Tumor necrosis factor like weak inducer of apoptosis (TWEAK) Promotes Inflammatory Activity in Keratinocytes with IL-17 and TNF to Drive Psoriasis

Abstract

Abstract Psoriasis is an autoimmune skin disease caused by hyper-proliferation of keratinocytes driven by distinct inflammatory cells making cytokines such as IL-17 and TNF. Our previous studies with knockout animals revealed that the TNF-related cytokine TWEAK (TNFSF12) was also a critical contributor to skin inflammation and could be a potential therapeutic target in psoriasis. As Fn14, the receptor for TWEAK, is expressed by keratinocytes, we examined the inflammatory effects of TWEAK alone and with IL-17A and TNF in modulating psoriatic genes in human keratinocytes using RNA-seq. We found that TWEAK upregulated the expression of multiple chemokines and cytokines, such as IL-36G, IL-23A, IL-19, CCL5, CCL20, and other inflammation-associated genes, that have previously been found highly expressed in the skin of patients with psoriasis. TWEAK’s action was partially overlapping with IL-17 and TNF, but interestingly, in combination with IL-17 or TNF, TWEAK had strong synergistic effects in enhancing the expression of a number of these inflammatory genes. We then tested the impact of TWEAK neutralization on already existing skin inflammation in an imiquimod-induced psoriasis model. Mice treated therapeutically with anti-TWEAK showed significantly decreased numbers of immune cell infiltrates in the skin, with fewer γδ T cells, neutrophils and macrophages. These mice also exhibited a marked reduction in epidermal thickening, similar to mice treated with anti-IL-17 alone. Furthermore, co-neutralization of TWEAK and IL-17 demonstrated a greater effect in terms of reducing clinical symptoms. These data suggest that blocking TWEAK could be considered as a potential therapeutic avenue in humans to overcome the pathophysiology of psoriasis.