title: Deletion of astroglial CXCL10 delays clinical onset but does not affect progressive axon loss in a murine autoimmune multiple sclerosis model.
abstract: Multiple sclerosis (MS) is characterized by central nervous system (CNS) inflammation, demyelination, and axonal degeneration. CXCL10 (IP-10), a chemokine for CXCR3+ T cells, is known to regulate T cell differentiation and migration in the periphery, but effects of CXCL10 produced endogenously in the CNS on immune cell trafficking are unknown. We created floxed cxcl10 mice and crossed them with mice carrying an astrocyte-specific Cre transgene (mGFAPcre) to ablate astroglial CXCL10 synthesis. These mice, and littermate controls, were immunized with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG peptide) to induce experimental autoimmune encephalomyelitis (EAE). In comparison to the control mice, spinal cord CXCL10 mRNA and protein were sharply diminished in the mGFAPcre/CXCL10fl/fl EAE mice, confirming that astroglia are chiefly responsible for EAE-induced CNS CXCL10 synthesis. Astroglial CXCL10 deletion did not significantly alter the overall composition of CD4+ lymphocytes and CD11b+ cells in the acutely inflamed CNS, but did diminish accumulation of CD4+ lymphocytes in the spinal cord perivascular spaces. Furthermore, IBA1+ microglia/macrophage accumulation within the lesions was not affected by CXCL10 deletion. Clinical deficits were milder and acute demyelination was substantially reduced in the astroglial CXCL10-deleted EAE mice, but long-term axon loss was equally severe in the two groups. We concluded that astroglial CXCL10 enhances spinal cord perivascular CD4+ lymphocyte accumulation and acute spinal cord demyelination in MOG peptide EAE, but does not play an important role in progressive axon loss in this MS model.
authors.forename: Emily
authors.initials: E
authors.lastname: Mills Ko
authors.forename: Joyce H
authors.initials: JH
authors.lastname: Ma
authors.forename: Fuzheng
authors.initials: F
authors.lastname: Guo
authors.forename: Laird
authors.initials: L
authors.lastname: Miers
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Lee
authors.forename: Peter
authors.initials: P
authors.lastname: Bannerman
authors.forename: Travis
authors.initials: T
authors.lastname: Burns
authors.forename: David
authors.initials: D
authors.lastname: Ko
authors.forename: Jiho
authors.initials: J
authors.lastname: Sohn
authors.affiliation: Institute for Pediatric Regenerative Medicine, UC Davis School of Medicine and Shriners Hospital, 2425 Stockton Blvd, Sacramento, CA 95817, USA. athena.soulika@ucdmc.ucdavis.edu.
authors.forename: Athena M
authors.initials: AM
authors.lastname: Soulika
authors.forename: David
authors.initials: D
authors.lastname: Pleasure
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001369:Axons / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002490:Central Nervous System / Q000473:pathology; D054357:Chemokine CXCL10 / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000473:pathology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D010446:Peptide Fragments / Q000633:toxicity; D013116:Spinal Cord / Q000473:pathology; D013154:Spleen / Q000473:pathology; D013997:Time Factors
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D004676:Myelin Basic Protein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55)