Purpose:Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe type of drug reaction that has significant mortality rate. Traditional treatments, including glucocorticoids and immunosuppressants, are sometimes insufficient. We present a case of severe paediatric DRESS unresponsive to conventional therapies, in which baricitinib, guided by single-cell RNA sequencing (scRNA-seq), led to clinical improvement. Single-cell transcriptomics is a revolutionary technology that allows scientists to measure the activity of all genes in individual cells on a large scale and has emerged as a tool for personalized therapeutic targeting. Patient and Methods:A 3-year-old male with DRESS triggered by phenobarbital presented with fever, skin rash, impaired liver function, eosinophilia, and cytomegalovirus infection. After failing high-dose corticosteroids, intravenous immunoglobulin, and etanercept, baricitinib was initiated. Peripheral blood mononuclear cells and skin biopsy samples underwent scRNA-seq to identify dysregulated pathways and potential therapeutic targets. Results:Baricitinib treatment led to resolution of skin lesions, normalization of eosinophil counts and liver function, and successful tapering of corticosteroids. Single-cell RNA sequencing uncovered that clusters of CD4+ and CD8+ T cells contain JAK2. Conclusion:Our findings suggest that baricitinib, a JAK1/2 inhibitor, is a safe and effective salvage therapy for corticosteroid-refractory paediatric DRESS. scRNA-seq can guide targeted treatment decisions in DRESS.

Original author’s response to ‘Mechanistic and systemic perspectives on TWEAK in pemphigus vulgaris’

Pemphigus relapse shows a nonrandom, site-specific pattern, with recurrent lesions preferentially occurring at previously affected anatomical locations. In a retrospective cohort of 105 patients, we found that spatial overlap between new-onset and relapse sites significantly exceeded random expectation and was independent of circulating autoantibody levels. Recurrent lesions were enriched for CD4+CD69+ and CD8+CD103+ tissue-resident memory T cells, suggesting a role for localized immune memory in disease recurrence.

BACKGROUND:Atopic dermatitis (AD) patients exhibit a paradox of impaired skin barrier with intense itching, yet often demonstrate rapid re-epithelialization after scratching. While basophils are key effector cells in allergic inflammation, their role in the subsequent tissue repair remains unexplored. OBJECTIVE:We investigated whether basophils, recruited during sensitized skin responses, contribute to wound healing. METHODS:Using single-cell RNA sequencing, flow cytometry, and immunofluorescence, we mapped basophil infiltration and activation in sensitizer (oxazolone)-induced skin injury models. We employed genetic (Mcpt8CT/+R26DTA/+) and antibody-mediated (anti-FcεRI) basophil depletion, as well as basophil-specific Il4/Il13 knockout mice (Il4/13fl/flMcpt8CT/+) to define their functional contribution. Macrophage polarization was assessed by flow cytometry, RT-qPCR, and immunohistochemistry. RESULTS:We identified a significant enrichment of basophils in wounded skin, peaking at day 3-6 post-injury. Sensitizer-challenge enhanced basophil recruitment and accelerated wound closure, angiogenesis, and re-epithelialization. Depletion of basophils severely impaired these repair processes. Mechanistically, basophils were the predominant source of IL-4 and IL-13 in the early wound microenvironment. These cytokines were essential for driving macrophage polarization toward a pro-repair M2 phenotype. Loss of IL4/IL13 specifically in basophils phenocopied the healing defects observed in basophil-deficient mice, and this could be rescued by local cytokine administration. CONCLUSION:Our study uncovers a novel pro-repair function of basophils in sensitizer-exposed skin. Beyond their well-known role in provoking itch and inflammation, basophils are critical for initiating type 2 immune-mediated tissue regeneration via IL-4/IL-13-dependent macrophage reprogramming. This axis represents a promising therapeutic target for chronic wounds, particularly in the context of allergic skin disorders.

