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Review
. 2020 Nov;57(11):4692-4703.
doi: 10.1007/s12035-020-02012-2. Epub 2020 Aug 10.

Fibrinogen and Neuroinflammation During Traumatic Brain Injury

Nurul Sulimai  1 , David Lominadze  2   3
Affiliations
Review

Fibrinogen and Neuroinflammation During Traumatic Brain Injury

Nurul Sulimai et al. Mol Neurobiol. 2020 Nov.

Abstract

Many neurodegenerative diseases such as Alzheimer's disease (AD), multiple sclerosis, and traumatic brain injury (TBI) are associated with systemic inflammation. Inflammation itself results in increased blood content of fibrinogen (Fg), called hyperfibrinogenemia (HFg). Fg is not only considered an acute phase protein and a marker of inflammation, but has been shown that it can cause inflammatory responses. Fibrin deposits have been associated with memory reduction in neuroinflammatory diseases such as AD and TBI. Reduction in short-term memory has been seen during the most common form of TBI, mild-to-moderate TBI. Fibrin deposits have been found in brains of patients with mild-to-moderate TBI. The vast majority of the literature emphasizes the role of fibrin-activated microglia as the mediator in the neuroinflammation pathway. However, the recent discovery that astrocytes, which constitute approximately 30% of the cells in the mammalian central nervous system, manifest different reactive states warrants further investigations in the causative role of HFg in astrocyte-mediated neuroinflammation. Our previous study showed that Fg deposited in the vasculo-astrocyte interface-activated astrocytes. However, little is known of how Fg directly affects astrocytes and neurons. In this review, we summarize studies that show the effect of Fg on different types of cells in the vasculo-neuronal unit. We will also discuss the possible mechanism of HFg-induced neuroinflammation during TBI.

Keywords: Astrocytes; Cortical contusion injury; Fg-PrPC complex; Neurodegeneration; Short-term memory.

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Figures

Figure 1.
Figure 1.. Mechanism of traumatic brain injury (TBI)-induced hyperfibrinogenemia (HFg)-mediated production of reactive oxygen species (ROS).
TBI results in inflammation causing astrocyte activation and HFg. The latter leads to Fg extravasation and its deposition in extravascular space. Fg deposited in vasculo-astrocyte interface also activates astrocytes. Reactive, toxic astrocytes overexpress cellular prion protein (PrPC) and tropomyosin receptor kinase B (TrkB). Close proximity of Fg and PrPC predisposes formation of Fg-PrPC complex. Overexpressed PrPC and Fg-PrPC complex result in production of ROS, while TrkB, via formation of nitric oxide (NO), also results in ROS generation. Increased ROS in neurovascular unit contributes to neurodegeneration.
Figure 2.
Figure 2.. Mechanism of fibrinogen (Fg)-induced neurodegeneration during traumatic brain injury (TBI).
TBI-induced hyperfibrinogenemia (HFg) promotes extravasation of Fg and its deposition in the vasculo-astrocyte endfeet interface. Deposited Fg activates astrocytes in part, through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ƘB) pathway. Activated astrocytes overexpress cellular prion protein (PrPC) and intracellular adhesion molecule-1 (ICAM-1), release interleukin-6 (IL-6) and C-X-C motif chemokine 10 (CXCL10) promoting inflammatory cascade and generate reactive oxygen species (ROS). Fg binds to astrocyte ICAM-1 and cellular prion protein (PrPC) further activating astrocytes and forming Fg-PrPC complex. All these effects lead to neurodegeneration. In parallel, Fg-PrPC complex that can be forming undegradable protein clamp could lead to plaque formation and further contribute to neurodegeneration and thus, short-term memory reduction.
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