title: Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation.
abstract: Blood-brain barrier disruption, microglial activation and neurodegeneration are hallmarks of multiple sclerosis. However, the initial triggers that activate innate immune responses and their role in axonal damage remain unknown. Here we show that the blood protein fibrinogen induces rapid microglial responses toward the vasculature and is required for axonal damage in neuroinflammation. Using in vivo two-photon microscopy, we demonstrate that microglia form perivascular clusters before myelin loss or paralysis onset and that, of the plasma proteins, fibrinogen specifically induces rapid and sustained microglial responses in vivo. Fibrinogen leakage correlates with areas of axonal damage and induces reactive oxygen species release in microglia. Blocking fibrin formation with anticoagulant treatment or genetically eliminating the fibrinogen binding motif recognized by the microglial integrin receptor CD11b/CD18 inhibits perivascular microglial clustering and axonal damage. Thus, early and progressive perivascular microglial clustering triggered by fibrinogen leakage upon blood-brain barrier disruption contributes to axonal damage in neuroinflammatory disease.
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Davalos
authors.forename: Jae Kyu
authors.initials: JK
authors.lastname: Ryu
authors.forename: Mario
authors.initials: M
authors.lastname: Merlini
authors.forename: Kim M
authors.initials: KM
authors.lastname: Baeten
authors.forename: Natacha
authors.initials: N
authors.lastname: Le Moan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Petersen
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Deerinck
authors.forename: Dimitri S
authors.initials: DS
authors.lastname: Smirnoff
authors.forename: Catherine
authors.initials: C
authors.lastname: Bedard
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hakozaki
authors.forename: Sara
authors.initials: S
authors.lastname: Gonias Murray
authors.forename: Jennie B
authors.initials: JB
authors.lastname: Ling
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
authors.forename: Jay L
authors.initials: JL
authors.lastname: Degen
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.forename: Katerina
authors.initials: K
authors.lastname: Akassoglou
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology* / Q000502:physiology; D001812:Blood-Brain Barrier / Q000473:pathology / Q000503:physiopathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D005337:Fibrin / Q000502:physiology; D005340:Fibrinogen / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000473:pathology* / Q000502:physiology; D036641:Microscopy, Fluorescence, Multiphoton; D017382:Reactive Oxygen Species / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology
chemical_list: D017382:Reactive Oxygen Species; D005337:Fibrin; D005340:Fibrinogen