Fibrin promotes oxidative stress and neuronal loss in traumatic brain injury via innate immune activation, 2024 Terry Dean et al

Abstract
Background
Traumatic brain injury (TBI) causes significant blood-brain barrier (BBB) breakdown, resulting in the extravasation of blood proteins into the brain. The impact of blood proteins, especially fibrinogen, on inflammation and neurodegeneration post-TBI is not fully understood, highlighting a critical gap in our comprehension of TBI pathology and its connection to innate immune activation.

Methods
We combined vascular casting with 3D imaging of solvent-cleared organs (uDISCO) to study the spatial distribution of the blood coagulation protein fibrinogen in large, intact brain volumes and assessed the temporal regulation of the fibrin(ogen) deposition by immunohistochemistry in a murine model of TBI. Fibrin(ogen) deposition and innate immune cell markers were co-localized by immunohistochemistry in mouse and human brains after TBI. We assessed the role of fibrinogen in TBI using unbiased transcriptomics, flow cytometry and immunohistochemistry for innate immune and neuronal markers in Fggγ390–396A knock-in mice, which express a mutant fibrinogen that retains normal clotting function, but lacks the γ390–396 binding motif to CD11b/CD18 integrin receptor.

Results
We show that cerebral fibrinogen deposits were associated with activated innate immune cells in both human and murine TBI. Genetic elimination of fibrin-CD11b interaction reduced peripheral monocyte recruitment and the activation of inflammatory and reactive oxygen species (ROS) gene pathways in microglia and macrophages after TBI. Blockade of the fibrin-CD11b interaction was also protective from oxidative stress damage and cortical loss after TBI.

Conclusions
These data suggest that fibrinogen is a regulator of innate immune activation and neurodegeneration in TBI. Abrogating post-injury neuroinflammation by selective blockade of fibrin’s inflammatory functions may have implications for long-term neurologic recovery following brain trauma.

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A New Therapeutic Target for Traumatic Brain Injury

The team leveraged genetic tools to identify a specific mutation in fibrin that can block it from activating immune cells without affecting the protein’s beneficial blood-clotting abilities. This is especially critical for traumatic brain injuries, as excessive bleeding into the brain has been known to occur among patients who were taking anticoagulant medications before their injury.

Akassoglou’s lab previously developed a drug, a therapeutic monoclonal antibody, that acts only on fibrin’s inflammatory properties, without adverse effects on blood coagulation. This fibrin-targeting immunotherapy protects from multiple sclerosis and Alzheimer’s disease in mice. A humanized version of this first-in-class fibrin immunotherapy is already in Phase 1 safety clinical trials by Therini Bio.

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Thread for their prior review article at Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics (2018, Nature Reviews Neuroscience)