Journal of dermatological science最新文献

Background: Biallelic pathogenic variants in DSG1 encoding desmoglein 1 cause severe atopic dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, whereas heterozygous variants result in palmoplantar keratoderma (PPK).

Objectives: Here we investigate genetic variants, pathophysiology and clinical findings of three patients with SAM syndrome and eleven patients diagnosed with PPK.

Methods: Genetic analysis was used to identify variants in DSG1. Immunofluorescence staining was performed to determine DSG1 protein expression in SAM patients.

Results: In SAM syndrome and PPK patients eleven novel variants in DSG1 were identified. In the SAM patients with a severe, intermediate and mild phenotype, we identified compound heterozygous, a known dominant, and homozygous variants, respectively, while clinical variability in PPK patients was observed. The variants in DSG1 for SAM and PPK included scarcely reported missense (n = 4), nonsense (n = 4), splice-site (n = 2) variants, a small deletion/duplication (n = 3) and a never reported gross deletion (n = 1). Immunofluorescence staining in skin of SAM patients showed that the severity of the symptoms correlates with total or partial extracellular absence of DSG1, suggesting a potential difference in protein stability. Hence, loss-of-function variants that occur in the extracellular or transmembrane domains of DSG1, resulted in loss of intercellular connecting and anchoring capability, while intracellular variants, partly preserve the adhesive function of DSG1.

Conclusion: Our results contribute to better understanding the genotype-phenotype correlation associated with DSG1 variants, although the exact pathophysiological mechanisms remain to be elucidated.

Background: Transient receptor potential vanilloid 4 (TRPV4) is a calcium ion channel that is widely expressed in various cells, and it regulates multiple physiological and pathological processes. In skin, TRPV4 senses temperature, mechanical and chemical stimuli. Although TRPV4 has been shown to regulate inflammatory in psoriasis, its role in atopic dermatitis (AD) remains unclear.

Objective: We aimed to elucidate the role of TRPV4 is AD pathogenesis and its potential as therapeutic target.

Methods: We used human skin samples from healthy and patients with AD for immunostaining. TRPV4 knock out (KO) mice and MC903-induced AD mouse models were used in vivo. HaCaT cells were used in vitro.

Results: TRPV4 was highly expressed in keratinocytes in lesional skin site of AD. TRPV4 KO mice had less severe dermatitis, barrier dysfunction and pruritus than WT mice in MC903-treated mouse model. TRPV4 KO mice had significantly decreased mRNA expression of type 2 inflammatory cytokines, including TSLP, interleukin (IL)-4, IL-13, and IL-31 via qPCR, and reduced protein levels of TSLP and IL-4 by ELISA. In vitro, oxidative stress promoted expression and activation of TRPV4, following enhanced TSLP expression in HaCaT cells. However, stimulation with IL-4 and IL-13 inhibited TRPV4 activation in HaCaT cells. Finally, treatment with selective TRPV4 antagonist HC-067047 significantly reduced the severity of MC903-induced AD-like dermatitis.

Conclusion: Our findings showed that TRPV4 mediates the expression of keratinocyte-derived TSLP and increases Th2 immunity and pruritus, highlighting TRPV4 as a novel therapeutic strategy for the treatment of AD.

Background: Tonsillectomy improves symptoms in patients with palmoplantar pustulosis (PPP) and suppresses disease progression in patients with pustulotic arthro-osteitis (PAO), highlighting the important role of tonsils in the pathogenesis of PPP/PAO.

Objective: To identify inflammatory pathways involved in the tonsil tissue of patients with PPP/PAO, and to clarify the characteristics of tonsillar microbiota.

Methods: We assessed gene expression in tonsil tissue obtained from PPP/PAO or recurrent tonsillitis (RT)/sleep apnea syndrome (SAS) patients using microarray and quantitative reverse transcription polymerase chain reaction analysis. We also performed a comprehensive analysis of the tonsillar microbiota using next-generation sequencing. Potential associations between tonsillar gene expression and bacterial composition or disease activities were evaluated.

Results: Twenty-five tonsils from PPP/PAO patients and 15 tonsils from RT/SAS patients were included. The gene expression of inflammatory cytokines and molecules involved in the Th17, Th2, and Treg pathways was significantly higher in PPP/PAO tonsils than in RT/SAS tonsils. A significant positive correlation between Streptococcus spp. and the expression of Th17 and Th2 pathway genes was revealed both in PPP/PAO and RT/SAS, however, different correlation patterns were observed between these groups for the other genera. PAO disease activity showed a negative correlation with the expression of CCR4, FOXP3, and CXCR3 genes.

Conclusion: PPP/PAO tonsils exhibit enhanced Th17, Th2, and Treg responses relative to RT/SAS, indicating a complex inflammatory condition. Streptococcus genus may be associated with inflammation, and interaction between microbiota and T cell immunity would be suggested in PPP/PAO tonsils. PAO disease activity inversely correlated with Treg response.

Background: Epidermal hyperinnervation is a partial cause of antihistamine-resistant itch. The nerve repulsion factor semaphorin 3 A (Sema3A) plays a key role in regulating intraepidermal nerve fiber density. In a preliminary study, we screened pre-existing drugs for potential Sema3A inducers and identified benzimidazole anthelmintics as Sema3A inducers in normal human epidermal keratinocytes (NHEKs).

Objective: This study aimed to investigate the mechanisms underlying Sema3A induction by benzimidazole anthelmintics, such as parbendazole, in NHEKs.

Methods: Parbendazole was added to NHEKs or a reconstructed human epidermis (RHE) model and incubated for 24 h at 37°C. Sema3A expression levels were analyzed by quantitative real-time PCR and enzyme-linked immunosorbent assay. Cell viability was assessed using a cell-counting kit-8 assay or methylthiazole tetrazolium assay. The molecular mechanisms of Sema3A induction by parbendazole were examined using signaling inhibitors and siRNAs. Phosphorylation of Jun-N-terminal kinase (JNK) and c-Jun was analyzed by western blotting.

Results: Parbendazole dose-dependently increased Sema3A gene expression and extracellular secretion in NHEKs, with similar results observed in RHE models. Parbendazole also upregulated the expression of the nerve repulsion factor KAL-1 mRNA. Regarding nerve elongation factors, parbendazole decreased nerve growth factor levels, whereas amphiregulin and artemin remained unchanged. Parbendazole promoted JNK and c-Jun phosphorylation in NHEKs. JNK inhibitors suppressed parbendazole-mediated Sema3A induction. Additionally, siRNA targeting c-Jun and the AP-1 inhibitor T-5224 both suppressed parbendazole-induced Sema3A upregulation.

Conclusion: Parbendazole dose-dependently induced Sema3A expression via the JNK/c-Jun signaling axis. Benzimidazole anthelmintics may have potential for developing new antipruritic drugs.