Abstract

Sweet syndrome (SS) as a prototypic neutrophilic dermatosis (NDs) shares certain clinical and histologic features with monogenic auto-inflammatory disorders in which interleukin (IL)-1 cytokine family members play an important role. This has led to the proposal that NDs are polygenic auto-inflammatory diseases and has fuelled research to further understand the role of IL-1 family members in the pathogenesis of NDs. The aim of this study was to characterise the expression of the IL-1 family members IL-1β, IL-36γ, IL-33 and IL-1R3 (IL-1RaP) in SS. The expression profile of IL-1β, IL-33, IL-36γ and their common co-receptor IL-1R3 was analysed by immunohistochemistry, in situ hybridisation and double immunofluorescence (IF) in healthy control skin (HC) and lesional skin samples of SS. Marked overexpression of IL-1β in the dermis of SS (p < 0.001), and a non-significant increase in dermal (p = 0.087) and epidermal (p = 0.345) IL-36γ expression compared to HC was observed. Significantly increased IL-1R3 expression within the dermal infiltrate of SS skin samples (p = 0.02) was also observed, whereas no difference in IL-33 expression was found between SS and HC (p = 0.7139). In situ hybridisation revealed a good correlation between gene expression levels and the above protein expression levels. Double IF identifies neutrophils and macrophages as the predominant sources of IL-1β. This study shows that IL-1β produced by macrophages and neutrophils and IL-1R3 are significantly overexpressed in SS, thereby indicating a potential pathogenic role for this cytokine and receptor in SS.

The effect of ageing of the same donor on dermal fibroblast heterogeneity was tested in a dermal fibroblast lineage (ASF-4 cell lineage) isolated from the inner side of the upper arm of a healthy male donor (age 36) for 35 years. Single-cell RNA sequencing of cultured cells frozen at Passage 10 at the age of 36 and 72 years showed that genes involved in extracellular matrix remodelling were downregulated with donor ageing, which is a different observation from those reported in the previous studies. Based on the scRNA-Seq results, we identified a cellular senescence-associated gene EFEMP2.

Abstract

The aim of this study is to examine the effects of ageing on dermal fibroblast heterogeneity based on samples obtained from the same donor. We used a dermal fibroblast lineage (named ASF-4 cell lines) isolated from the inner side of the upper arm of a healthy male donor over a 35-year period, beginning at 36 years of age. Because clonal analysis of ASF-4 cell lines demonstrated a donor age-dependent loss of proliferative capacity and acquisition of senescent traits at the single-cell level, cultured cells frozen at passage 10 at ages 36 and 72 years were subjected to single-cell RNA sequencing. Transcriptome analysis revealed an increase in senescent fibroblasts and downregulation of genes associated with extracellular matrix remodelling with ageing. In addition, two putative differentiation pathways, with one endpoint consisting of senescent fibroblasts and the other without, were speculated using a pseudo-time analysis. Knockdown of the characteristic gene of the non-senescent fibroblast cluster endpoint, EFEMP2, accelerated cellular senescence. This was also confirmed in two other normal human dermal fibroblast cell lines. The detection of a common cellular senescence-related gene from single-donor analysis is notable. This study provides new insights into the behaviour of dermal fibroblasts during skin ageing.

Abstract

Psoriasis, a well-established T-cell mediated dermatosis, exhibits a robust correlation with obesity and systemic inflammation, manifesting psoriasis skin lesions and premature immunosenescence within the peripheral blood and lesion. Intermittent fasting (IF) has exhibited various beneficial effects in reducing inflammation, resisting oxidative stress and slowing ageing, as well as losing weight. A form of IF known as time-restricted feeding (TRF) restricts daily caloric intake within 4–8 h. Nonetheless, the advantageous impacts of TRF on psoriasis still require further verification. We measured the acanthosis in Imiquimod (IMQ)-induced psoriasis mice and evaluated their pathological phenotypes. Our study examined the effects of a 2-week TRF on body weight and metabolic parameters. The subsets of T cells in spleens and skin lesions were accessed by flow cytometry. Cytokines and senescence-associated genes were evaluated by immunofluorescence and RT-qPCR. RNA sequencing was conducted on skin lesions. According to our findings, a 2-week TRF attenuates psoriasis-like lesions in mice with reduced inflammatory cytokines and mitigated immunosenescence. TRF increased the counts of CD4⁺ T_reg cells in skin lesions while reducing the counts of Th₂ and Th₁₇ cells in spleens. Furthermore, the administration of TRF resulted in a decrease in the population of CD4⁺ senescent T cells in both the dermis and spleens, concomitant with the expression of senescence-associated genes in spleen CD4⁺ T cells. The outcomes mentioned above provide valuable evidence in support of TRF for the management of psoriasis.

