Experimental Dermatology最新文献

Hidradenitis suppurativa (HS) is an autoinflammatory skin disease characterised by deep-seated and painful nodules, abscesses and draining tunnels that extensively penetrate the dermis in the axillae, inguinal and gluteal areas. The exact aetiology remains unclear. However, current evidence suggests that HS originates from an intrinsic defect within the hair follicle, leading to follicular obstruction, cyst development and eventual rupture, which triggers an inflammatory reaction. The initiation, progression and maintenance of the disease may involve functional abnormalities in keratinocytes (KCs), significantly contributing to the production of proinflammatory cytokines within and around the affected tissue and increased infiltration of immune cells. This review synthesises current evidence on KCs in HS, emphasising their genetic background and metabolic dysregulation. It comprehensively evaluates the cytokine milieu influenced by KCs within affected tissues. Notably, it highlights the diverse phenotypes of KCs within draining tunnels, underscoring their heterogeneity and implications for disease progression.

Alopecia areata is a typical skin disease with unmet needs. So far, it has been understood that the main cause of the intractability of chronic cases is the decrease in inflammatory cell infiltration and falling into the telogen-like phase. However, in some cases, even in long-term chronic cases, inflammatory cell infiltration can be seen, so that we speculate that the long-term persistence of these perifollicular cells may be the reason for the lack of improvement as skin resident memory T (T_RM) cells. To investigate the presence of T_RM, nine treatment-resistant chronic AA patients and 5 acute AA patients were employed for staining with CD69 and CD103 as markers for identifying skin T_RM cells. This study revealed the number of CD8⁺CD103⁺ T and CD69⁺CD103⁺ T cells tended to increase with increasing disease duration and refractoriness. In one case of AA refractory to conventional treatment, an oral JAK inhibitor (JAKi) showed dramatic efficacy with a reduction in the number of infiltrating CD103⁺ cells, including CD8⁺CD103⁺ T and CD69⁺CD103⁺ T cells. These results suggest that refractory cases in the chronic phase tend to have more infiltrating skin T_RM cells, and JAKi may be effective in the refractory cases of chronic AA.

Matrix metalloproteinases (MMPs) are involved in the degradation of the extracellular matrix (ECM) and are found to participate in all stages of tumour progression including modifying signalling pathways, regulating cytokines and promoting tumour growth, particularly by inducing angiogenesis and facilitating cancer spread. Extensive research has been concentrated on identifying and developing MMP inhibitors for cancer treatment, including melanoma, with particular focus on MMP-2, MMP-9 and MMP-14. MMP-2 and MMP-9 are gelatinases involved in collagen degradation, tumour invasion and angiogenesis, while MMP-14 activates other MMPs and promotes tumour cell migration. Early broad-spectrum MMP inhibitors showed limited success and significant side effects. However, selective MMP inhibitors offer a more targeted approach that may address these problems. By focusing on specific MMPs essential for melanoma invasion, metastasis and angiogenesis, these inhibitors have the potential to improve treatment efficacy and reduce the off-target effects seen with earlier broad-spectrum therapies. Recent years have seen a marked increase in studies on natural MMP inhibitors for melanoma, driven by their biocompatibility and reduced side effects. In addition to inhibiting MMPs, many of these inhibitors also provide antioxidant, anti-inflammatory and immune-modulatory benefits, thus enhancing their therapeutic potential and overall effectiveness in cancer treatment. These findings highlight the promising role of MMP inhibitors in melanoma therapy, suggesting a shift towards more targeted and combinatory treatment strategies. This review aims to provide an up-to-date overview of the advancements and therapeutic prospects of both synthetic and natural MMP inhibitors in melanoma treatment.

Abnormal NF-κB activity has been previously implicated in a range of immune-mediated disorders. Here, we aimed to elucidate the genetic basis underlying the co-occurrence of vitiligo, Addison's disease and granuloma annulare in a 43-year-old woman. Whole-exome sequencing identified a heterozygous splice-site variant (c.1364+1G>A, p.Met455fsTer1) in IKBKB, encoding the Inhibitor of κB kinase subunit beta (IKKβ), predicted to result in a premature stop codon. Immunoblotting of keratinocytes transfected with the mutant construct demonstrated the presence of a truncated form of IKKβ. Using a luciferase reporter assay under the control of NF-κB–responsive element, we demonstrated significantly reduced activity of the mutant protein compared to wild-type, supporting a loss-of-function mechanism. In line with this observation, the mutant protein was found to result in decreased expression levels of genes known to be regulated by NF-κB. Furthermore, HeLa cells transfected with the p.Met455fsTer1 variant or IKBKB-targeted siRNA exhibited markedly reduced levels of p105 and its processed form p50, compared with HeLa cells transfected with wild-type IKBKB or control siRNA, respectively. Collectively, these findings indicate that a loss-of-function effect in IKBKB may underlie the co-occurrence of a number of immune-mediated disorders through disruption of NF-κB signalling.

Enhancer of Zeste Homologue 2 (EZH2) is an epigenetic regulator involved in immune cell differentiation and function; however, its role in psoriasis remains unknown. This study aimed to evaluate EZH2 expression in peripheral blood mononuclear cells from patients with psoriasis and explore its potential functional relevance to disease pathogenesis. Peripheral blood samples were obtained from 40 psoriasis patients and 18 healthy controls, and EZH2 expression in T cell and monocyte subsets was analysed by flow cytometry. EZH2 expression was significantly reduced in circulating CD8+ naïve and memory T cells, as well as in monocyte subsets from psoriasis patients compared to healthy controls. EZH2 levels in CD8+ naïve T cells showed a significant inverse correlation with disease severity scores. Functional analyses revealed that pharmacological EZH2 inhibition suppressed IL-17A expression in peripheral blood mononuclear cells under IL-23/IL-1β stimulation. In addition, immunofluorescence staining identified EZH2-positive T cells and monocytes within psoriatic skin lesions. Collectively, these findings suggest that EZH2 may be involved in the regulation of type 3 inflammatory responses and may therefore represent an epigenetic regulator contributing to psoriasis pathogenesis.