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.
Highlights
Psoriasis is a chronic inflammatory skin condition affecting 2–3% of the population, characterised by epidermal hyperproliferation triggered primarily by a T-cell mediated response, i.e., “inside-out” signalling events [1]
Semi-quantitative analysis of nuclei staining in dermal layers confirmed enhanced inflammatory cell infiltrate in psoriatic tissue that was two-fold higher for psoriatic border regions (PN) and four-fold higher in psoriatic plaque (PP) regions than normal controls (NN) biopsies (Figure 1f)
We report for the first time a detailed comparison of the gene and protein expression profiles of CX26 and CX43 in NN, PN and PP tissue biopsies
Summary
Psoriasis is a chronic inflammatory skin condition affecting 2–3% of the population, characterised by epidermal hyperproliferation triggered primarily by a T-cell mediated response, i.e., “inside-out” signalling events [1]. Increased expression of the gap junction protein connexin (CX26), encoded by GJB2/CX26, was first reported in psoriatic tissue in the 1990s [7,8]. RNAseq analysis determined that CX26 was within the top 100 genes upregulated in the psoriatic transcriptome [9], the role of CX26 in psoriasis and differential levels of expression within plaque border areas have not been studied in detail. Six connexins assemble to form normally closed hemichannels (HC) in the plasma membrane, followed by intercellular alignment and docking with neighbouring hemichannels to form intercellular gap junctions These channels enable the exchange of metabolites and signalling molecules throughout the avascular epidermis. Exposure of normal fibroblasts to the pro-inflammatory mediator peptidoglycan, isolated from Staphylococcus aureus enhanced cytokine release, an event protected by Gap. Inhibition of connexin signalling reduces pro-inflammatory events and may hold therapeutic benefit
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