Desmoglein-4 Deficiency Exacerbates Psoriasiform Dermatitis in Rats While Psoriasis Patients Displayed a Decreased Gene Expression of DSG4

Abstract

Desmogleins are involved in cell adhesion conferring structural skin integrity. However, their role in inflammation has been barely studied, and whether desmoglein-4 modulates psoriasis lesions is completely unknown. In this study, we assessed the impact of desmoglein-4 deficiency on the severity of imiquimod (IMQ)-induced skin inflammation and psoriasiform lesions. To this end, desmoglein-4−/− Oncins France Colony A (OFA) with Sprague–Dawley (SD) genetic background were used. Additionally, human RNA-Seq datasets from psoriasis (PSO), atopic dermatitis (AD), and a healthy cohort were analyzed to obtain a desmosome gene expression overview. OFA rats displayed an intense skin inflammation while SD showed only mild inflammatory changes after IMQ treatment. We found that IMQ treatment increased CD3+ T cells in skin from both OFA and SD, being higher in desmoglein-4-deficient rats. In-depth transcriptomic analysis determined that PSO displayed twofold less DSG4 expression than healthy samples while both, PSO and AD showed more than three-fold change expression of DSG3 and DSC2 genes. Although underlying mechanisms are still unknown, these results suggest that the lack of desmoglein-4 may contribute to immune-mediated skin disease progression, promoting leukocyte recruitment to skin. Although further research is needed, targeting desmoglein-4 could have a potential impact on designing new biomarkers for skin diseases.

Desmosomes as Signaling Hubs in the Regulation of Cell Behavior

“…Treatment of DSG4-deficient rats with the TLR7 ligand imiquimod induced a skin inflammation with increased expression of the pro-inflammatory cytokines IL-1β and IL-8. Although the molecular mechanisms are unclear and experiments using isolated keratinocytes are missing, these data suggest a role for DSG4 in suppressing TLR-mediated inflammatory processes ( Moreno-Sosa et al, 2021 ). In contrast to the suprabasal DSG1 and DSG4 isoforms, basally expressed DSG3 appeared to promote inflammation.…”

Insights into Nutritional Strategies in Psoriasis

“…There are known to be a few global gene knock-in or knockout mouse models developing a Ps-like phenotype ( Supplementary Material Table S1 ) or other genetic designs that modulate mutant alleles [ 76 , 77 ]. Supplementary Material Table S1 presents the main engineered mouse models of Ps [ 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ].…”

Contribution of Dysregulated DNA Methylation to Autoimmunity

“…Psoriasis is linked to aberrant crosstalk between dendritic cells, T cells, and keratinocytes to produce multiple inflammatory cytokines and growth factors [ 78 , 79 , 80 , 81 , 82 ]. Strikingly, although extensive studies over immune skin cells have been done, regulation of the immune response by DNA methylation in psoriasis has barely been addressed.…”