Nemolizumab demonstrates efficacy against pruritus and eczema by inhibiting IL-31 signaling in patients with atopic dermatitis. However, its effect on the systemic immune response at the molecular level remains unknown. In this study, we aimed to elucidate it by investigating plasma proteins and pathways modulated by nemolizumab under concomitant topical treatment. Plasma protein profiling was conducted for 25 Japanese patients with atopic dermatitis who received a single 60 mg dose of nemolizumab at baseline and 1, 2, 4, and 8 weeks after administration using the SomaScan 7k assay. Proteome data were analyzed through differential expression, linear regression, and enrichment analyses, which revealed upregulation of pathways such as neutrophil degranulation and integrin signaling, alongside downregulation of PTEN signaling. Although nemolizumab did not induce substantial changes at the individual protein level, it tended to reverse disease-associated alterations in many key pathways, as revealed by enrichment analysis using proteins with statistically significant but modest expression changes. In addition, we identified pathways and proteins—including TARC (thymus and activation-regulated chemokine)/CCL17—that were associated with pruritus and eczema severity. In conclusion, proteins and pathways involved in the systemic immune response modulated by nemolizumab were identified, potentially reflecting its therapeutic effects. The M525101-05 study (jRCT2080225290) was registered on July 22, 2020, and the MIT-502 study (jRCT1030230474) was registered on November 22, 2023.

BackgroundSalbutamol is a well-established β2-adrenergic receptor agonist used clinically for the reversal of bronchospasm. A functional β2-adrenergic receptor agonist network exists in the skin, which can alter skin cell migration and proliferation, inhibit angiogenesis, and alter wound re-epithelialization, suggesting a potential role for a β2-adrenergic receptor agonist applied topically for the prevention and treatment of scarring. Reduced scarring has been observed in an in vivo pig model, whereby a 50% reduction in skin scar area and hyperpigmentation was observed after topical application of salbutamol. Objectives: We conducted a double-blind, placebo-controlled, randomized, dose-escalation clinical trial. This was designed to investigate both the safety and efficacy of topical salbutamol for the improvement of scar appearance when applied as a cutaneous gel to sutured wound margins on the arms of healthy volunteers. Methods: In a phase I, single-center, double-blind, placebo (vehicle) controlled, randomized, dose-escalation trial on 45 healthy human volunteers, 1 ml salbutamol topical gel was administered once daily to one 2-cm full-thickness incision site on each arm of the trial participants for 60 days. Each participant was allocated to only 1 dosing group (group 1: 2.5 mM, group 2: 5 mM, and group 3: 10 mM). Pharmacokinetic and clinical assessments of safety and efficacy were performed over a 12-month period. Scarring was assessed by validated clinical scoring systems by both investigator and participant over 12 months. Results: In healthy human volunteers, tolerability assessments indicated zero incidences of edema, exudate, bleeding, or infection at any salbutamol-treated site irrespective of dose. All participants at every time point had peak plasma levels of salbutamol below the prespecified limit of 30 ng/ml. In efficacy assessments of the scars, no statistically significant improvements were noted in the mean difference between salbutamol-treated scars at any dose compared with placebo at months 7, 9, or 12 for either the investigator or participants’ assessments. Conclusions: There are no clinically significant safety signals after the cutaneous administration of salbutamol gel (0.2–10 mM) in humans either local to the site of injury and drug administration or arising from systemic exposure to salbutamol, but the extent of salbutamol absorption decreases as the wound heals, confirming that re-epithelialization of the wound limits the potential for systemic absorption. This trial was prospectively registered with the Medicines and Healthcare products Regulatory Agency with the European Union Drug Regulating Authorities Clinical Trials (EudraCT number: 2017-003118-15).

Mucosal-associated invariant T (MAIT) cells are a unique subset of innate-like T lymphocytes that recognize microbial-derived vitamin B metabolites presented by the nonpolymorphic MR1 (major histocompatibility complex class I–related protein). These cells comprise about 1–10% of circulating T cells in humans and are abundant at mucosal surfaces, including the skin. MAIT cells possess a semi-invariant TCR (typically, TRAV1-2/TRAJ33 in humans) and can be activated by riboflavin metabolites such as 5-OP-RU (5-[2-oxopropylideneamino]-6-d-ribitylaminouracil) and 5-OE-RU (5-2-oxoethylideneamino]-6-d-ribitylaminouracil) as well as through cytokine-mediated pathways independent of MR1. Upon activation, MAIT cells quickly produce proinflammatory cytokines, including IFN-γ, TNF-α, and IL-17, and perform cytotoxic functions by releasing granzyme B and perforin. This review thoroughly explores the role of MAIT cells in skin immunity and skin diseases. We detail their involvement in inflammatory skin conditions such as psoriasis, atopic dermatitis, and hidradenitis suppurativa, where alterations in MAIT cell numbers and functions have been observed. The review also addresses MAIT cells’ roles in wound healing, tissue repair, and antimicrobial defense within the skin. Furthermore, we evaluate the potential of targeting MAIT cells for therapy, including how current treatments affect them and the development of new immunometabolic strategies. Gaining a better understanding of MAIT cell biology in skin contexts could provide new insights into the development of skin diseases and lead to innovative dermatological treatments.

