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Abstract Psoriasis is an immune-mediated skin disease associated with neurogenic inflammation, but the underlying molecular mechanism remains unclear. We demonstrate here that acid-sensing ion channel 3 (ASIC3) exacerbates psoriatic inflammation through a sensory neurogenic pathway. Global or nociceptor-specific Asic3 knockout (KO) in female mice alleviates imiquimod-induced psoriatic acanthosis and type 17 inflammation to the same extent as nociceptor ablation. However, ASIC3 is dispensable for IL-23-induced psoriatic inflammation that bypasses the need for nociceptors. Mechanistically, ASIC3 activation induces the activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons to promote neurogenic inflammation. Botulinum neurotoxin A and CGRP antagonists prevent sensory neuron-mediated exacerbation of psoriatic inflammation to similar extents as Asic3 KO. In contrast, replenishing CGRP in the skin of Asic3 KO mice restores the inflammatory response. These findings establish sensory ASIC3 as a critical constituent in psoriatic inflammation, and a promising target for neurogenic inflammation management.

Abstract Immune cell trafficking, an essential mechanism for maintaining immunological homeostasis and mounting effective responses to infections, operates under a stringent regulatory framework. Recent advances have shed light on the perturbation of cell migration patterns, highlighting how such disturbances can propagate inflammatory diseases from their origin to distal organs. This review collates and discusses current evidence that demonstrates atypical communication between the gut and skin, which are conventionally viewed as distinct immunological spheres, in the milieu of inflammation. We focus on the aberrant, reciprocal translocation of immune cells along the gut-skin axis as a pivotal factor linking intestinal and dermatological inflammatory conditions. Recognizing that the translation of these findings into clinical practices is nascent, we suggest that therapeutic strategies aimed at modulating the axis may offer substantial benefits in mitigating the widespread impact of inflammatory diseases.

Abstract Cutaneous squamous carcinoma is the second most common epithelial malignancy, associated with significant morbidity, mortality, and economic burden. However, the mechanisms underlying cSCC remain poorly understood. In this study, we identified TGM3 as a novel cSCC tumor suppressor that acts via the PI3K-AKT axis. RT-qPCR, IHC and western blotting were employed to assess TGM3 levels. TGM3-overexpression/knockdown cSCC cell lines were utilized to detect TGM3’s impact on epithelial differentiation as well as tumor cell proliferation, migration, and invasion in vitro. Additionally, subcutaneous xenograft tumor models were employed to examine the effect of TGM3 knockdown on tumor growth in vivo. Finally, molecular and biochemical approaches were employed to gain insight into the tumor-suppressing mechanisms of TGM3. TGM3 expression was increased in well-differentiated cSCC tumors, whereas it was decreased in poor-differentiated cSCC tumors. Loss of TGM3 is associated with poor differentiation and a high recurrence rate in patients with cSCC. TGM3 exhibited tumor-suppressing activity by regulating cell proliferation, migration, and invasion both in vitro and in vivo. As a novel cSCC tumor differentiation marker, TGM3 expression was positively correlated with cell differentiation. In addition, our results demonstrated an interaction between TGM3 and KRT14 that aids in the degradation of KRT14. TGM3 deficiency disrupts keratinocytes differentiation, and ultimately leads to tumorigenesis. Furthermore, RNA-sequence analysis revealed that loss of TGM3 enhanced EMT via the PI3K-AKT signaling pathway. Deguelin, a PI3K-AKT inhibitor, blocked cSCC tumor growth induced by TGM3 knockdown in vivo. Taken together, TGM3 inhibits cSCC tumor growth via PI3K-AKT signaling, which could also serve as a tumor differentiation marker and a potential therapeutic target for cSCC. Proposed model depicted the mechanism by which TGM3 suppress cSCC development. TGM3 reduces the phosphorylation level of AKT and degrades KRT14. In the epithelial cell layer, TGM3 exhibits a characteristic pattern of increasing expression from bottom to top, while KRT14 and pAKT are the opposite. Loss of TGM3 leads to reduced degradation of KRT14 and activation of pAKT, disrupting keratinocyte differentiation, and eventually resulting in the occurrence of low-differentiated cSCC.

