The fibrin-derived γ377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease

Abstract

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.

Alzheimer's disease peptide β-amyloid interacts with fibrinogen and induces its oligomerization

“…As a control, we tested whether a random peptide derived from fibrinogen (γ377-γ395) could inhibit the Aβ42-fibrinogen interaction. This peptide is known to inhibit the interaction between fibrinogen and integrin receptor Mac-1 (27), but it did not inhibit the Aβ42-fibrinogen interaction (Fig. 4B).…”

Chronic relapsing experimental allergic encephalomyelitis (CREAE) in plasminogen activator inhibitor‐1 knockout mice: the effect of fibrinolysis during neuroinflammation

“…Furthermore, in a tumour necrosis factor transgenic mouse model of MS, reduced neuroinflammation and decreased demyelination were observed in genetically or pharmacologically fibrin-depleted mice, with a resultant lengthened lifespan compared with WT or vehicle-injected animals [45]. Additionally, fibrinogen can stimulate secretion of pro-inflammatory cytokines and chemokines, and is a potent stimulator of macrophage and microglial activation [45,46] via interaction with the MAC-1 receptor. As fibrin is capable of modulating inflammation via a number of different mechanisms, it is clear that removal of this plasma protein, by enhancing fibrinolysis, can produce extremely beneficial results.…”

A bloody brake on myelin repair

“…Petersen et al show that the fibrinogen-cleaving enzyme ancrod -an anticoagulant from a snake venom that has been proposed (although not approved) as a treatment for ischaemic stroke -enhanced the remyelination of demyelinated axons. A mouse model of MS has previously been shown to benefit from ancrod and fibrinogen depletion 7 , owing in part to anti-inflammatory effects. However, it is possible that myelin repair is also improved in these animals.…”