title: Plasminogen Deficiency Delays the Onset and Protects from Demyelination and Paralysis in Autoimmune Neuroinflammatory Disease.
abstract: Multiple sclerosis (MS) is a neuroinflammatory, demyelinating disease of the CNS. Fibrinogen deposition at sites of blood-brain barrier breakdown is a prominent feature of neuroinflammatory disease and contributes to disease severity. Plasminogen, the primary fibrinolytic enzyme, also modifies inflammatory processes. We used a murine model of MS, experimental autoimmune encephalomyelitis (EAE), to evaluate the hypothesis that the loss of plasminogen would exacerbate neuroinflammatory disease. However, contrary to initial expectations, EAE-challenged plasminogen-deficient (Plg-) mice developed significantly delayed disease onset and reduced disease severity compared with wild-type (Plg+) mice. Similarly, pharmacologic inhibition of plasmin activation with tranexamic acid also delayed disease onset. The T-cell response to immunization was similar between genotypes, suggesting that the contribution of plasminogen was downstream of the T-cell response. Spinal cords from EAE-challenged Plg-mice demonstrated significantly decreased demyelination and microglial/macrophage accumulation compared with Plg+mice. Although fibrinogen-deficient mice or mice with combined deficiencies of plasminogen and fibrinogen had decreased EAE severity, they did not exhibit the delay in EAE disease onset, as seen in mice with plasminogen deficiency alone. Together, these data suggest that plasminogen and plasmin-mediated fibrinolysis is a key modifier of the onset of neuroinflammatory demyelination.SIGNIFICANCE STATEMENTMultiple sclerosis is a severe, chronic, demyelinating disease. Understanding the pathobiology related to the autoreactive T-cell and microglial/macrophage demyelinating response is critical to effectively target therapeutics. We describe for the first time that deficiency of plasminogen, the key fibrinolytic enzyme, delays disease onset and protects from the development of the paralysis associated with a murine model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Administration of a widely used, pharmacologic inhibitor of plasminogen activation, tranexamic acid, also delays the onset of neuroinflammation associated with EAE.
authors.affiliation: Divisions of Hematology.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Shaw
authors.affiliation: Divisions of Hematology.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Divisions of Hematology.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: McElhinney
authors.affiliation: Division of Rheumatology, Cincinnati Children's Research Foundation, Cincinnati Children's Hospital, Cincinnati, Ohio 45229.
authors.forename: Sherry
authors.initials: S
authors.lastname: Thornton
authors.affiliation: Experimental Hematology and Cancer Biology, and.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Flick
authors.affiliation: Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, and.
authors.forename: Adam
authors.initials: A
authors.lastname: Lane
authors.affiliation: Experimental Hematology and Cancer Biology, and.
authors.forename: Jay L
authors.initials: JL
authors.lastname: Degen
authors.affiliation: Neurological Disease, Gladstone Institutes, San Francisco, California 94158, and.
authors.forename: Jae Kyu
authors.initials: JK
authors.lastname: Ryu
authors.affiliation: Neurological Disease, Gladstone Institutes, San Francisco, California 94158, and.|Department of Neurology, University of California, San Francisco, San Francisco, California 94158.
authors.forename: Katerina
authors.initials: K
authors.lastname: Akassoglou
authors.affiliation: Divisions of Hematology, eric.mullins@cchmc.org.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Mullins
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010243:Paralysis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D010958:Plasminogen / Q000172:deficiency*
chemical_list: D010958:Plasminogen
keywords: fibrinogen; fibrinolysis; mice; neuroinflammation; plasminogen