Fibrinogen deposition promotes neuroinflammation and fibrin-derived γ377-395 peptide ameliorates neurological deficits after ischemic stroke

Abstract

Background: Fibrin(ogen) deposition in the central nervous system (CNS) contributes to neuropathological injury; however, its role in ischemic stroke is unknown. In this study, we identified fibrinogen as a novel proinflammatory regulator of post-stroke neuroinflammation and revealed the neuro-protection effect of fibrin-derived γ^377-395peptide in stroke.

Methods: Fibrinogen depletion and fibrinogen-derived γ^377-395peptide treatment were performed 2 h after establishing a permanent middle cerebral artery occlusion (pMCAO) model. The infarction volume, neurological score, fibrin(ogen) deposition, and inflammatory response were evaluated 24 h after occlusion. Both in vivo and in vitro studies were conducted to assess the therapeutic potential of the γ^377-395peptide in blocking the interactions between fibrin(ogen) and neutrophils.

Results: Fibrin(ogen) deposited in the infarct core promoted post-stroke inflammation and exacerbated neurological deficits in the acute phase after stroke onset. Reducing fibrinogen deposition resulted in a decrease in infarction volume, improved neurological scores, and reduced inflammation in the brain. Additionally, the presence of neutrophil accumulation near fibrin(ogen) deposits was observed in ischemic lesions, and the engagement of fibrin(ogen) by integrin receptor α_Mβ₂ promoted neutrophil activation and post-stroke inflammation. Finally, inhibiting fibrin(ogen)-mediated neutrophil activation using a fibrinogen-derived γ^377-395peptide significantly attenuated neurological deficits.

Conclusions: Fibrin(ogen) is a crucial regulator of post-stroke inflammation and contributes to secondary brain injury. The inflammation induced by fibrin(ogen) is primarily driven by neutrophils during acute ischemic stroke and can be ameliorated using the fibrin-derived γ^377-395peptide. Targeting the fibrin(ogen)-mediated neuropathological process represents a promising approach for neuroprotective therapy after stroke while preserving its beneficial coagulation function.

Keywords: Fibrinogen deposition; Ischemic stroke; Neuroinflammation; Neutrophil; Post-stroke inflammation.