Targeting fibroblast growth factor-inducible-14 signaling protects from chronic relapsing experimental autoimmune encephalomyelitis.
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.
Mueller
A M
AM
Department of Neurology, University of Regensburg, Universitaetsstr. 84, 93053 Regensburg, Germany.
Pedré
X
X
Kleiter
I
I
Hornberg
M
M
Steinbrecher
A
A
Giegerich
G
G
D000818:Animals; D019138:Antibodies, Blocking / Q000096:biosynthesis / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D002908:Chronic Disease; D000074049:Cytokine TWEAK; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007106:Immune Sera / Q000096:biosynthesis / Q000494:pharmacology; D008024:Ligands; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D018655:Lymphocyte Count; D008565:Membrane Proteins / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein / Q000037:antagonists & inhibitors / Q000633:toxicity; D018992:Myelin-Associated Glycoprotein / Q000037:antagonists & inhibitors / Q000633:toxicity; D063308:Myelin-Oligodendrocyte Glycoprotein; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D055502:Secondary Prevention; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000473:pathology; D048069:Tumor Necrosis Factors / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology
D019138:Antibodies, Blocking; D051017:Apoptosis Regulatory Proteins; D018925:Chemokines; D000074049:Cytokine TWEAK; D007106:Immune Sera; D008024:Ligands; D008565:Membrane Proteins; C571327:Mog protein, mouse; C571328:Mog protein, rat; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D011993:Recombinant Fusion Proteins; C497771:Tnfsf12 protein, rat; D048069:Tumor Necrosis Factors; D019444:Vaccines, DNA; C112971:fibroblast growth factor 14; D005346:Fibroblast Growth Factors