Dysregulation of Connexin Expression Plays a Pivotal Role in Psoriasis

Abstract

Background: Psoriasis, a chronic inflammatory disease affecting 2–3% of the population, is characterised by epidermal hyperplasia, a sustained pro-inflammatory immune response and is primarily a T-cell driven disease. Previous work determined that Connexin26 is upregulated in psoriatic tissue. This study extends these findings. Methods: Biopsies spanning psoriatic plaque (PP) and non-involved tissue (PN) were compared to normal controls (NN). RNA was isolated and subject to real-time PCR to determine gene expression profiles, including GJB2/CX26, GJB6/CX30 and GJA1/CX43. Protein expression was assessed by immunohistochemistry. Keratinocytes and fibroblasts were isolated and used in 3D organotypic models. The pro-inflammatory status of fibroblasts and 3D cultures was assessed via ELISA and RnD cytokine arrays in the presence or absence of the connexin channel blocker Gap27. Results: Connexin26 expression is dramatically enhanced at both transcriptional and translational level in PP and PN tissue compared to NN (>100x). In contrast, CX43 gene expression is not affected, but the protein is post-translationally modified and accumulates in psoriatic tissue. Fibroblasts isolated from psoriatic patients had a higher inflammatory index than normal fibroblasts and drove normal keratinocytes to adopt a “psoriatic phenotype” in a 3D-organotypic model. Exposure of normal fibroblasts to the pro-inflammatory mediator peptidoglycan, isolated from Staphylococcus aureus enhanced cytokine release, an event protected by Gap27. Conclusion: dysregulation of the connexin26:43 expression profile in psoriatic tissue contributes to an imbalance of cellular events. Inhibition of connexin signalling reduces pro-inflammatory events and may hold therapeutic benefit.

The human Discs large protein (Dlg1) interacts with and maintains Connexin 43 at the plasma membrane in keratinocytes

“…2 A,B). Cx43 is normally associated with the lower layers, which comprise less-differentiated epithelial cells ( O'Shaughnessy et al, 2021 ), therefore these differences might reflect the capacity for differentiation of the individual cell types. Co-immunoprecipitation experiments showed that anti-Dlg1 antibody could immunoprecipitate Dlg1 and Cx43 from cell lysates of HaCaT, HEK293 and NIKS cells ( Fig.…”

Multi‐omics integration reveals a core network involved in host defence and hyperkeratinization in psoriasis

“…Activated neutrophils then produce proinflammatory mediators, such as cytokines (IL36β/γ) 57 and AMPs (LCN2, S100A12), in the skin. 58 These proinflammatory mediators stimulate the keratinocytes leading to hyperkeratinization ultimately leading to the overexpression of keratinocyte differentiation markers (SPRR1B/2A/2D/2E, GJB2/6) [59][60][61] and proteases (KLK7/13). 62 Overall, our results indicate that using a multi-omics approach we can help identify the core pathways involved in the pathogenesis of psoriasis.…”

Connexins in epidermal health and diseases: insights into their mutations, implications, and therapeutic solutions

“…Its levels were slightly elevated in some studies (Labarthe et al, 1998), while others reported a decrease in psoriatic lesions (Liang et al, 2019). This discrepancy might be explained by recent findings suggesting that Cx43 in psoriatic tissues underwent post-translational modifications, especially phosphorylation that might interfere with Cx43 biogenesis rather than increased mRNA production (O'Shaughnessy et al, 2021). Interestingly, IL-22, a cytokine involved in psoriatic keratinocyte hyperproliferation, seems to downregulate Cx43 expression, further hindering GJIC (Liang et al, 2019).…”