TWEAK/Fn14 Activation Contributes to the Pathogenesis of Bullous Pemphigoid

Abstract

TWEAK participates in various cellular effects by engaging its receptor of Fn14. Increased levels of soluble TWEAK are associated with systemic autoimmunity in patients with lupus erythematosus, rheumatoid arthritis, or dermatomyositis. However, the role of TWEAK in bullous pemphigoid (BP) remains unknown. In this study, we found an elevated serum level of TWEAK and a positive correlation between serum TWEAK and anti-BP180 antibodies. Immunohistochemistry showed strong TWEAK and Fn14 expression and implied an opposite relationship between the TWEAK and BP180 expression in skin samples from BP patients. In vitro TWEAK stimuli reduced BP180 expression in HaCaT cells and inhibited the adhesion of cells to the culture dish. Consistently, the transfection of Fn14 small interfering RNA preserved BP180 and protected cells from losing adherence. Moreover, such effect of TWEAK correlated with activation of the extracellular signal-regulated kinase and NF-κB pathways and downstream ADAMs. By silencing ADAM17 with small interfering RNA, we showed that ADAM17 participated in TWEAK-induced BP180 loss. Therefore, TWEAK may contribute to the pathogenesis of BP by reducing BP180 expression and cellular adherence, involving the activation of ERK and NF-κB pathways. TWEAK may serve as a biomarker or therapeutic target of BP.

Anti-Double-Stranded DNA IgG Participates in Renal Fibrosis through Suppressing the Suppressor of Cytokine Signaling 1 Signals

“…In addition, the expression levels of TWEAK and Fn14 increase in kidneys of MRL/lpr mice. TWEAK and Fn14 activate in kidneys of mice with LN, contributing to glomerular and interstitial fibrosis by promoting the production of TGF-β1, monocyte chemotactic protein-1, interferon gamma-induced protein 10, and chemokine (C–C motif) ligand 5 (33, 38, 39). Therefore, the SOCS1 levels correlate negatively with anti-dsDNA IgG and profibrotic factors in LN.…”

TWEAK/Fn14 Interaction Confers Aggressive Properties to Cutaneous Squamous Cell Carcinoma

“…TWEAK is mainly produced by immune cells especially macrophages/monocytes infiltrating inflamed tissues (Wang et al, 2017). Fn14 is weakly expressed in cells under physiological conditions, but may be upregulated upon inflammatory responses (Burkly, 2014;Liu et al, 2017a). Fn14 is also highly expressed in tumor cells or human papillomaviruseinfected keratinocytes, the latter of which harbor tumorigenicity (Cheng et al, 2015b;Hu et al, 2017).…”

Tumor Necrosis Factor Receptor Mediates Fibroblast Growth Factor-Inducible 14 Signaling

“…Both TWEAK and Fn14 are highly expressed in various cutaneous inflammatory disorders, including lupus erythematosus [11, 31], psoriasis [7], atopic dermatitis [8], skin warts [9], and bullous pemphigoid [10]. The downstream cytokines, such as RANTES, MACP-1, IP-10, MIP-1α, ICAM-1, and VCAM-1, are produced locally, reflecting the activation of the TWEAK/Fn14 pathway [7-11, 21, 32].…”

“…Apoptosis of keratinocytes is also prominent in skin lesions of bullous pemphigoid [35]. Moreover, TWEAK/Fn14 activation has been found to be remarkable in skin lesions of patients with bullous pemphigoid and to contribute to loss of BP180 and cellular adherence, which are central to the pathogenesis of bullous pemphigoid [10]. …”

“…Moreover, the TWEAK/Fn14 signals participate in the development of various dermatoses, such as psoriasis [7], atopic dermatitis [8], cutaneous vasculitis [18], human papillomavirus (HPV) infection [9], and bullous pemphigoid [10]. TWEAK/Fn14 activation also contributes to the biological processes of tumors [19].…”