“Therapeutic targeting of tumor necrosis factor like weak inducer of apoptosis (TWEAK) in psoriasis”

Abstract

Abstract Excessive activity of TNF and IL-17 in keratinocytes can drive psoriatic skin inflammation and their targeting is highly advantageous in psoriasis patients, but whether these cytokines act with other inflammatory molecules is unknown. Previously, we demonstrated with knockout mice that the TNF-related cytokine TWEAK (TNFSF12) was a major driver of skin inflammation in the imiquimod model of psoriasis. Here, we found that mice carrying a deletion of TWEAK’s receptor, Fn14 (TNFRSF12A), specifically in keratinocytes, exhibited reduced psoriasis features, including less epidermal hyperplasia and poor expression of genes associated with human psoriasis. Further, RNA-seq analysis in human keratinocytes demonstrated that TWEAK strongly synergizes with either TNF or IL-17A in upregulating the transcripts for psoriasis-associated chemokines and cytokines, implying that TWEAK co-operates with TNF and IL-17 to enhance feedback inflammatory activity. Correspondingly, administration of anti-TWEAK antibody demonstrated therapeutic efficacy in the psoriasis mouse model and was equally as effective as antibodies to IL-17A or TNF in reducing clinical and immunological features of psoriasis-like skin inflammation, while co-neutralization of TWEAK with either cytokine had no additional therapeutic effect, reinforcing the conclusion that all three cytokines act together. We conclude that TWEAK blockade could be another potential therapeutic avenue in patients with psoriasis that might be equally as useful as blocking TNF and IL-17. Future studies targeting TWEAK in clinical trials for psoriasis may then be warranted. Supported by NIH grant AR072640