ObjectivesNumerous observational studies have reported associations between circulating cytokines and atopic dermatitis (AD); however, the causal relationships between them remain unclear. To explore the causal correlations and direction of causal effects between AD and levels of 91 circulating cytokines.MethodsTwo-sample Mendelian randomization (MR) analyses were conducted to examine the causal relationships between 91 circulating cytokines and AD using summary statistics from genome-wide association studies (GWAS). Reverse MR analyses were performed to investigate reverse causation. Pleiotropy and heterogeneity tests were conducted to assess the robustness of the findings. Additional transcriptome database and clinical peripheral blood mononuclear cells (PBMCs) samples were utilized to validate the results of MR analyses.ResultsLevels of interleukin (IL)-13, IL-18 Receptor 1, Tumor necrosis factor ligand superfamily member 14 (TNFSF14), TNF-related activation-induced cytokine (TRANCE), C-X-C motif chemokine (CXCL)11, IL-33, TNF-beta and CD5 were suggestively associated with the risk of AD (odds ratio, OR: 1.202, 95% CI: 1.018–1.422, p = 0.030; OR: 1.029, 95% CI: 1.029–1.157, p = 0.004; OR: 1.159, 95% CI: 1.018–1.320, p = 0.026; OR: 1.111, 95% CI: 1.016–1.214, p = 0.020; OR: 0.878, 95% CI: 0.783–0.984, p = 0.025; OR: 0.809, 95% CI: 0.661–0.991, p = 0.041; OR: 0.945, 95% CI: 0.896–0.997, p = 0.038; OR: 0.764, 95% CI: 0.652–0.895, p = 8.26e-04). In addition, levels of cytokines including Axin-1, CXCL5, CXCL10, Oncostatin-M (OSM), Sulfotransferase 1A1 (SULT1A1) and TNFSF14 were suggested to be consequences of AD (Beta: -0.080, p = 0.016; Beta: -0.062, p = 0.036; Beta: -0.066, p = 0.049; Beta: -0.073, p = 0.013; Beta: -0.089, p = 0.008; Beta: -0.079, p = 0.031). IL-13, IL-18R1, TNFSF14, and TRANCE were upregulated in both lesional skin biopsies and PBMCs from AD patients.ConclusionThe study indicates that several cytokines, including IL-13, IL-18R1, TNFSF14, TRANCE, CXCL11, IL-33, TNF-beta, and CD5, are upstream of AD development, whereas a few circulating cytokines are potentially downstream in the development of AD.

Dedicator of cytokinesis 8 (DOCK8) deficiency represents a primary immunodeficiency with a wide range of clinical symptoms, including recurrent infections, atopy, and increased malignancy risk. This study presents a case of a 6-year-old girl with DOCK8 deficiency, characterized by severe, treatment-resistant herpetic infections who was successfully treated with siltuximab and glucocorticoids. The successful use of siltuximab in achieving remission highlights the pivotal role of interleukin-6 (IL-6) in DOCK8 deficiency pathogenesis and suggests that IL-6 modulation can be critical in managing DOCK8 deficiency-related viral infections, which may inform future therapeutic strategies for DOCK8 deficiency and similar immunodeficiencies.

Background Atopic dermatitis (AD) has a reported prevalence of 3% in adolescents aged 13-14 years in China. However, studies evaluating the efficacy and safety of Janus kinase 1-selective inhibitors in AD in patients from China are limited. Abrocitinib is an oral, once-daily, Janus kinase 1-selective inhibitor approved for the treatment of moderate-to-severe AD in adults and adolescents in the United States and in adults in China. The efficacy of abrocitinib as monotherapy or in combination with medicated topical therapy has been demonstrated in multiple phase 3 clinical trials in adolescent and adult patients with moderate-to-severe AD. In a separate phase 3 trial of adolescent patients (JADE TEEN [NCT03796676]), abrocitinib administered in combination with medicated topical therapy was effective in improving the signs and symptoms of moderate-to-severe AD, with an acceptable safety profile. JADE TEEN was conducted in several countries, including China. Objective To assess the efficacy and safety of abrocitinib in combination with topical therapy in Chinese adolescents with moderate-to-severe AD enrolled in JADE TEEN. Methods: In JADE TEEN, adolescent patients (aged 12 to 17 years) were randomly assigned (1:1:1) to receive abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 weeks in combination with medicated topical therapy. This post hoc analysis included data from patients enrolled in JADE TEEN from mainland China. Assessments included the proportion of patients at week 12 who achieved an Investigator's Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with a =2-grade improvement from baseline, =75% improvement from baseline in Eczema Area and Severity Index (EASI-75), and =4 point improvement from baseline in Peak Pruritus Numerical Rating Scale (PP-NRS4; used with permission from Regeneron Pharmaceuticals, Inc., and Sanofi). Change from baseline in Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) total score at week 12 was also assessed. Safety was assessed by treatment emergent adverse event (TEAE) monitoring. Results: Of 285 patients enrolled in JADE TEEN, 52 (18.2%) were enrolled from mainland China and consisted of 14, 18, and 20 patients who were randomly assigned to receive abrocitinib 200 mg, abrocitinib 100 mg, and placebo, respectively. Median age at baseline was 15.0 years (interquartile range [IQR], 14.0-17.0 years), and median duration since onset of AD was 9.8 (IQR, 4.4-13.7) years. At week 12, a higher proportion of patients treated with abrocitinib at either dose compared with placebo achieved efficacy responses of IGA 0/1 (abrocitinib 200 mg, 46.2%; abrocitinib 100 mg, 46.7%; placebo, 22.2%), EASI-75 (69.2%; 73.3%; 27.8%), and PP-NRS4 (63.6%; 50.0%; 20.0%). Decreases from baseline in PSAAD total score were greater in patients treated with abrocitinib at either dose compared to placebo at week 12 (abrocitinib 200 mg, -3.4; abrocitinib 100 mg, -3.2; placebo, -1.8). Response rates were largely comparable between patients from China and the overall JADE TEEN study population, although CIs were wider in the China subgroup because of the small sample size. In the China subgroup, TEAEs were experienced by 13 (92.9%), 16 (88.9%), and 15 (75.0%) patients in the abrocitinib 200 mg, abrocitinib 100 mg, and placebo groups, respectively. Compared to the overall population, there were no new safety signals identified in patients from China. Conclusions: Abrocitinib administered in combination with medicated topical therapy was effective and well tolerated in adolescent patients from China with moderate-to-severe AD. Efficacy and safety findings were consistent with the overall JADE TEEN population. [ABSTRACT FROM AUTHOR]