants and α-CGRP content of cell lysates in a dose-dependent manner with 1α,25(OH)2D3 being more potent. 25(OH)D3 and 1α,25(OH)2D3 also inhibited expression of IL-6 mRNA. VD may beneficially affect disorders involving Th17-type immunity by decreasing expression of IL-6 and α-CGRP by DRG nerves.

Senescent cells affect neighbouring cells via the senescence-associated secretory phenotype (SASP), which involves proinflammatory cytokines, chemokines and proteases. Camellia sinensis root extract (SENOMUNE) has shown therapeutic potential for skin aging-related disorders. However, whether it exerts senolytic effect remains to be explored. Thus, this study aimed to assess the senolytic properties of SENOMUNE in a stress-induced premature senescence model in normal human dermal fibroblasts (NHDFs) through cell viability assays, quantitative reverse transcription polymerase chain reaction, western blot and flow cytometry. NHDFs were induced to senescence using doxorubicin and insulin-like growth factor-1. The senolytic effect of SENOMUNE was evaluated by measuring senescence-associated β-galactosidase activity, gene and protein expression, and the apoptosis rate. SENOMUNE reduced the viability of senescent cells in a dose-dependent manner, with a more pronounced effect in senescent cells than in control cells. It was also associated with caspase-independent programmed cell death involving apoptosis-inducing factor and lysosomal membrane permeabilization in senescent cells. Moreover, SENOMUNE reduced the production of SASP factors, increased the expression of skin barrier-associated markers, and attenuated pigmentation by modulating the secretion of inflammatory cytokines. These effects were evaluated using conditioned media derived from senescent fibroblasts and validated through ex vivo skin biopsy experiments. Our results suggest that SENOMUNE exhibits senolytic properties and thus is a promising anti-aging phytopharmaceutical ingredient for managing skin-related disorders.

Lipoid proteinosis (LP) is a rare autosomal recessive disorder caused by loss-of-function mutations in the extracellular matrix protein 1 (ECM1) gene. While the clinical features of LP are well documented, the cellular mechanisms underlying its oral manifestations, particularly the direct consequences of ECM1 deficiency in oral keratinocytes, remain poorly understood. This study investigated the role of ECM1 in human oral keratinocytes (HOK) using an in vitro gain- and loss-of-function model. Functional assays were performed to evaluate proliferation, migration, keratinization and epithelial-mesenchymal transition (EMT)-like remodelling, complemented by transcriptomic sequencing (RNA-seq) to profile global transcriptional changes. ECM1 knockdown inhibited HOK proliferation and migration, while concomitantly promoting keratinization and an EMT-like remodelling response. Protein-level analyses confirmed activation of the TGF-β/Smad signalling pathway, with elevated p-Smad2/3 and increased secretion of TGF-β1 and MMP-9. RNA-seq analysis identified perturbations in genes and pathways governing cell cycle, motility and differentiation. Immunohistochemical validation in LP patient tissue showed COL4A1 deposition matching the characteristic PAS-positive hyaline material. Loss of ECM1 function may contribute to oral LP features through a dual mechanism: impairing tissue repair by hampering keratinocyte proliferation and migration, and promoting tissue remodelling through aberrant keratinization and an EMT-like phenotypic shift. These findings offer a cell-based model for understanding the oral manifestations of LP and highlight the epithelial contribution to LP-associated tissue remodelling.

Skin pigmentation disorders with dermal melanin involvement are therapeutically challenging due to poor responsiveness to conventional treatments and unclear pathogenesis. While melanin in the dermis is typically cleared by macrophages, human dermal fibroblasts (HDFs) can also internalize extracellular melanosome clusters (EMC) and apoptotic melanocytes that have occasionally been observed in the dermis, which may contribute to persistent pigment-related abnormalities. However, the functional impact of phagocytosis for fibroblasts remains unclear. In this study, HDFs were incubated with EMC or apoptotic MNT-1 melanoma cells (ApoMNT-1)-both exposing the phagocytic "eat-me" signal phosphatidylserine-confirming their internalization via Annexin V and TEM assays. Phagocytosis of EMC and ApoMNT-1 significantly upregulated the mRNA expression of IL-6, IL-8, IL-1β, PTGS2, and NF-κB, as well as the protein levels. Additionally, HDF proliferation was markedly inhibited, and the mRNA and protein levels of COL-1 and COL-3 were reduced. Furthermore, HDF mitochondrial function was impaired by the phagocytosis of EMC or ApoMNT-1, as indicated by decreases in basal respiration, ATP production, glycolysis, glycolytic capacity, and mitochondrial membrane potential. These results suggest that HDF internalization of EMC and apoptotic melanocytes triggers pro-inflammatory responses, inhibits cell proliferation and collagen synthesis, and impairs mitochondrial function. These findings provide novel insights into the biological mechanisms of dermal melanin-related processes and the functional changes of dermal fibroblasts after melanin phagocytosis, which lays a foundation for further in vivo studies on dermal hyperpigmentation.

