title: PARP-1 deficiency increases the severity of disease in a mouse model of multiple sclerosis.
abstract: Poly(ADP-ribose) polymerase-1 (PARP-1) has been implicated in the pathogenesis of several central nervous system (CNS) disorders. However, the role of PARP-1 in autoimmune CNS injury remains poorly understood. Therefore, we studied experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis in mice with a targeted deletion of PARP-1. We identified inherent physiological abnormalities in the circulating and splenic immune composition between PARP-1(-/-) and wild type (WT) mice. Upon EAE induction, PARP-1(-/-) mice had an earlier onset and developed a more severe EAE compared with WT cohorts. Splenic response was significantly higher in PARP-1(-/-) mice largely because of B cell expansion. Although formation of Th1 and Th17 effector T lymphocytes was unaffected, PARP-1(-/-) mice had significantly earlier CD4+ T lymphocyte and macrophage infiltration into the CNS during EAE. However, we did not detect significant differences in cytokine profiles between PARP-1(-/-) and WT spinal cords at the peak of EAE. Expression analysis of different PARP isozymes in EAE spinal cords showed that PARP-1 was down-regulated in WT mice and that PARP-3 but not PARP-2 was dramatically up-regulated in both PARP-1(-/-) and WT mice, suggesting that these PARP isozymes could have distinct roles in different CNS pathologies. Together, our results indicate that PARP-1 plays an important role in regulating the physiological immune composition and in immune modulation during EAE; our finding identifies a new aspect of immune regulation by PARPs in autoimmune CNS pathology.
authors.affiliation: Department of Cell Biology and Human Anatomy, School of Medicine, University of California, Davis, Sacramento, California 95817, USA.
authors.forename: Vimal
authors.initials: V
authors.lastname: Selvaraj
authors.forename: Mangala M
authors.initials: MM
authors.lastname: Soundarapandian
authors.forename: Olga
authors.initials: O
authors.lastname: Chechneva
authors.forename: Ambrose J
authors.initials: AJ
authors.lastname: Williams
authors.forename: Maxim K
authors.initials: MK
authors.lastname: Sidorov
authors.forename: Athena M
authors.initials: AM
authors.lastname: Soulika
authors.forename: David E
authors.initials: DE
authors.lastname: Pleasure
authors.forename: Wenbin
authors.initials: W
authors.lastname: Deng
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000276:immunology; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D013116:Spinal Cord / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D007527:Isoenzymes; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C459820:Parp2 protein, mouse