BACKGROUND AND PURPOSE:Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by oxidative stress and immune dysregulation. Fibroblast growth factor-inducible 14 (Fn14) has been implicated in tissue injury, but its specific role in SLE pathogenesis remains unclear. This study investigates whether Fn14 modulates disease severity by driving oxidative stress and the subsequent imbalance of Th17/Treg cells. EXPERIMENTAL APPROACH:Lupus was induced in both wild-type and Fn14 knockout mice via pristane administration. Disease severity was evaluated through lupus nephritis, skin lesions and arthritis, along with oxidative stress markers. Proteomic analysis of kidney tissue identified dysregulated redox-regulatory proteins. In vitro, TWEAK-pretreated mouse glomerular mesangial cells were assessed for Fn14-mediated oxidative responses. Flow cytometry quantified the impact of Fn14 on the balance of Th17 and Treg cells. KEY RESULTS:Fn14-deficient mice exhibited significantly reduced lupus severity across all affected organs. This protection was accompanied by decreased oxidative stress markers and increased NRF2 levels. Proteomic analysis confirmed that Fn14 deficiency reversed the dysregulation of multiple redox-regulatory proteins in kidney tissue. In vitro, TWEAK pretreatment sensitized mesangial cells to oxidative challenge, potentiating reactive oxygen species (ROS) generation while simultaneously suppressing antioxidant defences. Furthermore, Fn14 deficiency corrected the Th17/Treg imbalance associated with oxidative stress. CONCLUSION AND IMPLICATIONS:Fn14 deficiency alleviates lupus severity by mitigating oxidative stress and correcting the Th17/Treg imbalance. The TWEAK/Fn14 axis promotes oxidative injury by priming target cells for exaggerated pro-oxidant responses while compromising antioxidant systems. These results highlight the therapeutic potential of targeting Fn14 to counteract oxidative stress and immune dysregulation in SLE.

BACKGROUND:Pemphigus vulgaris (PV) is a severe autoimmune blistering disease characterized by immune inflammatory response imbalance. The role of the proinflammatory cytokine tumour necrosis factor-like weak inducer of apoptosis (TWEAK) in the pathogenesis of PV is unclear. OBJECTIVES:To evaluate the inflammatory status in PV and investigate the role of TWEAK in initiating and exacerbating inflammation, as well as its effects on desmoglein (Dsg) internalization at keratinocyte membranes induced by PV cell models and individual PV IgG components. METHODS:We collected serum samples from 60 patients with new-onset PV and 55 healthy controls, to evaluate correlations between serum anti-Dsg antibody levels and disease severity, inflammatory cytokines [TWEAK, interleukin (IL)-1β, IL-2R, IL-6, IL-10, tumour necrosis factor (TNF)-α] and chemokines (CCL2, CCL5, CXCL8). Subsequently, lesional skin samples from nine patients were collected to analyse local TWEAK, PV IgG expression and immune cell infiltration. Finally, an in vitro PV cell model was established to investigate the inflammatory potential and cell adhesion injury of PV IgG, individual PV IgG components and TWEAK induction. RESULTS:Serum anti-Dsg1 antibody levels in patients with new-onset PV were positively correlated with the Pemphigus Disease Area Index score and levels of inflammatory cytokines (TWEAK, IL-6, TNF-α) and chemokines (CCL5, CXCL8). Furthermore, infiltration of immune cells (neutrophils, macrophages and T cells) was seen in the perilesional areas of skin lesions. In vitro experiments showed that TWEAK exacerbates desmosomal internalization in keratinocytes triggered by PV IgG components. Moreover, PV IgG components induce overexpression of TWEAK and CXCL8 in keratinocytes, whereas IL-6, TNF-α and CCL5 were upregulated via TWEAK-dependent pathways, amplifying inflammatory cascades. CONCLUSIONS:This study found elevated levels of inflammatory cytokines (TWEAK, IL-6, TNF-α) and chemokines (CCL5, CXCL8) in the circulation of patients with PV, which correlated with disease severity. Additionally, localized immune dysregulation involving neutrophils, macrophages and T cells was seen in PV skin lesions. We highlight the involvement of TWEAK in enhancing chemokine expression and cell adhesion injury in PV, which suggests a promising therapeutic avenue targeting TWEAK and inflammatory cytokines in the management of PV.

