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

Dimitrios Davalos, Jae Kyu Ryu, Mario Merlini, Kim M. Baeten, Natacha Le Moan, Mark A. Petersen, Thomas J. Deerinck, Dimitri S. Smirnoff, Catherine Bedard, Hiroyuki Hakozaki, Sara Gonias Murray, Jennie B. Ling, Hans Lassmann, Jay L. Degen, Mark H. Ellisman and Katerina Akassoglou ()
Additional contact information
Dimitrios Davalos: Gladstone Institute of Neurological Disease, University of California, San Francisco
Jae Kyu Ryu: Gladstone Institute of Neurological Disease, University of California, San Francisco
Mario Merlini: Gladstone Institute of Neurological Disease, University of California, San Francisco
Kim M. Baeten: Gladstone Institute of Neurological Disease, University of California, San Francisco
Natacha Le Moan: Gladstone Institute of Neurological Disease, University of California, San Francisco
Mark A. Petersen: Gladstone Institute of Neurological Disease, University of California, San Francisco
Thomas J. Deerinck: University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA
Dimitri S. Smirnoff: Gladstone Institute of Neurological Disease, University of California, San Francisco
Catherine Bedard: Gladstone Institute of Neurological Disease, University of California, San Francisco
Hiroyuki Hakozaki: National Center for Microscopy and Imaging Research, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA
Sara Gonias Murray: Gladstone Institute of Neurological Disease, University of California, San Francisco
Jennie B. Ling: Gladstone Institute of Neurological Disease, University of California, San Francisco
Hans Lassmann: Centre for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria
Jay L. Degen: Cincinnati Children’s Hospital Research Foundation and University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
Mark H. Ellisman: University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA
Katerina Akassoglou: Gladstone Institute of Neurological Disease, University of California, San Francisco

Nature Communications, 2012, vol. 3, issue 1, 1-15

Abstract: 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.

Date: 2012
References: Add references at CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/ncomms2230 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms2230

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms2230

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().