The Journal of investigative dermatology最新文献

Skin barrier dysfunction initiates or deteriorates various cutaneous problems, such as atopic dermatitis. At high concentrations, the nonreducing disaccharide trehalose (α-d-glucopyranosyl α-d-glucopyranoside) induces a transient senescence-like state in fibroblasts and promotes wound repair. In this study, we investigated the effect of trehalose on normal human keratinocytes and demonstrated its specific role in the skin barrier. RNA-sequencing analysis revealed that trehalose regulates the expression of many skin barrier-associated genes. T helper 2 cytokines IL-4/IL-13 were observed to downregulate several differentiation markers (FLG, loricrin, keratin 1, and keratin 10) and epidermal antimicrobial proteins in monolayer-cultured keratinocytes and living skin equivalents and impaired skin barrier function in living skin equivalents, all of which were significantly upregulated or restored by trehalose. Trehalose inhibited IL-33 expression and reduced nuclear IL-33 levels by activating MAPK/extracellular signal-regulated kinase kinase 5-extracellular signal-regulated kinase 5 and suppressing extracellular signal-regulated kinase kinase 1/2-extracellular signal-regulated kinase pathway. It also increased NRF2 activation to trigger antioxidant enzyme production through JNK, thus neutralizing IL-4/IL-13-mediated oxidative stress. Trehalose prevented IL-4/IL-13-mediated signal transducer and activator of transcription 3/signal transducer and activator of transcription 6 activation and restored IL-4/IL-13-suppressed skin barrier molecules through IL-33 downregulation and NRF2 activation. This study demonstrated that trehalose may play a role in skin barrier repair in atopic dermatitis.

Vδ1 T cells are a subpopulation of γδT cells found in human dermis. Much less is known regarding their role and function in skin health and disease than regarding the roles of murine skin-resident γδT cells. In this study, we report the successful integration of Vδ1 T cells into long-term fibroblast-derived matrix skin equivalents. We isolated Vδ1 T cells from human blood, where they are rare, and established conditions for the integration and maintenance of the freshly isolated Vδ1 T cells in the skin equivalents. Plated on top of the dermal equivalents, almost all Vδ1 T cells migrated into the dermal matrix where they exerted their influence on both the dermal equivalents and the epithelium. Vδ1 T cells contributed to epidermal differentiation of HaCaT cells as indicated by histology, expression of epidermal differentiation markers, and RNA-sequencing expression profile. When complemented with the carcinoma-derived SCC13 cells instead of HaCaT, our data suggest a role for Vδ1 T cells in slowing growth of the tumor cells, as indicated by reduced stratification and changes in gene expression profiles. Together, we demonstrate the successful establishment of human Vδ1 T cell-competent skin equivalents and skin carcinoma equivalents and provide evidence for molecular and functional consequences of the Vδ1 T cells on their respective environment.

Imaging Mass Cytometry (IMC) is a technology that enables comprehensive analysis of cellular phenotypes at the tissue level. We performed a multi-parameter characterization of structural and immune cell populations in psoriatic skin and synovial tissue samples aimed at characterizing immune cell differences in patients with psoriasis, psoriatic arthritis (PsA). A panel of 33 antibodies was used to stain selected immune and structural cell populations. IMC data were segmented into single cells based on combinations of antibody stains. Single cells were then clustered into cell categories based on pre-specified markers. The spatial relationships of different cell populations were assessed using neighborhood analysis. Among all cell types in the skin and synovium, lymphoid cells accounted for the most prevalent cell type. T cells and macrophages were the most prevalent immune cell type in the synovium and B cells and NK cells were also identified. Neighborhood analysis showed high correlation between synovial T cells, B cells, macrophages, dendritic cells and neutrophils suggesting spatial organization. Innate and adaptive immune cells can be reliably identified using IMC in skin and synovium. Inter-patient heterogeneity exists in tissue cell populations. IMC provides opportunities for exploring in depth underlying immunological mechanisms driving psoriasis and PsA.

T-cell-mediated oral mucocutaneous inflammatory conditions including oral lichen planus (OLP) are common but development of new treatments aimed at relieving symptoms and controlling OLP progression are hampered by the lack of experimental models. Here, we developed a tissue-engineered oral mucosal equivalent (OME) containing polarised T-cells to replicate OLP pathogenesis. Peripheral blood CD4+ and CD8+ T-cells were isolated, activated and polarised into Th1 and cytotoxic T-cells (Tc). OME were constructed by culturing oral keratinocytes on an oral fibroblast-populated hydrogel to produce a stratified squamous epithelium. OME stimulated with IFN-γ and TNF-α or medium from Th1 cells caused increased secretion of inflammatory cytokines/chemokines. A model of T-cell-mediated inflammatory disease was developed by combining OME on top of a Th1/Tc-containing hydrogel, followed by epithelial stimulation with IFN-γ/TNF-α. T-cell recruitment towards the epithelium was associated with increased secretion of T-cell chemoattractants CCL5, CXCL9 and CXCL10. Histological assessment showed tissue damage associated with cleaved-caspase-3 and altered laminin-5 expression. Treatment with inhibitors directed against JAK, K_Ca3.1 channels or clobetasol in solution and/or via a mucoadhesive patch prevented cytokine/chemokine release and tissue damage. This disease model has potential to probe for mechanisms of pathogenesis or as a test platform for novel therapeutics or treatment modalities.

Targeted systemic immune-modulating drugs (IMDs) to treat atopic dermatitis (AD) were highly efficacious in randomized trials. Trials with limited number of subjects leave questions about their safety. We describe a data and analytics structure for the production of timely, high-quality evidence on the comparative safety of recently approved IMDs in patients with AD in clinical practice. We established a series of sequential propensity score (PS)-balanced cohorts that grow in size with each annual data refresh. Nine health outcomes of interest plus conjunctivitis as a positive tracer outcome were identified. The initial treatment comparison was dupilumab, an interleukin-4/13 inhibitor, or tralokinumab, an interleukin-13 inhibitor, versus abrocitinib/upadacitinib, both JAK inhibitors. The first analysis cycle (December 2021-February 2023) compared 269 patients initiating JAK inhibitors and 2,650 initiating IL-4/IL-13 inhibitors. Patient characteristics were well balanced after PS-matching. Outpatient infections within 180 days occurred in 18% of JAK-1 inhibitor initiators versus 12% of dupilumab/ tralokinumab initiators (RR=1.50; 0.96 to 2.33) whereas acne risks were 7% vs. 3%, respectively (RR=2.29, 0.96 to 5.46). This sequential monitoring system will produce essential knowledge on the safety of IMDs to treat AD based on its growing study size of patients observed in clinical practice.