title: Peripheral and central neuronal ATF3 precedes CD4+ T-cell infiltration in EAE.
abstract: Experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis produced by immunization with myelin oligodendrocyte glycoprotein (MOG) and adjuvants, results from profound T-cell mediated CNS demyelination. EAE is characterized by progressive, ascending motor dysfunction and symptoms of ongoing pain and hypersensitivity, in some cases preceding or concomitant with the motor deficits. In this regard, the EAE model mimics major features of multiple sclerosis, where a central neuropathic pain state is common. Although the latter condition is presumed to arise from a CNS loss of inhibitory controls secondary to the demyelination, dysfunction of sensory neurons may also contribute. Based on our previous studies that demonstrated the utility of monitoring expression of activating transcription factor 3 (ATF3), a sensitive marker of injured sensory neurons, here we followed both ATF3 and CD4+ T cells invasion of sensory ganglia (as well as the CNS) at different stages of the EAE model. We found that ATF3 is induced in peripheral sensory ganglia and brainstem well before the appearance of motor deficits. Unexpectedly, the ATF3 induction always preceded T cell infiltration, typically in adjacent, but non-overlapping regions. Surprisingly, control administration of the pertussis toxin and/or Complete Freund's adjuvants, without MOG, induced ATF3 in sensory neurons. In contrast, T cell infiltration only occurred with MOG. Taken together, our results suggest that the clinical manifestations in the EAE result not only from central demyelination but also from neuronal stress and subsequent pathophysiology of sensory neurons.
authors.affiliation: Department Anatomy, University California San Francisco, San Francisco, CA 94158, United States. Electronic address: nmfrezel@gmail.com.
authors.forename: Noémie
authors.initials: N
authors.lastname: Frezel
authors.affiliation: Department Anatomy, University California San Francisco, San Francisco, CA 94158, United States. Electronic address: f.sohet@ucsd.edu.
authors.forename: Fabien
authors.initials: F
authors.lastname: Sohet
authors.affiliation: Department Anatomy, University California San Francisco, San Francisco, CA 94158, United States. Electronic address: rdaneman@ucsd.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Daneman
authors.affiliation: Department Anatomy, University California San Francisco, San Francisco, CA 94158, United States. Electronic address: allan.basbaum@ucsf.edu.
authors.forename: Allan I
authors.initials: AI
authors.lastname: Basbaum
authors.affiliation: Department Anatomy, University California San Francisco, San Francisco, CA 94158, United States. Electronic address: joao.braz2@ucsf.edu.
authors.forename: Joao M
authors.initials: JM
authors.lastname: Braz
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology*; D005260:Female; D005620:Freund's Adjuvant / Q000633:toxicity; D005724:Ganglia / Q000187:drug effects / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000633:toxicity; D037342:Pertussis Toxin / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D010446:Peptide Fragments; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C445081:myelin oligodendrocyte glycoprotein (35-55); D016173:Macrophage Colony-Stimulating Factor; D005620:Freund's Adjuvant; D037342:Pertussis Toxin
keywords: ATF3; Demyelination; Dorsal root ganglion; Experimental allergic encephalomyelitis; Myelin oligodendrocyte glycoprotein; Pertussis toxin; Spinal cord