This review examines age-related hair greying as a potential imbalance in the HFSC-MeSC-niche network in terms of time, space and signal quality. We define signal quality as the effective strength, temporal precision and noise-to-threshold relationship of niche-derived cues that regulate MeSC activation. We propose that ageing may progressively weaken the temporal coordination between HFSC activation and MeSC responsiveness. ECM remodelling and altered guidance-related cues may further impair MeSC niche engagement. Meanwhile, chronic oxidative stress, low-grade inflammation and stress-related sympathetic norepinephrine signalling may increase background noise, distort signal timing and push the MeSC activation threshold upward, so residual MeSC-lineage cells may fail to engage effectively with the niche. Such functional uncoupling may represent an early or intermediate stage, whereas sustained genotoxic stress or niche failure can eventually drive irreversible MeSC depletion. Based on this, the article constructs an integrative model, emphasizing that future intervention strategies may need to shift from simply protecting MeSCs to preserving the temporal and spatial coupling of the HFSC-MeSC-niche network. Potential approaches may include reducing chronic niche stress, maintaining HFSC-MeSC communication, preserving ECM organization and improving the timing and strength of pro-pigmentation cues. We further propose that hair greying may provide an accessible visual readout of stem-cell niche ageing.

Chronic spontaneous urticaria (CSU) is a mast cell-driven inflammatory disease frequently accompanied by anxiety, depression, sleep disturbance, fatigue, and impaired quality of life. Pruritus, disturbed sleep, psychosocial burden, and treatment-related effects are established contributors to this neuropsychiatric and functional burden. Whether immune-to-brain signalling provides an additional mechanism in a susceptible subgroup remains unknown. This hypothesis-driven narrative review examines the blood-brain barrier (BBB) as one potential interface linking CSU-associated inflammation to central effects. CSU studies report systemic inflammatory, vascular, and neuroimmune signals, including cytokine signatures, circulating matrix metalloproteinase-9, and substance P-MRGPRX2-related findings. Their potential neurovascular relevance is inferred from experimental or other disease settings rather than demonstrated in CSU per se. Our targeted search identified no human CSU studies assessing regional BBB permeability with dynamic contrast-enhanced magnetic resonance imaging or tracer methods, blood-cerebrospinal fluid barrier function with the albumin quotient, serum S100B, or brain endothelial tight-junction integrity, including claudin-5 or occludin. Structural and functional neuroimaging findings in CSU do not establish barrier dysfunction. Systemic mastocytosis provides comparative evidence for mast-cell-related neuropsychiatric manifestations, although barrier involvement remains unproven. We therefore propose neurovascular alteration as a testable, non-exclusive risk modifier whose relevance to CSU pathophysiology and psychiatric symptoms remains to be established.

Autophagy is increasingly recognised as a regulator of epithelial stress adaptation in the skin, but its role in inflammatory dermatoses remains difficult to interpret because autophagy intersects with barrier biology, keratinocyte differentiation, immune signalling, intracellular trafficking and lysosomal degradation. Keratinocytes are immune-competent epithelial cells that integrate cytokine exposure, oxidative stress, microbial sensing and tissue injury into inflammatory output. In this review, we synthesize evidence on keratinocyte autophagy as a disease-dependent regulator of epidermal homeostasis and cutaneous inflammation. We summarize core autophagy machinery, selective autophagy programs relevant to epidermal differentiation and the interpretive value of autophagic flux and lysosomal competence. We then discuss how autophagy influences keratinocyte differentiation, organelle clearance, lipid handling, barrier support, inflammatory restraint and stress adaptation. Disease-specific evidence is reviewed in psoriasis, AP1S3-associated pustular autoinflammation, atopic dermatitis and vitiligo. Across these settings, keratinocyte autophagy cannot be classified as uniformly protective or pathogenic; its effects depend on inflammatory context, trafficking state, cell-type-specific outputs and the ability of lysosomes to complete degradation. We also consider lessons from other barrier epithelia, therapeutic implications and common methodological limitations. A keratinocyte-centered, flux-aware interpretation provides a framework for organizing disease-specific autophagy biology and for designing more rigorous mechanistic studies in inflammatory dermatoses.

Psoriasis is a common immune-mediated inflammatory disease that often worsens during cold weather, yet the mechanisms linking cold exposure to enhanced psoriatic inflammation remain poorly understood. Shuai and colleagues identify a distinct macrophage population induced by cold stress in the dermal adipose layer, characterized by heightened lipid metabolism and IL-1β production. These macrophages promote IL-17A-producing γδT-cell responses in a mouse model of psoriasis, uncovering a potential cellular mechanism through which cold environments exacerbate psoriatic inflammation via immune-metabolic pathways.

