Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation.
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.
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.
Jae Kyu
JK
Ryu
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.|Division of Neonatology, Department of Pediatrics, University of California San Francisco, San Francisco, California 94143, USA.
Mark A
MA
Petersen
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.
Sara G
SG
Murray
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.
Kim M
KM
Baeten
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.
Anke
A
Meyer-Franke
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.
Justin P
JP
Chan
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.
Eirini
E
Vagena
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.
Catherine
C
Bedard
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.
Michael R
MR
Machado
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.
Pamela E
PE
Rios Coronado
Department of Neurology, University of California San Francisco, San Francisco, California 94143, USA.|Program in Immunology, University of California San Francisco, San Francisco, California 94143, USA.
Thomas
T
Prod'homme
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94158, USA.
Israel F
IF
Charo
Centre for Brain Research, Medical University of Vienna, Vienna A-1090, Austria.
Hans
H
Lassmann
Division of Experimental Hematology, Cincinnati Children's Hospital Research Foundation and University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
Jay L
JL
Degen
Department of Neurology, University of California San Francisco, San Francisco, California 94143, USA.|Program in Immunology, University of California San Francisco, San Francisco, California 94143, USA.
Scott S
SS
Zamvil
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.|Department of Neurology, University of California San Francisco, San Francisco, California 94143, USA.|Program in Immunology, University of California San Francisco, San Francisco, California 94143, USA.
Katerina
http://orcid.org/0000-0002-2632-1465
K
Akassoglou
D056704:Adaptive Immunity / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology; D000073883:CX3C Chemokine Receptor 1; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000276:immunology; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology; D018925:Chemokines; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D003711:Demyelinating Diseases / Q000235:genetics / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005337:Fibrin; D005340:Fibrinogen / Q000276:immunology* / Q000494:pharmacology; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005802:Genes, MHC Class II / Q000235:genetics / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D007150:Immunohistochemistry; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology*
D039481:CD11b Antigen; D000073883:CX3C Chemokine Receptor 1; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D018925:Chemokines; C471885:Cx3cr1 protein, mouse; C485433:Cxcl10 protein, mouse; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; C499308:Rag2 protein, mouse; D011948:Receptors, Antigen, T-Cell; D019707:Receptors, Chemokine; C064658:RAG-1 protein; D005337:Fibrin; D005340:Fibrinogen