Objective Cardiac involvement is a major cause of morbidity in systemic lupus erythematosus (SLE). Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is elevated in SLE, but its contribution to lupus-associated cardiac injury is unclear. We investigated the role of TWEAK/fibroblast growth factor-inducible 14 (Fn14) signaling in SLE-related cardiomyopathy and its potential as a biomarker and therapeutic target.Methods Serum TWEAK, inflammatory cytokines, autoantibodies, and oxidative stress markers were measured in 242 patients with SLE and 66 age- and sex-matched controls, with correlation to echocardiographic, electrocardiographic, and myocardial enzyme findings. Cardiac pathology and redox signaling were assessed in pristane-induced lupus models using wild-type mice and mice deficient of Fn14 by histopathology, immunoblotting, immunofluorescence, and quantitative proteomics. Direct effects of TWEAK on mitochondrial oxidative stress, antioxidant signaling, and apoptosis were examined in primary cardiomyocytes isolated from MRL/lpr mice who were lupus prone.Results Serum TWEAK levels were significantly elevated in patients with SLE and were highest in those with cardiac abnormalities compared with healthy controls. TWEAK correlated positively with malondialdehyde, 8-hydroxy-2'-deoxyguanosine, disease activity, and inflammatory cytokines and inversely with superoxide dismutase. Elevated baseline TWEAK predicted new cardiac abnormalities during follow-up and declined with clinical improvement. In mice with lupus, Fn14 deficiency reduced cardiac reactive oxygen species accumulation, restored Nrf2/HO-1 antioxidant signaling, attenuated histopathological injury, and preserved cardiac function. In vitro, TWEAK induced mitochondrial superoxide production, suppressed Nrf2 signaling, and promoted apoptosis in lupus-prone cardiomyocytes.Conclusion TWEAK/Fn14 signaling drives oxidative stress-mediated cardiomyocyte injury in SLE and represents a promising biomarker and therapeutic target for lupus-associated cardiac damage.

Insect-related dermatitis (IRD) has emerged as a significant public health concern. However, its risk distribution and epidemic dynamics remain poorly understood. Here, we project the current and future risk distributions of dermatitis-causing insects (DCIs) across China. The maximum entropy modeling was adopted to project the suitability distribution of eight main DCIs. Our findings reveal a significant concentration of risk distributions for both DCIs and IRD southeast of the Heihe-Tengchong Line in China. Furthermore, our projections indicate that most DCIs are expected to experience an increase in their suitability distribution under future climate change. These shifts are closely related to future changes of temperature and precipitation. Further field validation of key DCIs confirmed that the observed suitable regions would expand northward with growing temperature and precipitation. Collectively, the above results revealed the risk distribution of DCIs and IRD in China, providing valuable references for disease management and prevention of IRD.

Bullous pemphigoid (BP) is a chronic autoimmune blistering disorder characterized by dermal-epidermal separation and immune cell infiltration. The mechanisms underlying epithelial barrier dysfunction in BP remain incompletely understood. Here, we identify transforming growth factor alpha (TGF-α) as a key regulator of BP pathogenesis through disruption of cellular junctions and induction of pro-inflammatory responses. Elevated TGF-α levels in BP lesions correlated with disease severity. Mechanistically, TGF-α downregulated BP180 expression, upregulated matrix metalloproteinases (MMPs), and enhanced chemokine secretion in keratinocytes via epidermal growth factor receptor (EGFR) activation and downstream phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling. Pharmacological inhibition of EGFR and PI3K/Akt pathways mitigated these effects, highlighting their critical roles in disease progression. Additionally, tumor necrosis factor-like weak inducer of apoptosis (TWEAK) signaling was found to amplify TGF-α secretion, further exacerbating inflammatory responses. These findings suggest that TGF-α drives BP pathogenesis by compromising cell adhesion and promoting tissue inflammation. Targeting TGF-α or its downstream effectors may offer novel therapeutic strategies for BP treatment.

