This last decade, it has been established that antagonism of IL-17 is sufficient to reverse psoriasis features. IL-17 mainly secreted by Th-17 T-cells is now considered as the psoriasis main driver (Guttman-Yassky and Krueger, 2017).

In the search for specific strategies to improve skin resilience towards inflammation, we designed a 3D in vitro human reconstructed epidermis (RHE) model that recapitulates activated CD4+ T cells-mediated conditions of psoriasis driven by Th-17 cytokines (IL-17A and TNF-). Our data demonstrated an increase of psoriasis biomarkers at the mRNA levels, including IL-19, IL-23, DEFB4 and S100A7, as well as IL-19 and IL-23 levels in tissue culture supernatants. Full-transcriptome testing identified additional deregulated genes from 4 major psoriasis-related pathways, i.e. antimicrobial defenses, chemotaxis and inflammatory response (mainly linked to the NF-κB pathway).
Signal transduction was further characterized based on primary keratinocytes, which were challenged following the same protocol as for the RHE. We demonstrated the activation of NF-κB by transactivation assay, and identified STAT3 and PPAR through the transcription factor activation profiling technology.
Recent publications recognized IκBζ, an atypical nuclear IκB protein encoded by the NFKBIZ gene (nuclear factor of κ light polypeptide gene enhancer in B cells inhibitor ζ), as a key driver in the development of psoriasis (Johansen et al., 2015). IκBζ is critically involved in the downstream effects of IL-17 and was identified as a key transcriptional regulator of psoriasis signature genes (Muller et al., 2018). Furthermore, NFKBIZ has been identified as a psoriasis susceptibility locus (Tsoi et al., 2015). We demonstrated from both RHE and monolayer keratinocytes that a synergistic stimulation with IL-17 and TNF- strongly up-regulates NFKBIZ and results in IκBζ accumulation.

The relevance of the model was further demonstrated through the pre-clinical development of TEM1657, a first-in-class API candidate targeting IκBζ for the treatment of psoriasis.

In vitro Th-17 inflammatory skin models as a promising tool for psoriasis research and drug development