Skin aging is a multifactorial process characterized by the progressive decline of tissue structure, function and regenerative capacity. Although numerous interventions have been developed to improve the clinical manifestations of aging, most primarily alleviate downstream consequences rather than directly targeting the molecular mechanisms underlying tissue deterioration. Recent advances in single-cell and spatial transcriptomic technologies have fundamentally transformed our understanding of skin aging by identifying cell type-specific transcriptional programmes and uncovering novel regulators of epidermal homeostasis, dermal remodelling and intercellular communication. These high-resolution atlases have generated an expanding repertoire of candidate rejuvenation targets, many of which consist of intracellular regulatory proteins that have traditionally been considered difficult to manipulate using conventional pharmacological approaches. In parallel, rapid progress in RNA engineering has established nucleic acid therapeutics as a versatile approach for precise molecular intervention. Among these, messenger RNA (mRNA) therapeutics are particularly well suited to the molecular landscape emerging from skin aging atlases because they enable transient restoration of proteins that are lost during aging. Advances in lipid nanoparticles, extracellular vesicles and microneedle-based delivery systems are rapidly improving the feasibility of local cutaneous administration. In this review, we discuss the emerging rejuvenation targets identified by single-cell and spatial transcriptomic atlases and examine recent advances in RNA-based therapeutics and mRNA delivery strategies that are paving the way for precision skin rejuvenation.

Bullous pemphigoid (BP) is an autoimmune blistering disease of the elderly who are frequently colonised by Staphylococcus aureus, particularly strains producing the superantigen toxic shock syndrome toxin-1 (TSST-1). Given the ability of TSST-1 to engage the T cell receptor (TCR) Vβ2 chain, we investigated whether superantigen (SAg) exposure in BP is associated with alterations in peripheral T cell populations. CD4[+] T cells were isolated from peripheral blood mononuclear cells (PBMCs) from BP patients and age-matched healthy controls. T cell responsiveness to TSST-1, staphylococcus enterotoxin G (SEG), and staphylococcus enterotoxin-like-I (SEl-I) was assessed via proliferation assays, and the TCR Vβ repertoire was analysed by RT-qPCR of bulk CD4[+] T cells and flow cytometry of conventional CD4[+], CD8[+], and regulatory T cell (Treg, CD4[+]FoxP3[+]) subsets. Contrary to expectations, proliferative responses to TSST-1 were significantly lower in BP samples than in controls, while responses to SEG and SEl-I were comparable. RT-qPCR revealed no expansion of Vβ2[+] in bulk CD4[+] T cells, and surface phenotyping detected no enrichment of Vβ2[+] cells within conventional CD4[+] or CD8[+] T populations. In contrast, Vβ2[+] cells were selectively enriched within the Treg compartment. These findings indicate that peripheral T cell responses to TSST-1 are attenuated in BP and are associated with subset-specific skewing of the TCR repertoire. These findings are consistent with increased regulatory features in the peripheral immune compartment that may limit systemic SAg reactivity. Studies examining lesional skin immune populations are needed to determine whether local T cell responses differ from those observed in peripheral blood.

Spleen tyrosine kinase (Syk) regulates immune responses and has been implicated in haematopoietic and epithelial cancers. Although our previous studies showed that Syk modulates keratinocyte differentiation and UVB-induced inflammation, its role in UVB-related cutaneous squamous cell carcinoma (cSCC) remains unclear. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells and is expressed in healthy skin but reduced in non-melanoma skin cancers and sun-exposed skin. This study investigated the role of Syk in cSCC and TRAIL-induced apoptosis. Immunohistochemistry revealed elevated phosphorylated and total Syk levels in SCC tissues compared with normal skin. In SCC12 cells, TRAIL induced dose-dependent apoptosis, which was enhanced by pharmacological Syk inhibition or Syk silencing. Combination treatment with TRAIL and Syk inhibitors increased annexin V positivity and cleavage of caspase-3, PARP1 and Bid, accompanied by reduced Mcl-1 expression. Mechanistically, TRAIL induced Src and Syk phosphorylation. TRAIL-induced Syk activation was suppressed by Src inhibition but not by EGFR inhibition, indicating that Syk activation is Src-dependent but EGFR-independent in this pathway. Syk inhibition further reduced TRAIL-activated Akt and MAPK signalling, while Akt activation may play a role in regulating SCC12 survival. These results suggest that targeting Syk sensitizes TRAIL-mediated apoptosis and may offer a promising therapeutic strategy for treating cutaneous SCC.

Melasma is a chronic relapsing hyperpigmentary disorder with difficult long-term management. In this review, melasma is proposed as a disorder of persistent melanocyte activation sustained within a photoaged dermal microenvironment. This microenvironment, composed of senescent fibroblasts, UV-activated sebocytes and vascular components, functions as a dermal melanogenic field that continuously provides melanogenic signalling. We further propose that melasma may arise within a melanogenic window, a phase characterized by a photoaged dermis and melanocytes that remain responsive to melanogenic stimulation. This window may result from dermal ageing preceding melanocyte ageing. This asynchronous cellular ageing may explain the characteristic midlife onset, chronic relapsing course and later life attenuation of melasma. From a therapeutic perspective, effective long-term management of melasma may require not only suppression of persistent melanocyte activation but also modulation of the photoaged dermal microenvironment.