Mechanistic Investigation of WWOX Function in NF-kB-Induced Skin Inflammation in Psoriasis

Abstract

Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation, aberrant differentiation of keratinocytes, and dysregulated immune responses. WW domain-containing oxidoreductase (WWOX) is a non-classical tumor suppressor gene that regulates multiple cellular processes, including proliferation, apoptosis, and migration. This study aimed to explore the possible role of WWOX in the pathogenesis of psoriasis. Immunohistochemical analysis showed that the expression of WWOX was increased in epidermal keratinocytes of both human psoriatic lesions and imiquimod-induced mice psoriatic model. Immortalized human epidermal keratinocytes were transduced with a recombinant adenovirus expressing microRNA specific for WWOX to downregulate its expression. Inflammatory responses were detected using Western blotting, real-time quantitative reverse transcription polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay. In human epidermal keratinocytes, WWOX knockdown reduced nuclear factor-kappa B signaling and levels of proinflammatory cytokines induced by polyinosinic: polycytidylic acid [(poly(I:C)] in vitro. Furthermore, calcium chelator and protein kinase C (PKC) inhibitors significantly reduced poly(I:C)-induced inflammatory reactions. WWOX plays a role in the inflammatory reaction of epidermal keratinocytes by regulating calcium and PKC signaling. Targeting WWOX could be a novel therapeutic approach for psoriasis in the future.

In Silico Analysis Highlights Potential Predictive Indicators Associated with Secondary Progressive Multiple Sclerosis

“…The WWOX gene encodes for a tumor suppressor, mainly correlating its function to cancer [ 97 ], but it is also associated with the CNS’s development and function [ 98 ], as well as with immune cell proliferation and maturation [ 99 , 100 ]. While the exact molecular cascades regulated by WWOX are still being investigated [ 100 , 101 ], the WWOX gene exhibits higher transcriptional levels in inflammatory conditions [ 100 ]. The literature suggests a potential association of WWOX with MS [ 98 , 102 ], consistent with our results.…”

“…Indeed, Ca 2+ is an essential signaling molecule that controls a wide range of biological functions. The immune system is not an exception: here, Ca 2+ plays a central role in several functions in immune cells and inflammation [ 100 , 104 ]. In particular, through the calcineurin–NFAT pathway, it regulates the transcription of genes essential for innate and adaptive immunity [ 105 ].…”