Elevated periostin levels are commonly observed in conditions characterised by increased IgE and eosinophilia, such as bullous pemphigoid (BP), which typically presents with eosinophil infiltration and elevated IgE levels. To explore the link between periostin levels and key clinical parameters in BP, serum periostin levels were assessed in 55 classic BP patients and 55 healthy controls using ELISA. Upon admission, the BP Disease Area Index (BPDAI) score, autoantibody levels, and peripheral blood immune cells of BP patients were evaluated. The investigation also employed the Olink proteomic platform to analyse circulating proinflammatory biomarkers. The results indicated significantly higher periostin levels in BP patients, showing a strong positive correlation with BPDAI scores, which was more pronounced compared to the correlation between BPDAI scores and BP 180 IgG or eosinophil counts. Correlation analysis revealed positive links between periostin levels in serum and attributes such as urticaria/erythema lesions, total IgE levels, serum BP180 IgG, BP180 IgE, BP230 IgE, and blood eosinophil counts. The findings from the Olink proteomic analysis provided additional evidence of the connection between periostin and type II inflammation in BP, which was further validated by the observed positive correlation between periostin and IL-13 using ELISA. Furthermore, it was observed that serum periostin levels decreased post-effective treatment. Overall, this study underscores a compelling association between periostin expression and the activity and severity of BP, as well as its reflection of type II inflammation.

Tissue-resident memory T (Trm) cells, once heralded as gatekeepers of localized immune protection, have emerged as central players in the pathogenesis of chronic inflammation and autoimmunity at epithelial barriers. At the heart of this immunological paradox lies the dynamic interplay between Trm and regulatory T (Treg) cells-a tissue-encoded checkpoint that calibrates immune defense against the need for tolerance and repair. Disruption of this axis unleashes the latent pathogenicity of Trm cells, fueling persistent inflammation, epithelial dysfunction, and disease relapse. Here, we propose that the Trm-Treg interaction acts as a molecular rheostat that tunes immune homeostasis at barrier sites. We dissect the tissue-specific mechanisms that sustain this alliance, highlight its failure in diseases such as inflammatory bowel disease (IBD), psoriasis, and chronic obstructive pulmonary disease (COPD), and explore emerging therapeutic strategies aimed at recalibrating this immune checkpoint to restore durable epithelial tolerance.

INTRODUCTION:The accumulation of reactive oxygen species (ROS) in diabetic wounds leads to inflammation and impaired neovascularization. Recent studies have indicated that carbon dot nanozymes (C-dots) exhibiting superoxide dismutase (SOD)-like activity can neutralize excessive ROS and mitigate diseases associated with oxidative stress. OBJECTIVES:Our study was designed to evaluate the therapeutic impact of C-dots on the healing of diabetic wounds and to unravel the complex molecular mechanisms through which these nanozymes modulate oxidative stress and inflammatory responses within the wound microenvironment. METHODS AND RESULTS:We synthesized C-dots from carbon fiber and confirmed their structure using transmission electron microscopy. The presence of carbon-carbon double bonds on the C-dots was verified with X-ray photoelectron spectroscopy. We assessed the scavenging capacity of C-dots for superoxide anion, hydroxyl radical, and nitric oxide radical using electron spin resonance spectroscopy. Their SOD-like activity and total antioxidant capacity were evaluated with commercial assay kits. In vitro experiments showed that C-dots effectively scavenged excessive ROS, protecting human keratinocytes, vascular endothelial cells, and fibroblasts from oxidative stress-induced damage. Concurrently, C-dots increased the migratory capacity of fibroblasts. In a streptozocin-induced diabetic mice model, C-dots application enhanced skin wound healing, evidenced by accelerated re-epithelialization and orderly collagen matrix assembly. Mechanistic investigations indicated that C-dots markedly suppressed ROS generation and diminished the levels of inflammatory cytokines in the wound environment. Additionally, C-dots induced an M2 polarization phenotype in macrophages and promoted neovascularization, indicating a transition from the inflammatory to the proliferative phase. Quantitative proteomic analysis was conducted to further clarify the underlying mechanisms of C-dots in ameliorating diabetic wounds. CONCLUSION:C-dots represent a robust nanomaterial-based strategy for treating diabetic wounds, with the ability to accelerate healing by alleviating oxidative stress, mitigating harmful inflammatory responses, and fostering angiogenesis. This highlights their significant therapeutic potential in the field of biomedicine.

