NEDD4 Is Involved in Inflammation Development during Keloid Formation

Abstract

Keloids mark a chronic inflammatory disease characterized by a fibroproliferative disorder of the skin. A genome-wide association study showed that single-nucleotide polymorphism rs8032158 in the neural precursor cell-expressed NEDD4 gene, which has six protein-coding transcript variants (TVs), is genetically linked to keloids. Here, we show that the high frequency of risk allele C in rs8032158 in keloid patients is associated with a selectively higher expression of TV3 of NEDD4 to activate the NF-kB pathway. Comparisons of keloid scars with normal skin samples that do not have the single-nucleotide polymorphism allele and were derived from different anatomical sites showed stronger expressions of NEDD4 TV3 and activated forms of NF-kB and STAT3 in keloid scars. Forced expression or selective knockdown of NEDD4 TV3 increased or decreased NF-kB activation in vitro. Furthermore, NEDD4 knockdown suppressed NF-kBedependent inflammation development in vivo. Mechanistic analysis showed that NEDD4 TV3 is involved in NF-kB activation through its association with the adaptor protein RIP. These results suggest that NEDD4 TV3 is a potential diagnostic marker and therapeutic target for chronic skin diseases, including keloid.

Pleiotropy and Specificity: Insights from the Interleukin 6 Family of Cytokines

“…Consistent with these findings, comparative analysis between GWAS data and the targets or regulatory genes of the inflammation amplifier has revealed significant relationships with human inflammatory diseases, including autoimmune diseases (Murakami et al, 2013). Indeed, the amplifier has been associated with several human diseases (Fujita et al, 2019;Lee et al, 2012). In addition, other IL-6 family members, such as LIF and IL-27, are associated with chronic obstructive pulmonary diseases (Hobbs et al, 2016;Hu et al, 2011).…”

<p>Neuronal Precursor Cell Expressed Developmentally Down Regulated 4 (NEDD4) Gene Polymorphism Contributes to Keloid Development in Egyptian Population</p>

“…They revealed a significant increase in the CC genotype in keloid patients, and showed that the rs8032158 T allele was associated with a reduced risk of keloid scarring. Also Fujita et al 16 examined 20 skin keloid specimens and found that most of them have the risk C/C genotype in rs8032158.…”

“…In addition, it was found that CC genotypes cause a higher level of NEDD4 TV3 which, reportedly, acts strongly together with the RIP adapter protein to cause NF-kB activation. 16 The role of the NEDD4 TV3 signaling pathway in the aetiopathogenesis of the keloid is evaluated and its potential role as a therapeutic objective is evaluated 16 . Fujita et al 16 studied the immunohistochemical expression of NEDD4 in different samples of normal and human keloid skin using an anti-NEDD4 antibody that identifies all TVs types.…”

“…16 The role of the NEDD4 TV3 signaling pathway in the aetiopathogenesis of the keloid is evaluated and its potential role as a therapeutic objective is evaluated 16 . Fujita et al 16 studied the immunohistochemical expression of NEDD4 in different samples of normal and human keloid skin using an anti-NEDD4 antibody that identifies all TVs types. They discovered that NEDD4 was equally expressed in keratinocytes and fibroblasts of both keloid and normal skin, but quantitative PCR and electrophoresis showed that NEDD4 TV3 was considerably more profuse in keloid skin in comparison with normal skin tissue.…”

“…12 In keloids, few studies investigated the polymorphism of the NEDD4 gene rs8032158 in different populations with controversial results. [13][14][15][16] The following current study aimed to shed light on the possible association between SNP NEDD4 rs8032158 and the keloid through the evaluation of its gene polymorphism in Egyptian keloid patients, in addition to correlating its estimated results with the available clinical aspects of keloid lesions in those patients.…”