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

Nat Commun. 2015 Sep 10;6:8164. doi: 10.1038/ncomms9164.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / drug effects
  • Adaptive Immunity / genetics
  • Adaptive Immunity / immunology
  • Animals
  • Antigen Presentation / drug effects
  • Antigen Presentation / genetics
  • Antigen Presentation / immunology
  • Autoimmunity / drug effects
  • Autoimmunity / genetics
  • Autoimmunity / immunology*
  • Blood-Brain Barrier
  • Brain / drug effects
  • Brain / immunology*
  • Brain / metabolism
  • Brain / pathology
  • CD11b Antigen / genetics
  • CD11b Antigen / immunology
  • CX3C Chemokine Receptor 1
  • Cell Proliferation
  • Chemokine CCL2 / immunology
  • Chemokine CXCL10 / genetics
  • Chemokine CXCL10 / immunology
  • Chemokines
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology
  • Demyelinating Diseases / genetics
  • Demyelinating Diseases / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Fibrin
  • Fibrinogen / immunology*
  • Fibrinogen / pharmacology
  • Flow Cytometry
  • Gene Expression Profiling
  • Genes, MHC Class II / genetics
  • Genes, MHC Class II / immunology*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / immunology
  • Immunohistochemistry
  • Macrophages / immunology*
  • Mice
  • Mice, Knockout
  • Microglia
  • Myelin-Oligodendrocyte Glycoprotein / immunology
  • Rats
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / immunology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spinal Cord / drug effects
  • Spinal Cord / immunology*
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Th1 Cells / immunology*

Substances

  • CD11b Antigen
  • CX3C Chemokine Receptor 1
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Chemokine CXCL10
  • Chemokines
  • Cx3cr1 protein, mouse
  • Cxcl10 protein, mouse
  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Myelin-Oligodendrocyte Glycoprotein
  • Rag2 protein, mouse
  • Receptors, Antigen, T-Cell
  • Receptors, Chemokine
  • RAG-1 protein
  • Fibrin
  • Fibrinogen