Potential of a bacterial immunomodulatory enzyme to restore health in a Th17 cytokine cocktail-induced skin psoriasis model

Psoriasis is a chronic disorder, characterized by immune dysregulation and inflammation, presenting in the form of hyperproliferation and impaired differentiation of keratinocytes. Th17-type cytokines are pivotal in regulating dendritic cell activation, antigen processing and presentation, cell adhesion and migration. Th17 cells are also critical for the production of cytokines and chemokines central to the development and progression of psoriasis. Here, streptococcal C5a peptidase (ScpA), a potent anaphylatoxin, was investigated as a potential anti-inflammatory therapeutic agent in a Th17 cytokine-induced pathogenesis of psoriasis in vitro model. Preclinical healthy human keratinocyte-derived epidermal equivalents (HEEs) were developed using neonatal human epidermal keratinocytes. Psoriatic HEEs were generated by stimulating HEEs with a Th17 cytokine cocktail (IL-17 and IL-22). These psoriatic HEEs were then treated with ScpA and a standard psoriasis medication, retinoic acid (RA). Histological analysis and barrier function assays revealed that the cellular barrier integrity was compromised under psoriatic conditions induced by the Th17 cytokine cocktail. While treatment with either ScpA and RA significantly restored the barrier function, superior restoration was achieved by ScpA. Additionally, immunofluorescence and gene expression studies showed a reversal of psoriatic HEEs towards a phenotype resembling healthy HEEs following treatment with both drugs. ScpA does not cleave IL-17 or IL-22 directly, but it has been shown to cleave complement factors C5a and C3 and IFN-γ, mediators known to be upregulated in psoriatic inflammation. Thus, this study suggests that ScpA, a bacterial immunomodulatory enzyme, can modulate a downstream Th17-driven inflammatory response. • Healthy human epidermis equivalents (HEEs) were generated • Th-17 cytokines induced psoriatic conditions in the generated HEEs • Streptococcal C5a peptidase (ScpA) restored health in Th-17 induced psoriatic HEEs • ScpA dampens psoriatic disease progression irrespective of the triggering cytokines