title: Tissue remodeling in periplaque regions of multiple sclerosis spinal cord lesions.
abstract: Our knowledge of multiple sclerosis (MS) neuropathology has benefited from a number of studies that provided an in-depth description of plaques and, more recently, diffuse alterations of the normal-appearing white or grey matter. However, there have been few studies focusing on the periplaque regions surrounding demyelinated plaques, notably in MS spinal cords. In this context, the present study aimed to analyze the molecular immunopathology of periplaque demyelinated lesions (PDLs) in the spinal cord of patients with a progressive form of MS. To achieve this goal, the neuropathological features of PDLs were analyzed in postmortem tissues derived from the cervical spinal cord of 21 patients with primary or secondary progressive MS. We found that PDLs covered unexpectedly large areas of incomplete demyelination and were characterized by the superimposition of pro- and anti-inflammatory molecular signatures. Accordingly, macrophages/microglia accumulated in PDLs but exhibited a poor phagocytic activity toward myelin debris. Interestingly, while genes of the oligodendrocyte lineage were consistently down-regulated in PDLs, astrocyte-related molecules such as aquaporin 4, connexin 43 and the glutamate transporter EAAT1, were significantly upregulated in PDLs at the mRNA and protein levels. Overall, our work indicates that in the spinal cord of patients with a progressive form of MS, a tissue remodeling process that is temporally remote from plaque development takes place in PDLs. We propose that in spinal cord PDLs, this process is supported by subtle alterations of astrocyte functions and by low-grade inflammatory events that drive a slowly progressive loss of myelin and a failure of remyelination.
authors.affiliation: INSERM U1028, CNRS UMR 5292, Lyon Neuroscience Research Center, Neuro-Oncology and Neuro-Inflammation Team, Lyon, France; University Lyon 1, Lyon, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Lieury
authors.forename: Marie
authors.initials: M
authors.lastname: Chanal
authors.forename: Géraldine
authors.initials: G
authors.lastname: Androdias
authors.forename: Richard
authors.initials: R
authors.lastname: Reynolds
authors.forename: Sylvie
authors.initials: S
authors.lastname: Cavagna
authors.forename: Pascale
authors.initials: P
authors.lastname: Giraudon
authors.forename: Christian
authors.initials: C
authors.lastname: Confavreux
authors.forename: Serge
authors.initials: S
authors.lastname: Nataf
mesh_terms: D000328:Adult; D051401:Aquaporin 4 / Q000378:metabolism; D002574:Cervical Vertebrae; D018031:Connexin 43 / Q000378:metabolism; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D005260:Female; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D017628:Microglia / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000276:immunology* / Q000473:pathology*; D009186:Myelin Sheath / Q000276:immunology / Q000473:pathology; D009836:Oligodendroglia / Q000276:immunology / Q000473:pathology; D010587:Phagocytosis; D013116:Spinal Cord / Q000276:immunology* / Q000473:pathology*
chemical_list: C496030:AQP4 protein, human; D051401:Aquaporin 4; D018031:Connexin 43; D027341:Excitatory Amino Acid Transporter 1; C500216:GJA1 protein, human; C493394:SLC1A3 protein, human
keywords: astrocyte; axonal loss; demyelination; microglia; multiple sclerosis; periplaque