Remote, noninvasive biospecimen collection methods can address geographic and mobility-related barriers to participation in translational research for connective tissue disorders. We evaluated the feasibility of combining noninvasive skin tape stripping and Tasso capillary blood collection to molecularly profile lupus and morphea in remote settings using mailed kits. RNA extraction was optimized from 20 serial tape strips per site, with overnight shipping and scraping samples in buffer without sonication, yielding the highest concentration and quality. We enrolled 8 patients with lupus, 3 patients with morphea, and 8 healthy controls. Microarray analysis identified upregulation of CXCL9, CCR6, and PDGFRA in lupus and morphea skin. Proteomic analysis revealed elevated IFN-γ, TNFRSF4, and ANGPT2 in lupus serum, with lower IL-13 than in controls. Morphea samples showed increased expression of markers, including PDGFRA, P2RX1, and KALRN. Distinct gene expression signatures of CTGF, TNFRSF4, and MAFB in lupus skin and ALOX15, KALRN, and P2RX1 in morphea skin enabled differentiation between morphea and lupus. CXCL9 and IFN-γ biomarkers were confirmed in other publicly available datasets at both the protein and RNA levels. These findings provide proof of concept that remote RNA and protein profiling is feasible and reproducibly identifies canonical and, to our knowledge, previously unreported disease markers; however, the small number of patients and the lack of more complete characterization of the participants studied require that further studies are needed to establish the role of these findings in the pathogenesis of lupus and morphea. This approach enables broader inclusion of underserved patients and offers a scalable model for remote biomarker studies in dermatologic and autoimmune research.

Skin transplantation is commonly used to compensate for normal cutaneous tissues in full-thickness wounds or surgically excised skin. Despite complete termination of initial blood flow, transplanted skin usually maintains its dermal and epidermal structures without scar formation. However, the precise role of engrafted cells in maintaining epidermal and dermal homeostasis remains unclear. In this study, we investigated the chronological changes in neonatal full-thickness skin grafts on mice at the histological and single-cell transcriptomic levels. We found devastating necrotic changes in the dermal and epidermal tissues on postoperative day 3, followed by significant regeneration of follicular and interfollicular tissues after postoperative day 6. We identified a unique mesenchymal subpopulation that expressed keratinocyte-specific genes (keratin 5 gene Krt5, Epcam, and Irf6) involved in mesenchymal–epithelial transition. Mesenchymal cells transitioning to epithelial cells showed keratinocyte differentiation activity both in vitro and in vivo. These results highlight the contribution of unique mesenchymal cell populations to epithelial regeneration after severe necrosis of a skin graft.

Patients with neurofibromatosis type 1 develop multiple cutaneous neurofibromas (cNFs) for which no effective drug therapy exists; mainstay treatment remains physical removal. However, clinical trials testing new drugs are ongoing, and quantitative techniques based on cNF biology are needed to measure changes in cNF after treatment. cNF tumor bulk is composed of extracellular matrix and inflammatory cells that dictate their stiffness. No studies have reported measuring the stiffness change in neurofibromas, which would indicate shrinking of the tumor bulk. The goal of this study was to evaluate 2 different instruments—the Rex Gauge durometer (denoted as REX) and the Delfin SkinFibroMeter (denoted as DELFIN)—in reproducibly measuring cNF stiffness. Ninety-seven neurofibromas from patients with neurofibromatosis type 1 on different skin areas were measured at each of 2 visits about 2 weeks apart. The DELFIN had moderate within-tumor agreement (intraclass correlation coefficient = 0.607, 95% confidence interval = 0.512–0.691) and moderate within-visit agreement (intraclass correlation coefficient = 0.732, 95% confidence interval = 0.665–0.786), and the REX had moderate within-tumor agreement (intraclass correlation coefficient = 0.740, 95% confidence interval = 0.631–0.816) and excellent within-visit agreement (intraclass correlation coefficient = 0.937, 95% confidence interval = 0.913–0.953), while accounting for repeated visits and tumor measurements clustered within each patient. We found that both the DELFIN and REX are easy to use and reliable, providing consistent quantification of cNF stiffness.