TWEAK/Fn14 Activation Participates in Skin Inflammation

Received May 18, 2017; Accepted Aug 1, 2017

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1. Introduction

Tumor necrosis factor- (TNF-) like weak inducer of apoptosis (TWEAK) is a member of the TNF ligand superfamily and is initially described as an inducer of apoptosis in transformed cell lines [1]. TWEAK acts via binding to its sole receptor—fibroblast growth factor-inducible 14 (Fn14), the smallest member of the TNF receptor (TNFR) superfamily [2]. The specificity of TWEAK binding to Fn14 has been confirmed in multiple experiments [3]. TWEAK is broadly expressed by monocytes, dendritic cells, and natural killer (NK) cells, and macrophages/monocytes are the main source of soluble TWEAK (sTWEAK) in inflammatory tissues [4–8]. The immune organs, including the spleen, lymph nodes, and appendix, also express TWEAK [1, 4]. TWEAK has also been detected in various tumor cell lines [9–12]. Fn14 is widely expressed in various tissues including the skin, heart, brain, kidney, colon, small intestine, skeletal muscle, and pancreas [2, 13–17]. In normal tissues, the expression of TWEAK and Fn14 is relatively low. Elevated expression of TWEAK and Fn14 is usually seen in response to stress, tissue injury, or remodeling [18–20]. Optimal TWEAK-mediated activation of Fn14 promotes productive tissue responses after injury; however, excessive or persistent Fn14 upregulation and TWEAK/Fn14 activation often induce various pathological responses [21]. TWEAK/Fn14 signaling pathway participates in multiple biological activities, including the proliferation, differentiation, migration and death (apoptosis/necrosis) of cells [22–28], angiogenesis [2, 29], and inflammatory responses [2, 30].

Inflammation is one of the basic characteristics of skin disorders, especially the chronic inflammatory diseases that include psoriasis, atopic dermatitis (AD), cutaneous vasculitis, and cutaneous lupus erythematosus [31]. The occurrence of psoriasis varies according to age and geographic region, with the estimates of prevalence in adults ranged from 0.51% to 11.43% and in children from 0% to 1.37% [32]. AD is even more prevalent among people of any age. In developed countries, the...