Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation

Jae Kyu Ryu, Mark A. Petersen, Sara G. Murray, Kim M. Baeten, Anke Meyer-Franke, Justin P. Chan, Eirini Vagena, Catherine Bedard, Michael R. Machado, Pamela E. Rios Coronado, Thomas Prod'homme, Israel F. Charo, Hans Lassmann, Jay L. Degen, Scott S. Zamvil () and Katerina Akassoglou ()
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Jae Kyu Ryu: Gladstone Institute of Neurological Disease, University of California
Mark A. Petersen: Gladstone Institute of Neurological Disease, University of California
Sara G. Murray: Gladstone Institute of Neurological Disease, University of California
Kim M. Baeten: Gladstone Institute of Neurological Disease, University of California
Anke Meyer-Franke: Gladstone Institute of Neurological Disease, University of California
Justin P. Chan: Gladstone Institute of Neurological Disease, University of California
Eirini Vagena: Gladstone Institute of Neurological Disease, University of California
Catherine Bedard: Gladstone Institute of Neurological Disease, University of California
Michael R. Machado: Gladstone Institute of Neurological Disease, University of California
Pamela E. Rios Coronado: Gladstone Institute of Neurological Disease, University of California
Thomas Prod'homme: University of California San Francisco
Israel F. Charo: Gladstone Institute of Cardiovascular Disease, University of California
Hans Lassmann: Centre for Brain Research, Medical University of Vienna
Jay L. Degen: Cincinnati Children’s Hospital Research Foundation and University of Cincinnati College of Medicine
Scott S. Zamvil: University of California San Francisco
Katerina Akassoglou: Gladstone Institute of Neurological Disease, University of California

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: Abstract Autoimmunity and macrophage recruitment into the central nervous system (CNS) are critical determinants of neuroinflammatory diseases. However, the mechanisms that drive immunological responses targeted to the CNS remain largely unknown. Here we show that fibrinogen, a central blood coagulation protein deposited in the CNS after blood–brain barrier disruption, induces encephalitogenic adaptive immune responses and peripheral macrophage recruitment into the CNS leading to demyelination. Fibrinogen stimulates a unique transcriptional signature in CD11b+ antigen-presenting cells inducing the recruitment and local CNS activation of myelin antigen-specific Th1 cells. Fibrinogen depletion reduces Th1 cells in the multiple sclerosis model, experimental autoimmune encephalomyelitis. Major histocompatibility complex (MHC) II-dependent antigen presentation, CXCL10- and CCL2-mediated recruitment of T cells and macrophages, respectively, are required for fibrinogen-induced encephalomyelitis. Inhibition of the fibrinogen receptor CD11b/CD18 protects from all immune and neuropathologic effects. Our results show that the final product of the coagulation cascade is a key determinant of CNS autoimmunity.

Date: 2015
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DOI: 10.1038/ncomms9164

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