Deficiency of Fibroblast Growth Factor-Inducible 14 (Fn14) Preserves the Filtration Barrier and Ameliorates Lupus Nephritis

Abstract

TNF ligand superfamily member 12, also known as TNF-related weak inducer of apoptosis (TWEAK), acts through its receptor, fibroblast growth factor-inducible 14 (Fn14), to mediate several key pathologic processes involved in tissue injury relating to lupus nephritis. To explore the potential for renal protection in lupus nephritis by targeting this pathway, we introduced the Fn14 null allele into the MRL-lpr/lpr lupus mouse strain. At 26-38 weeks of age, female Fn14-knockout MRL-lpr/lpr mice had significantly lower levels of proteinuria compared with female wild-type MRL-lpr/lpr mice. Furthermore, Fn14-knockout mice had significantly improved renal histopathology accompanied by attenuated glomerular and tubulointerstitial inflammation. There was a significant reduction in glomerular Ig deposition in Fn14-knockout mice, despite no detectable differences in either serum levels of antibodies or splenic immune cell subsets. Notably, we found that the Fn14-knockout mice displayed substantial preservation of podocytes in glomeruli and that TWEAK signaling directly damaged barrier function and increased filtration through podocyte and glomerular endothelial cell monolayers. Our results show that deficiency of the Fn14 receptor significantly improves renal disease in a spontaneous lupus nephritis model through prevention of the direct injurious effects of TWEAK on the filtration barrier and/or modulation of cytokine production by resident kidney cells. Thus, blocking the TWEAK/Fn14 axis may be a novel therapeutic intervention in immune-mediated proliferative GN.

HPV Type 16 Infection Switches Keratinocytes from Apoptotic to Proliferative Fate under TWEAK/Fn14 Interaction

“…As a novel member of the tumor necrosis factor (TNF)-ligand superfamily, TNF-like weak inducer of apoptosis (TWEAK) promotes the expression of proinflammatory mediators from various cell types, including endothelial cells, epithelial cells, and keratinocytes (Chen et al, 2011a;Xia et al, 2014;Jin et al, 2004). Fibroblast growth factor inducible 14 (Fn14) is a sole known receptor for TWEAK, and induces the phosphorylation of IκB kinase in keratinocytes when bound to TWEAK, followed by augmented production of RANTES (regulated on activation normal T-cell expressed and secreted) (Jin et al, 2004).…”

Out of the TWEAKlight: Elucidating the Role of Fn14 and TWEAK in Acute Kidney Injury

“…The current update is focused on the contribution of TWEAK/Fn14 to AKI and will not discuss the involvement of TWEAK in immune and nonimmune proteinuric kidney diseases. [6][7][8][9][10][11] TWEAK, Fn14, And CD163 TWEAK activates the Fn14 receptor and is scavenged by macrophage-derived CD163 (Fig. 1).…”

Is Urinary Tumor Necrosis Factor-like Weak Inducer of Apoptosis a Biomarker of Lupus Nephritis?

“…Fn14-knockout MRL-lpr/lpr mice demonstrated markedly lower levels of proteinuria compared with wild-type MRL-lpr/lpr mice. Fn14-knockout mice also showed significantly attenuated glomerular and tubulointerstitial inflammation [14]. It was reported that TWEAK induced mesangial cells, podocytes, and endothelial cells to secrete pro-inflammatory chemokines including MCP-1, IP-10 and RANTES (CCL5), which are crucial in the pathogenesis of LN [15].…”