Abstract

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune skin disease which occurs independently and in conjunction with systemic lupus erythematosus. Drug development for CLE is severely lacking. Anandamide (AEA) is a primary endocannabinoid which exhibits immunomodulatory effects through mixed cannabinoid receptor agonism. We evaluated AEA as topical treatment for CLE and assessed benefits of nanoparticle encapsulation (AEA-NP) on cutaneous drug penetration, delivery and biological activity. Compared to untreated controls, AEA-NP decreased IL-6 and MCP-1 in UVB-stimulated keratinocytes (p < 0.05) in vitro. In BALB/c mice, AEA-NP displayed improved cutaneous penetration, extended release and persistence of AEA in the follicular unit extending to the base after 24 h. Utilizing the MRL-lpr lupus murine model, twice weekly treatment of lesions with topical AEA-NP for 10 weeks led to decreased clinical and histologic lesion scores compared to unencapsulated AEA and untreated controls (p < 0.05). Prophylactic application of AEA-NP to commonly involved areas on MRL-lpr mice similarly resulted in decreased clinical and histologic scores when compared to controls (p < 0.05), and reduced C3 and IBA-1 in lesional tissue (p < 0.05). The demonstrated clinical and immunomodulatory effects of treatment with AEA support its potential as therapy for CLE. This work also suggests that encapsulation of AEA improves penetration and treatment efficacy. Future studies will be conducted to assess full therapeutic potential.

Abstract

The formation of hypertrophic scars and keloids is strongly associated with mechanical stimulation, and myofibroblasts are known to play a major role in abnormal scar formation. Wounds in patients with neurofibromatosis type 1 (NF1) become inconspicuous and lack the tendency to form abnormal scars. We hypothesized that there would be a unique response to mechanical stimulation and subsequent scar formation in NF1. To test this hypothesis, we investigated the molecular mechanisms of differentiation into myofibroblasts in NF1-derived fibroblasts and neurofibromin-depleted fibroblasts and examined actin dynamics, which is involved in fibroblast differentiation, with a focus on the pathway linking LIMK2/cofilin to actin dynamics. In normal fibroblasts, expression of α-smooth muscle actin (α-SMA), a marker of myofibroblasts, significantly increased after mechanical stimulation, whereas in NF1-derived and neurofibromin-depleted fibroblasts, α-SMA expression did not change. Phosphorylation of cofilin and subsequent actin polymerization did not increase in NF1-derived and neurofibromin-depleted fibroblasts after mechanical stimulation. Finally, in normal fibroblasts treated with Jasplakinolide, an actin stabilizer, α-SMA expression did not change after mechanical stimulation. Therefore, when neurofibromin was dysfunctional or depleted, subsequent actin polymerization did not occur in response to mechanical stimulation, which may have led to the unchanged expression of α-SMA. We believe this molecular pathway can be a potential therapeutic target for the treatment of abnormal scars.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease in which defective T cells, immune complex deposition and other immune system alterations contribute to pathological changes of multiple organ systems. The vitamin D metabolite c is a critical immunomodulator playing pivotal roles in the immune system. Epidemiological evidence indicates that vitamin D deficiency is correlated with the severity of SLE. Our aim is to investigate the effects of 1,25(OH)2D3 (VitD3) on the activation of myeloid dendritic cells (mDCs) by autologous DNA-containing immune complex (DNA-ICs), and the effects of VitD3 on immune system balance during SLE. We purified DNA-ICs from the serum of SLE patients and isolated mDCs from normal subjects. In vitro studies showed that DNA-ICs were internalized and consumed by mDCs. VitD3 blocked the effects of DNA-ICs on RelB, IL-10 and TNF-α in mDCs. Further analysis indicated that DNA-ICs stimulated histone acetylation in the RelB promoter region, which was inhibited by VitD3. Knockdown of the histone deacetylase 3 gene (HDAC3) blocked these VitD3-mediated effects. Co-culture of mDCs and CD4⁺ T cells showed that VitD3 inhibited multiple processes mediated by DNA-ICs, including proliferation, downregulation of IL-10, TGF-β and upregulation of TNF-α. Moreover, VitD3 could also reverse the effects of DNA-IC-induced imbalance of CD4⁺ CD127⁻ Foxp3⁺ T cells and CD4⁺ IL17⁺ T cells. Taken together, our results indicated that autologous DNA-ICs stimulate the activation of mDCs in the pathogenesis of SLE, and VitD3 inhibits this stimulatory effects of DNA-ICs by negative transcriptional regulation of RelB gene and maintaining the Treg/Th17 immune cell balance. These results suggest that vitamin D may have therapeutic value for the treatment of SLE.

Abstract

The latest generation ultraviolet (UV) dermatoscopes, which emit UV light at a wavelength of 365 nm and enlarge lesions, are practical devices that can facilitate the diagnosis and follow-up of some dermatological diseases with fluorescence that can be observed in skin lesions. In 305 patients, 468 tunnels were evaluated: first in polarized mode and later in UV mode. The recorded samples were compared one-to-one by the same dermatologist. Due to the study's design, images were examined in three stages: tunnel borders, tunnel content and mite appearance. In UV mode, the entire body of mites gives a bright reflex along with an oval-shaped diagnostic clue well beyond the delta sign. The borders of the tunnel reflect brightly in UV mode, with borders that are more sharply visible than in polarized mode. Although the tunnel content cannot be clearly distinguished in polarized mode, especially in people with hyperkeratotic palms, or ‘working hands’ (e.g. farmers, mechanics and construction workers), with the bright reflex, the tunnel borders in UV mode give a bright reflection and provide a clear view of tunnels. Tunnel content gives a bright reflection in UV mode. Our results show that UV dermatoscopes provide more effective and clearer images than polarized dermatoscopes in the diagnosis of scabies.