Mueller, A. M. et al. Targeting fibroblast growth factor-inducible-14 signaling protects from chronic relapsing experimental autoimmune encephalomyelitis. J. Neuroimmunol. 159, 55-65
Department of Neurology, University of Regensburg, Universitaetsstr. 84, 93053 Regensburg, Germany. Journal of Neuroimmunology
(Impact Factor: 2.47).
03/2005; 159(1-2):55-65. DOI: 10.1016/j.jneuroim.2004.10.001
The TNF-related weak inducer of apoptosis (TWEAK) is a TNF family member mediating proinflammatory effects by its receptor fibroblast growth factor-inducible-14 (Fn14). We studied the role of TWEAK/Fn14 in experimental autoimmune encephalomyelitis (EAE) by protein vaccination with TWEAK and Fn14 and recombinant TWEAK-DNA, respectively. TWEAK-DNA vaccination worsened the clinical course of EAE and increased central nervous system (CNS) inflammation. TWEAK increased the secretion of CCL2 [monocyte chemotactic protein-1 (MCP-1)] by CNS endothelial cells and astrocytes in vitro, suggesting CCL2 as a critical mediator of TWEAKs proinflammatory effects. Vaccination with the extracellular domain of TWEAK or with Fn14 resulted in the induction of specific inhibitory antibodies and an amelioration of EAE signs in two different models in rats and mice. Spinal cord inflammatory infiltrates were significantly diminished. Purified IgG from TWEAK- or Fn14-vaccinated rats prevented TWEAK-induced production of CCL2 by endothelial cells. Blocking Fn14 signaling represents a novel approach with potential for the treatment of CNS autoimmunity.
Available from: Jeffrey A Winkles
- "In one study, Desplet-Jego et al. found that intraperitoneal administration of an anti-TWEAK-neutralizing monoclonal antibody (mAb) after the priming phase reduced leukocyte CNS infiltration and clinical score (47). In the second study, Mueller et al. showed that intraperitoneal injection of recombinant rat soluble TWEAK and Fn14 extracellular domain resulted in induction of neutralizing antibodies, causing a decrease in CNS inflammatory infiltration and EAE severity in both rat and mouse models (48). It has also been reported that soluble TWEAK overexpression, accomplished either by injection of a TWEAK expression plasmid (48) or the generation of TWEAK transgenic mice (49), increases EAE severity. "
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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.
Available from: europepmc.org
- "Blocking Fn14: TWEAK has been suggested to have a beneficial effect in the treatment of inflammatory diseases [28,29], EAE specifically . This suggestion is based on the ability of TWEAK to induce the secretion of pro-inflammatory cytokines such as IL-6 and MCP-1 , but mainly on the finding that blocking of the TWEAK:Fn14 interaction reduced disease severity in EAE [19,27]. We observed that Fn14·TRAIL lowered disease severity only when given from day 10 after MOG immunization. "
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ABSTRACT: Multiple sclerosis (MS) is a, T cell-mediated autoimmune disease, the management of which remains challenging. The recently described fusion protein, Fn14·TRAIL, combining the extracellular domain of Fn14 (capable of blocking the pro-inflammatory TWEAK ligand) fused to the extracellular domain of the TRAIL ligand (capable of sending apoptotic signals through its receptors on activated inflammatory cells) was designed to modulate the immune system as an anti-inflammatory agent. The present study explores the efficacy of this purified protein as an anti-inflammatory agent, using the animal model of MS - experimental autoimmune encephalomyelitis (EAE).
EAE was induced by myelin oligodendrocyte glycoprotein (MOG). Fn14·TRAIL or vehicle were injected daily for 4 to 16 days, at different time points after disease induction. Animals were examined daily and evaluated for EAE clinical signs. Lymphocytes were analyzed for ex vivo re-stimulation, cytokine secretion, transcription factor expression and subtype cell analysis. Spinal cords were checked for inflammatory foci. The Mann- Whitney rank sum test, Student's t-test or ANOVA were used for statistical analysis.
Significant improvement of EAE in the group treated with Fn14·TRAIL was noted from day 6 of disease onset and lasted until the end of follow-up (day 40 from disease induction), even in animals treated for 4 days only. Clinical improvement was linked to decreased lymphocyte infiltrates in the central nervous system (CNS) and to decreased Th1 and Th17 responses and to increased number of T- regulatory in the treated mice. No liver or kidney toxicity was evident. In vitro assays established the ability of Fn14·TRAIL to induce apoptosis of T cell lines expressing TRAIL receptors and TWEAK.
In this study we established the potency of Fn14·TRAIL, a unique fusion protein combining two potentially functional domains, in inhibiting the clinical course of EAE, even when given for a short time, without apparent toxicity. These findings make Fn14·TRAIL a highly promising agent to be used for targeted amelioration of neuro-inflammatory processes, as well as other autoimmune pathologies.
Available from: Taeko Dohi
- "Injury/disease target tissue Animal model (human injury/disease) Primary evidence CNS Experimental autoimmune encephalomyelitis (multiple sclerosis)[15,78,79]Cuprizone-induced demyelination (relevant to multiple sclerosis)Permanent middle cerebral artery occlusion (ischemic stroke)[46,48,81,82]Kidney Chronic graft-versus-host disease-induced nephritis (lupus nephritis)Acute kidney injury induced by folic acid (kidney injury)[38,39,83,84]Ischemia reperfusion injury (kidney injury)Joint Pristane-primed collagen-induced arthritis (RA)Collagen-induced arthritis (RA)Skeletal muscle Denervation-induced muscle wasting (muscle wasting diseases)Vasculature Atherosclerosis (cardiovascular disease)cytes and neurons), and progenitor cells (all reviewed in ref.), as well as renal cell types (mesangial cells, podocytes, and tubular cells)and mature skeletal muscle myocytes[41,72]. Also included are IECs and stromal cell types, both discussed within our focus on IBD further below. "
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ABSTRACT: The TWEAK/Fn14 pathway is a ligand/receptor pair of the TNFSF that has emerged as a prominent player in normal and pathological tissue remodeling. TWEAK/Fn14 pathway activation drives many processes relevant to autoimmune and inflammatory diseases. IBDs, including CD and UC, are chronic, relapsing inflammatory diseases of the GI tract. These diseases differ in their clinical, macroscopic, and histopathological presentation; however, pathological processes that prominently contribute, more or less in each case, include breakdown of the mucosal epithelial barrier, chronic inflammation, and tissue remodeling with fibrosis. TWEAK may promote the pathogenesis of IBD by signaling through Fn14, which can be up-regulated on IECs, thereby contributing to breakdown of the mucosal barrier; the induction of IEC-derived mediators that promote chronic inflammation and shape gut immunity against commensal flora; and delayed healing and fibrosis. TWEAK may also exert its action on endothelial and stromal cell types, including smooth muscle cells and fibroblasts, to promote chronic inflammation, dysregulated tissue repair, and fibrosis. Here, we review the data supporting an emerging role of the TWEAK/Fn14 pathway in autoimmune and inflammatory diseases, with a particular focus on IBD, and discuss how it interplays with other prominent pathways, including IL-13, TNF-α, and TGF-β, to aggravate and perpetuate the pathological processes underlying IBD.
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