The fibrin-derived gamma377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease.
Perivascular microglia activation is a hallmark of inflammatory demyelination in multiple sclerosis (MS), but the mechanisms underlying microglia activation and specific strategies to attenuate their activation remain elusive. Here, we identify fibrinogen as a novel regulator of microglia activation and show that targeting of the interaction of fibrinogen with the microglia integrin receptor Mac-1 (alpha(M)beta(2), CD11b/CD18) is sufficient to suppress experimental autoimmune encephalomyelitis in mice that retain full coagulation function. We show that fibrinogen, which is deposited perivascularly in MS plaques, signals through Mac-1 and induces the differentiation of microglia to phagocytes via activation of Akt and Rho. Genetic disruption of fibrinogen-Mac-1 interaction in fibrinogen-gamma(390-396A) knock-in mice or pharmacologically impeding fibrinogen-Mac-1 interaction through intranasal delivery of a fibrinogen-derived inhibitory peptide (gamma(377-395)) attenuates microglia activation and suppresses relapsing paralysis. Because blocking fibrinogen-Mac-1 interactions affects the proinflammatory but not the procoagulant properties of fibrinogen, targeting the gamma(377-395) fibrinogen epitope could represent a potential therapeutic strategy for MS and other neuroinflammatory diseases associated with blood-brain barrier disruption and microglia activation.
Adams
Ryan A
RA
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
Bauer
Jan
J
Flick
Matthew J
MJ
Sikorski
Shoana L
SL
Nuriel
Tal
T
Lassmann
Hans
H
Degen
Jay L
JL
Akassoglou
Katerina
K
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005337:Fibrin / Q000502:physiology*; D005340:Fibrinogen / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008969:Molecular Sequence Data; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D010446:Peptide Fragments / Q000502:physiology*
D016177:Macrophage-1 Antigen; C427756:P2-C protein, fibrinogen; D010446:Peptide Fragments; D005337:Fibrin; D005340:Fibrinogen