British Journal of Dermatology最新文献

Background and objectives: Arginase1 (ARG1) is an enzyme expressed by keratinocytes that drives several functions linked to skin barrier function. However, the mechanisms underpinning keratinocyte ARG1 function in barrier homeostasis is not fully elucidated. Atopic dermatitis (AD) is linked to impaired skin barrier via altered keratinocyte differentiation and susceptibility to infection. Therefore, we investigated the role of ARG1 in keratinocyte differentiation and anti-microbial responses.

Methods: In vitro 2D differentiation assays using ARG knockdown or ARG inhibited keratinocytes were used to explore the function of ARG1 in keratinocyte differentiation and barrier formation. ARG1 was also assessed in an ex vivo model of AD.

Results: ARG1 was strongly expressed in the apical layers of human skin, corresponding with high ARG1 expression in late differentiated keratinocytes. ARG was downregulated in an ex vivo AD model relative to controls, suggesting altered ARG1 is clinically relevant. ARG1 inhibition in keratinocytes led to a significant decrease in late differentiation markers Filaggrin (FLG), Involucrin (IVL), and Loricrin (LOR) and significant downregulation of the Anti-microbial Peptides (AMPs), Lipocalin 2 (LCN2), Kallikreins (KLKs) and Small Proline Rich Proteins (SPRRs). ARG forms part of the urea cycle and the action of ARG on L- arginine causes the production of L-ornithine and urea. L-ornithine, in turn, is catabolised for putrescine (Put) production. Supplementation with ARG products, Put and urea, could rescue late keratinocyte differentiation and AMP expression in ARG deficient cells.

Conclusions: ARG1 activity plays a major role in keratinocyte differentiation and AMP production. ARG1 is downregulated in AD, but in cell systems is amenable to rescue by ARG1 downstream products Put and urea. Manipulation of the ARG1 pathway may, therefore, have potential to be used for the management of skin conditions such as AD.

Background: Observational studies have demonstrated a close association between polyunsaturated fatty acids (PUFAs) and acne. However, the findings of clinical trials have been inconsistent, leaving the causal relationship between PUFAs and acne unclear.

Objectives: To investigate the causal association between genetically proxied PUFAs and acne risk.

Methods: Mendelian randomization (MR) was performed using single-nucleotide polymorphisms associated with PUFAs as instrumental variables. The causal associations between PUFAs and acne were estimated among 115,006 UK biobank participants and 363,927 participants of Finnish descent.

Results: Genetically predicted docosahexaenoic acid (DHA) levels (Beta= -0.303; 95% CI: -0.480 to -0.126; p = 7.74E-04) and its percentage to total fatty acids (Beta= -0.402; 95% CI: -0.651 to -0.258; p = 5.91E-06) showed a significant causal association with a decreased risk of acne. Conversely, genetically predicted percentages of linoleic acid (LA) in total fatty acids (Beta=0.768; 95% CI: 0.411-0.126; p = 2.87E-04) and omega-6: omega-3 (Beta=0.373; 95% CI: 0.142-0.604; p = 4.48E-03) were robustly associated with an increased risk of acne. These effects were attenuated after excluding a genetic variant of rs174528 located upstream of fatty acid desaturase 1 (FADS1), highlighting the biological link between FADS1 and delta-5 desaturase activity. Multivariable MR analysis indicated that PUFAs were causally associated with acne, independent of body mass index.

Conclusions: Our study indicates that high DHA levels and their ratios to total fatty acids have causal protective effects against acne, while high LA levels and omega-6: omega-3 ratio are associated with increased acne risk. This association was largely attributable to the influence of genetic variants related to FADS1.

Background: Epidermal differentiation disorders (EDDs, a.k.a. ichthyosis and palmoplantar keratoderma) are severe heritable skin conditions characterized by localized or generalized skin scaling and erythema.

Objectives: To identify novel genetic variants causing palmoplantar keratoderma (PPK) and progressive symmetric erythrokeratoderma (PSEK) phenotypes.

Methods: We performed whole exome sequencing in a large EDD cohort including PPK and PSEK phenotypes to identify novel genetic variants. We investigated the variant consequence using in silico predictions, assays in patient keratinocytes, high-resolution spatial transcriptomics, and quantitative cytokine profiling.

Results: We identified three unrelated kindreds with autosomal dominant transmission of heterozygous SLURP1 variants affecting the same amino acid within the signal peptide (c.65C>A, p.A22D, and c.65C>T, p.A22V). One (p.A22V) had isolated PPK, and two others (p.A22D) had PSEK and PPK. In silico modeling suggested that both variants alter pro-SLURP1 cleavage, appending two amino acids to the secreted protein, which we subsequently confirmed with mass spectrometry. In patient keratinocytes we found increased differentiation-induced SLURP1 expression and secretion compared to healthy control cells. Spatial transcriptomics revealed increased NF-κB signaling and innate immune activity which may contribute to epidermal hyperproliferation in dominant SLURP1-PPK/PSEK.

Conclusions: Our results expand the phenotypic spectrum of EDD due to SLURP1 pathogenic variants. While autosomal recessive Mal de Meleda is due to biallelic loss-of-function SLURP1 variants, our finding of autosomal dominant SLURP1 pathogenic variants in kindreds with PPK and PSEK suggests a novel mechanism of action. We found that heterozygous p.A22V and p.A22D SLURP1 variants append two amino acids to secreted SLURP1, increase differentiation-induced SLURP1 expression and secretion, and upregulate NF-κB signaling in PSEK cases.