Lipocalin 2 (LCN2) and the TWEAK/Fn14 signaling pathways are pivotal in psoriasis, influencing epidermal development, inflammatory cell chemotaxis, and inflammatory factor release. Despite their significant roles, the intricate relationship between LCN2 and TWEAK/Fn14 pathways remains unclear. Our study revealed the correlation between the expression of TWEAK, LCN2, and Fn14 in psoriatic lesions. We found that TWEAK is expressed by keratinocytes and macrophages, while LCN2 is expressed by keratinocytes and neutrophils. Surface plasmon resonance experiments demonstrated binding between LCN2 and Fn14, which was further validated by co-immunoprecipitation and cellular co-localization via immunofluorescence. In vitro, LCN2 promoted macrophage differentiation and TWEAK secretion, enhanced TWEAK and Fn14 expression in keratinocytes, and activated the MAPK signaling pathway. TWEAK upregulated LCN2 expression in neutrophils but not in keratinocytes. Bulk RNA-seq analysis revealed a synergistic effect of LCN2 and TWEAK in promoting inflammatory cytokine expression in keratinocytes, with enhanced MAPK pathway activation in the presence of M5 cytokines. Lcn2 knockout reduced Fn14 expression in skin lesions and serum TWEAK levels of imiquimod-induced murine psoriasis model, while Fn14 knockout attenuated the epidermal hyperplasia-promoting effects of TWEAK and LCN2. Overexpression of Fn14 in keratinocytes led to higher TWEAK expression upon LCN2 stimulation, suggesting a self-reinforcing loop among TWEAK, LCN2, and Fn14. We propose that LCN2 synergizes with TWEAK through Fn14 to drive psoriasis pathogenesis.

Background Rosacea is a common chronic inflammatory skin disease. Mast cells are implicated in the pathogenesis of rosacea. However, the therapeutic potential of tranilast, a mast cell membrane stabilizer, remains unexplored. This study aims to evaluate the efficacy and safety of tranilast monotherapy and in combination with minocycline in patients with moderate-to-severe rosacea.Methods This study has been registered on ClinicalTrials.gov (Registration No. NCT06307223). All enrolled patients with rosacea were randomly assigned to receive tranilast, minocycline, or a combination of both. Tranilast (0.1 g, three times daily) and minocycline (50 mg, once daily) were administered for 12 weeks, with follow-up every two weeks.Results Forty-five patients completed the study. At week 12, the combination group showed a significantly higher IGA success rate (93.33%) compared to the tranilast (53.33%) and minocycline (46.67%) groups (p < 0.05). The secondary endpoints, such as CEA success rate, erythema index, and erythema score, also favored the combination group over minocycline group (p = 0.021, 0.030, and 0.024, respectively).Conclusion In our study, patients with moderate to severe rosacea treated with tranilast showed a favorable clinical response and experienced no serious adverse events. The combination therapy yielded better outcomes than minocycline monotherapy, especially in improving facial erythema.

Pemphigus is a severe autoimmune blistering disease characterized by acantholysis triggered by autoantibodies against desmoglein 1 and 3 (DSG1/3). Apoptosis plays a pivotal role in facilitating acantholysis, yet the precise underlying mechanism remains obscure. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to promote apoptosis and disrupt cell junctions, although its involvement in pemphigus pathogenesis remains ambiguous. Our study observed decreased DSG1/3 expression alongside increased TWEAK/fibroblast growth factor-inducible 14 (Fn14) expression and keratinocyte apoptosis in both lesional and perilesional skin. In vitro experiments revealed that TWEAK-stimulated keratinocytes exhibited enhanced apoptosis, STAT1 phosphorylation, and reduced intercellular DSG1/3 expression. Notably, bulk-RNA sequencing unveiled that CASPASE-3 was responsible for mediating the DSG1/3 depletion, as confirmed by direct interaction with DSG1/3 in a co-immunoprecipitation assay. Naloxone, known for preserving cellular adhesion and preventing cell death, effectively reduced apoptosis and restored DSG1/3 levels in TWEAK-stimulated keratinocytes. The anti-apoptotic properties of naloxone were further validated in a murine pemphigus model. Our findings elucidate that TWEAK facilitates keratinocyte apoptosis by augmenting caspase-3 activity, leading to DSG1/3 depletion and apoptosis in pemphigus. Importantly, naloxone can counter TWEAK-induced apoptosis in pemphigus pathogenesis, offering a potential therapeutic intervention.