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 (αMβ2, 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-γ390-396A knock-in mice or pharmacologically impeding fibrinogen–Mac-1 interaction through intranasal delivery of a fibrinogen-derived inhibitory peptide (γ377-395) 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 γ377-395 fibrinogen epitope could represent a potential therapeutic strategy for MS and other neuroinflammatory diseases associated with blood-brain barrier disruption and microglia activation.
Microglia activation and cone disruption are the main alterations in the retina of human donors with COVID‐19
