TWEAK/Fn14 Axis-Targeted Therapeutics: Moving Basic Science Discoveries to the Clinic

Abstract

The TNF superfamily member TWEAK (TNFSF12) is a multifunctional cytokine implicated in physiological tissue regeneration and wound repair. TWEAK is initially synthesized as a membrane-anchored protein, but furin cleavage within the stalk region can generate a secreted TWEAK isoform. Both TWEAK isoforms bind to a small cell surface receptor named Fn14 (TNFRSF12A) and this interaction stimulates various cellular responses, including proliferation and migration. Fn14, like other members of the TNF receptor superfamily, is not a ligand-activated protein kinase. Instead, TWEAK:Fn14 engagement promotes Fn14 association with members of the TNFR associated factor family of adapter proteins, which triggers activation of various signaling pathways, including the classical and alternative NF-κB pathways. Numerous studies have revealed that Fn14 gene expression is significantly elevated in injured tissues and in most solid tumor types. Also, sustained Fn14 signaling has been implicated in the pathogenesis of cerebral ischemia, chronic inflammatory diseases, and cancer. Accordingly, several groups are developing TWEAK- or Fn14-targeted agents for possible therapeutic use in patients. These agents include monoclonal antibodies, fusion proteins, and immunotoxins. In this article, we provide an overview of some of the TWEAK/Fn14 axis-targeted agents currently in pre-clinical animal studies or in human clinical trials and discuss two other potential approaches to target this intriguing signaling node.

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

“…5,6,[30][31][32][33][34][35] The TWEAK/Fn14 system has a key role in cancer, ischemia, and sterile inflammatory injury of the central nervous system, liver, gut, peritoneum, the vasculature, skeletal muscle, heart, and kidneys. 16,36,37 In this regard, therapeutic agents targeting the TWEAK/ Fn14 axis have been tested in clinical trials in cancer, lupus nephritis, rheumatoid arthritis, and muscle atrophy 38 (Table 1).…”

Inflammation in the CNS: Advancing the Field Using Intravital Imaging

“…Notably, there is a preferential inhibition for TH1 cells by IDO-1 activation, although the activation of regulatory T-cells may also impede TH2 cells (102). There are controversial data surrounding QUIN's effect on T cell regulation, although it is currently thought that this process relies on a TRP-deficient microenvironment (105,107,108). KYN has been found to moderately impair the killing ability of natural killer cells, whereas KYN and 3-HAA both exert proapoptotic and suppressive effect on these cells (105,106,109).…”

“…Particles with a negative surface charge can bind to monocytes, marking them for sequestration by the spleen and preventing their migration and participation at the inflammation site (65). Interesting examples of polyanions with anti-inflammatory effects are dendritic polyglycerol sulfates (dPGS) (106)(107)(108). Studies with dPGS suggest that they are effective anti-inflammatory agents per se with strong inhibitory effects on inflammation-induced degenerative changes in microglia and the ability to rescue dendritic spine morphology (108).…”

“…Similar to MSCs, NSCs also express the complete and functional KP enzyme machinery (147). In addition, there is a plethora of studies that have demonstrated that QUIN, as well as KYN and 3-HA, have significant effects on proliferation and activation in specific T cell subsets (105,107,148). These studies indicate a key role of the KP in controlling proliferation and differentiation in various cell types.…”

“…Along with this distinct interstitial ECM, the CNS is also punctuated with perineuronal nets. The perineuronal nets are distinct ECM structures composed of chondroitin sulfate proteoglycans that form dense structures around certain subsets of neurons and provide support and stability to neural connections (107). Together, the CNS ECM provides protection from mechanical stress while supporting the function of the neural network (106).…”