Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation

• Published in: Nature communications Vol. 3; no. 1; p. 1227
• Main Authors: Davalos, Dimitrios, Kyu Ryu, Jae, Merlini, Mario, Baeten, Kim M., Le Moan, Natacha, Petersen, Mark A., Deerinck, Thomas J., Smirnoff, Dimitri S., Bedard, Catherine, Hakozaki, Hiroyuki, Gonias Murray, Sara, Ling, Jennie B., Lassmann, Hans, Degen, Jay L., Ellisman, Mark H., Akassoglou, Katerina
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27-11-2012; Nature Publishing Group; Nature Pub. Group
• Subjects: 631/250/256; 631/378/1341; 631/378/2596/1953; 692/699/375/1411/1666; Animals; Axons - pathology; Axons - physiology; Blood-Brain Barrier - pathology; Blood-Brain Barrier - physiopathology; Encephalomyelitis, Autoimmune, Experimental - pathology; Encephalomyelitis, Autoimmune, Experimental - physiopathology; Female; Fibrin - physiology; Fibrinogen - physiology; Humanities and Social Sciences; Mice; Mice, Inbred C57BL; Microglia - pathology; Microglia - physiology; Microscopy, Fluorescence, Multiphoton; multidisciplinary; Reactive Oxygen Species - metabolism; Science; Science (multidisciplinary); Spinal Cord - pathology; Spinal Cord - physiopathology
• ISSN: 2041-1723
• DOI: 10.1038/ncomms2230

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.
Multiple sclerosis is characterized by the activation of microglia cells. Davalos
et al
. investigate the early stages of neuroinflammation in mice and reveal that the plasma protein fibrinogen induces microglial clustering around the brain vasculature, which facilitates lesion formation and focal axonal damage.