Potential of a bacterial immunomodulatory enzyme to restore health in a Th1 cytokine cocktail induced skin psoriasis-like model.

Psoriasis is a chronic inflammatory disorder driven by immune dysregulation. A common characteristic is hyperproliferation and aberrant differentiation of keratinocytes. Th1-type cytokines, containing TNFα, IL-1α and IL-6, play a role in various cellular processes such as the activation of dendritic cells, antigen processing and presentation, cell adhesion and migration, as well as cytokine and chemokine production. They are believed to be key contributors to the pathogenesis of psoriasis. In this work, healthy human epidermis equivalents (HEEs) were developed using neonatal human epidermal keratinocytes. Psoriatic-like HEEs were created by stimulating healthy HEEs with a Th1 cytokine cocktail containing TNFα, IL-1α and IL-6. Streptococcal C5a peptidase (ScpA), a powerful anaphylatoxin, was investigated as a potential anti-inflammatory therapeutic in this model. Although ScpA does not cleave any of these cytokines directly, it has been reported to cleave complement factors, C5a and C3, and the inflammatory cytokine, interferon gamma - all markers elevated in psoriasis. Histological and barrier function studies revealed that the cellular barrier was compromised under psoriatic-like conditions induced by the Th1 cytokine cocktail, while treatment with ScpA and retinoic acid restored the barrier function. Immunofluorescence and gene expression analyses further demonstrated that treatment with ScpA promoted the recovery of psoriatic-like HEEs towards a healthy HEE phenotype. Taken together, the results indicated that ScpA provided greater restoration of health in an in vitro Th1 cytokine cocktail-induced psoriasis-like model than a standard psoriasis drug.