Dysregulation of connexin expression plays a pivotal role in psoriasis

O’Shaughnessy, E. M., Duffy, W., Garcia-Vega, L., Hussey, K., Burden, A. D., Zamiri, M. and Martin, P. E. (2021) Dysregulation of connexin expression plays a pivotal role in psoriasis. International Journal of Molecular Sciences, 22(11), 6060. (doi: 10.3390/ijms22116060) (PMCID:PMC8200029)

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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.

Item Type:Articles
Additional Information:This research was funded by The Psoriasis Association for a PhD studentship (ST3 15) (P.E.M., M.Z. and E.O.), a GCU PhD studentship (L.G.-V.) and a Vascular endowment fund (K.H. during his MD work).
Keywords:Psoriasis, epidermis, connexin26, connexin43, gap junction, hemichannels, connexin mimetic peptide.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Burden, Professor David and Zamiri, Dr Mozheh and Hussey, Keith
Authors: O’Shaughnessy, E. M., Duffy, W., Garcia-Vega, L., Hussey, K., Burden, A. D., Zamiri, M., and Martin, P. E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:International Journal of Molecular Sciences
Publisher:MDPI
ISSN:1422-0067
ISSN (Online):1422-0067
Published Online:04 June 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in International Journal of Molecular Sciences 22(11): 6060
Publisher Policy:Reproduced under a Creative Commons License

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