title: EphA4 receptor tyrosine kinase is a modulator of onset and disease severity of experimental autoimmune encephalomyelitis (EAE).
abstract: The EphA4 receptor tyrosine kinase is a major regulator of axonal growth and astrocyte reactivity and is a possible inflammatory mediator. Given that multiple sclerosis (MS) is primarily an inflammatory demyelinating disease and in mouse models of MS, such as experimental autoimmune encephalomyelitis (EAE), axonal degeneration and reactive gliosis are prominent clinical features, we hypothesised that endogenous EphA4 could play a role in modulating EAE. EAE was induced in EphA4 knockout and wildtype mice using MOG peptide immunisation and clinical severity and histological features of the disease were then compared in lumbar spinal cord sections. EphA4 knockout mice exhibited a markedly less severe clinical course than wildtype mice, with a lower maximum disease grade and a slightly later onset of clinical symptoms. Numbers of infiltrating T cells and macrophages, the number and size of the lesions, and the extent of astrocytic gliosis were similar in both genotypes; however, EphA4 knockout mice appeared to have decreased axonal pathology. Blocking of EphA4 in wildtype mice by administration of soluble EphA4 (EphA4-Fc) as a decoy receptor following induction of EAE produced a delay in onset of clinical symptoms; however, most mice had clinical symptoms of similar severity by 22 days, indicating that EphA4 blocking treatment slowed early EAE disease evolution. Again there were no apparent differences in histopathology. To determine whether the role of EphA4 in modulating EAE was CNS mediated or due to an altered immune response, MOG primed T cells from wildtype and EphA4 knockout mice were passively transferred into naive recipient mice and both were shown to induce disease of equivalent severity. These results are consistent with a non-inflammatory, CNS specific, deleterious effect of EphA4 during neuroinflammation that results in axonal pathology.
authors: Centre for Neuroscience Research, The University of Melbourne, Victoria, Australia.
authors: Kathryn M
authors: KM
authors: Munro
authors: Kirsty J
authors: KJ
authors: Dixon
authors: Melissa M
authors: MM
authors: Gresle
authors: Anna
authors: A
authors: Jonas
authors: Dennis
authors: D
authors: Kemper
authors: William
authors: W
authors: Doherty
authors: Louis J
authors: LJ
authors: Fabri
authors: Catherine M
authors: CM
authors: Owczarek
authors: Martin
authors: M
authors: Pearse
authors: Andrew W
authors: AW
authors: Boyd
authors: Trevor J
authors: TJ
authors: Kilpatrick
authors: Helmut
authors: H
authors: Butzkueven
authors: Ann M
authors: AM
authors: Turnley
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000473:pathology; D001369:Axons / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D007141:Immunoglobulin Fc Fragments / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology / Q000494:pharmacology; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology; D036122:Receptor, EphA4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology / Q000637:transplantation
chemical_list: D007141:Immunoglobulin Fc Fragments; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D036122:Receptor, EphA4
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