Fn14 deficiency ameliorates psoriasis-like skin disease in a murine model

Abstract

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine that acts through its receptor fibroblast growth factor-inducible 14 (Fn14). Recent studies demonstrated that the TWEAK/Fn14 signals participate in the development of psoriasis. The purpose of this study was to further explore the effect of Fn14 inhibition on experimental psoriasis. Psoriasis-like skin disease was induced in the wild-type and Fn14-knockout BALB/c mice. We found that Fn14 deficiency ameliorates psoriasis-like lesion in this model, accompanied by less inflammatory cell infiltration and proinflammatory cytokine production in lesional skin. The cutaneous expression of TNF receptor type 2 also decreased in the Fn14-deficient mice. Moreover, the topical application of TWEAK exacerbated psoriatic lesion in the wild-type but not in the Fn14-deficient mice. Furthermore, TWEAK promoted the expression of interleukin 8, keratin 17, and epidermal growth factor receptor (EGFR) but inhibited the expression of involucrin in psoriatic keratinocytes in vitro. Interestingly, such effect of TWEAK was abrogated by an EGFR inhibitor (erlotinib). TWEAK also enhances the proliferation and interleukin-6 production of dermal microvascular endothelial cells under psoriatic condition. In conclusion, TWEAK/Fn14 signals contribute to the development of psoriasis, and involves the modulation of resident cells and the transduction of the EGFR pathway. Fn14 inhibition might be a novel therapeutic strategy for patients with psoriasis.

Experimental atopic dermatitis is dependent on the TWEAK/Fn14 signaling pathway

“…We showed that TNFR2 is up‐regulated in psoriasis. Keratinocytes express TNFR2 predominantly with the addition of TWEAK and the TNFR2 expression decreases more obviously upon Fn14 inhibition in a psoriasis mouse model . In this study we found that, instead of TNFR2, TNFR1 is up‐regulated in skin lesion of atopic dermatitis and Fn14 deficiency reduces the TNFR1 expression profile.…”

“…Several studies have demonstrated that the predominant expression of TNFR2 accounts for the TWEAK‐induced proliferation of keratinocytes . In this study, we further determined the expression of TNF receptors in lesional skin of these mice on day 28.…”

“…Fn14 deficiency was introduced to BALB/c mice by using the clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR‐associated (Cas) protein 9 method . Mice were housed at the Medical Animal Center of Xi’an Jiaotong University.…”

“…Finally, sections were incubated with 3,3‐diaminobenzine‐chromogen substrate (Dako) and counterstained with hematoxylin and eosin solution in order. The positively stained epidermis was quantified by ImageJ software (National Institutes of Health, Bethesda, MD, USA), according to a previous method .…”

“…Previous studies have shown that Fn14 is more strictly expressed in resident cells under inflammatory conditions, while TWEAK can be released by inflammatory cells infiltrating affected tissue or activated in circulation . Targeting Fn14 in resident cells has become an efficient approach to suppress exacerbated inflammatory responses in skin diseases, including cutaneous lupus erythematosus and psoriasis . In patients with atopic dermatitis the serum levels of TWEAK are comparable with healthy controls , indicating that the TWEAK/Fn14 signals prefer local regulation of inflammatory responses in atopic dermatitis.…”