Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Activates Type I Interferon Signals in Lupus Nephritis

Abstract

Type I interferon (IFN) plays a central role in pathogenesis of systemic lupus erythematosus (SLE); tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been associated with a pathogenic role in lupus nephritis (LN). Thus we investigated whether TWEAK could induce the activation of type I IFN pathway in LN. We examined this in patient-derived peripheral blood mononuclear cells (PBMCs) as well as MRL/lpr mice, a murine LN model. Relative to the control cohorts, MRL/lpr mice showed severe histological changes, high index levels of renal damage, and elevated expression of type I IFN-inducible genes. After shRNA suppression of TWEAK, we observed that renal damage was significantly attenuated and expression of type I IFN-inducible genes was reduced in MRL/lpr mice. In parallel, siRNA of TWEAK also significantly reduced the expression of type I IFN-inducible genes in PBMCs relative to control transfections. In PBMCs, TWEAK stimulation also led to expression of type I IFN-inducible genes. Our results illustrate a novel regulatory role of TWEAK, in which its activity positively regulates type I IFN pathway in LN based on preclinical models. Our findings suggest TWEAK could act as a critical target in preventing renal damage in patients with LN.

TWEAK–Fn14 as a common pathway in the heart and the kidneys in cardiorenal syndrome

“…Several preclinical strategies target the TWEAK–Fn14 axis. The simplest strategy is small interfering RNA against TWEAK or Fn14, which successfully decreased TWEAK and Fn14 [155–158]. Another approach is the use of fusion proteins.…”

Transforming Growth Factor-β and Long Non-coding RNA in Renal Inflammation and Fibrosis

“…These may well be associated with the functions of lncRNAs in renal inflammation. For instance, lncRNAs may act as mediators in lupus nephritis pathogenesis to regulate inflammation and apoptosis of renal cells ( Xue et al, 2017 ; Liao et al, 2019 ; Chen et al, 2020 ).…”

Ginkgo Flavonol Glycosides or Ginkgolides Tend to Differentially Protect Myocardial or Cerebral Ischemia–Reperfusion Injury via Regulation of TWEAK-Fn14 Signaling in Heart and Brain

“…TWEAK–Fn14 axis has shown an increasingly important role in cardio-cerebral vascular diseases (Blanco-Colio, 2014). The interaction of TWEAK and Fn14 activates downstream signaling processes during disease development and progression, which includes mediating atrial-derived HL-1 myocytes hypertrophy via the JAK2/STAT3 signaling pathway (Hao et al, 2018), weakening the antiproliferative effects of miR-149 in osteosarcoma via the AKT serine/threonine kinase (PI3K/AKT) signaling pathway (Xu et al, 2018), inducing pro-fibrotic responses leading to heart failure via the NF-κB and/or AP-1 signaling pathway (Das et al, 2018), preventing renal damage in patients with lupus nephritis via type I interferon signaling pathway (Xue et al, 2017), and promoting wound healing processes through favoring regional inflammation, cytokine production, and extracellular matrix synthesis (Liu et al, 2018). In addition, TWEAK also participates in a variety of other diseases such as tumors (Hu et al, 2017), neonatal hypoxia–ischemia (Kichev et al, 2018), human glioma (Guan et al, 2017), psoriasis (Sidler et al, 2017), and chronic colitis (Son et al, 2013).…”