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Breaking boundaries-coagulation and fibrinolysis at the neurovascular interface.

Bardehle S, Rafalski VA, Akassoglou K - Front Cell Neurosci (2015)

Bottom Line: In particular, we focus on novel functions of fibrin-the final product of the coagulation cascade and the main substrate of plasmin-in the activation of immune responses and trafficking of immune cells into the brain.We also comment on the suitability of the coagulation and fibrinolytic systems as potential biomarkers and drug targets in diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD) and stroke.Studying coagulation and fibrinolysis as major molecular pathways that regulate cellular functions at the NVU has the potential to lead to the development of novel strategies for the detection and treatment of neurologic diseases.

View Article: PubMed Central - PubMed

Affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco San Francisco, CA, USA.

ABSTRACT
Blood proteins at the neurovascular unit (NVU) are emerging as important molecular determinants of communication between the brain and the immune system. Over the past two decades, roles for the plasminogen activation (PA)/plasmin system in fibrinolysis have been extended from peripheral dissolution of blood clots to the regulation of central nervous system (CNS) functions in physiology and disease. In this review, we discuss how fibrin and its proteolytic degradation affect neuroinflammatory, degenerative and repair processes. In particular, we focus on novel functions of fibrin-the final product of the coagulation cascade and the main substrate of plasmin-in the activation of immune responses and trafficking of immune cells into the brain. We also comment on the suitability of the coagulation and fibrinolytic systems as potential biomarkers and drug targets in diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD) and stroke. Studying coagulation and fibrinolysis as major molecular pathways that regulate cellular functions at the NVU has the potential to lead to the development of novel strategies for the detection and treatment of neurologic diseases.

No MeSH data available.


Related in: MedlinePlus

The coagulation and proteolytic cascades at the neurovascular interface. (A) Fibrinogen leakage in the central nervous system (CNS) and activation of the plasminogen activation (PA) system occur following blood-brain-barrier (BBB) disruption. The molecular network of fibrin and the PA system enable inflammation and neurodegeneration via activation of microglia, macrophages, and leukocytes. (B) A series of proteolytic events converts extravasated fibrinogen into insoluble fibrin, which can be cleaved into FDPs. Fibrin and FDPs interact with cellular receptors to induce inflammation, degeneration, and repair inhibition in the nervous system. tPA, tissue plasminogen activator; PAI-1, plasminogen activator inhibitor-1; FDPs, fibrin degradation products.
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Figure 1: The coagulation and proteolytic cascades at the neurovascular interface. (A) Fibrinogen leakage in the central nervous system (CNS) and activation of the plasminogen activation (PA) system occur following blood-brain-barrier (BBB) disruption. The molecular network of fibrin and the PA system enable inflammation and neurodegeneration via activation of microglia, macrophages, and leukocytes. (B) A series of proteolytic events converts extravasated fibrinogen into insoluble fibrin, which can be cleaved into FDPs. Fibrin and FDPs interact with cellular receptors to induce inflammation, degeneration, and repair inhibition in the nervous system. tPA, tissue plasminogen activator; PAI-1, plasminogen activator inhibitor-1; FDPs, fibrin degradation products.

Mentions: The pivotal fibrinolytic functions of the PA system were discovered in Plg-deficient mice, which show impaired wound healing, severe thrombosis, early lethality and delayed nerve regeneration (Bugge et al., 1995; Akassoglou et al., 2000). Interestingly, this phenotype is rescued by fibrinogen deficiency, suggesting that fibrin(ogen) is the main physiologic substrate for plasmin in vivo (Bugge et al., 1996; Akassoglou et al., 2000). Besides binding plasmin, fibrin(ogen) interacts with cell surface receptors expressed by different cell types in the CNS, including microglia (Adams et al., 2007; Davalos et al., 2012; Ryu et al., 2015), neurons (Schachtrup et al., 2007), astrocytes (Schachtrup et al., 2010) and Schwann cells (Akassoglou et al., 2002; reviewed in Davalos and Akassoglou, 2012; Ryu et al., 2009). Thus, fibrinogen acts as a molecular switch linking the PA system to activation of cell intrinsic signaling pathways involved in immune response and CNS homeostasis/neuronal functions (Figure 1).


Breaking boundaries-coagulation and fibrinolysis at the neurovascular interface.

Bardehle S, Rafalski VA, Akassoglou K - Front Cell Neurosci (2015)

The coagulation and proteolytic cascades at the neurovascular interface. (A) Fibrinogen leakage in the central nervous system (CNS) and activation of the plasminogen activation (PA) system occur following blood-brain-barrier (BBB) disruption. The molecular network of fibrin and the PA system enable inflammation and neurodegeneration via activation of microglia, macrophages, and leukocytes. (B) A series of proteolytic events converts extravasated fibrinogen into insoluble fibrin, which can be cleaved into FDPs. Fibrin and FDPs interact with cellular receptors to induce inflammation, degeneration, and repair inhibition in the nervous system. tPA, tissue plasminogen activator; PAI-1, plasminogen activator inhibitor-1; FDPs, fibrin degradation products.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4584986&req=5

Figure 1: The coagulation and proteolytic cascades at the neurovascular interface. (A) Fibrinogen leakage in the central nervous system (CNS) and activation of the plasminogen activation (PA) system occur following blood-brain-barrier (BBB) disruption. The molecular network of fibrin and the PA system enable inflammation and neurodegeneration via activation of microglia, macrophages, and leukocytes. (B) A series of proteolytic events converts extravasated fibrinogen into insoluble fibrin, which can be cleaved into FDPs. Fibrin and FDPs interact with cellular receptors to induce inflammation, degeneration, and repair inhibition in the nervous system. tPA, tissue plasminogen activator; PAI-1, plasminogen activator inhibitor-1; FDPs, fibrin degradation products.
Mentions: The pivotal fibrinolytic functions of the PA system were discovered in Plg-deficient mice, which show impaired wound healing, severe thrombosis, early lethality and delayed nerve regeneration (Bugge et al., 1995; Akassoglou et al., 2000). Interestingly, this phenotype is rescued by fibrinogen deficiency, suggesting that fibrin(ogen) is the main physiologic substrate for plasmin in vivo (Bugge et al., 1996; Akassoglou et al., 2000). Besides binding plasmin, fibrin(ogen) interacts with cell surface receptors expressed by different cell types in the CNS, including microglia (Adams et al., 2007; Davalos et al., 2012; Ryu et al., 2015), neurons (Schachtrup et al., 2007), astrocytes (Schachtrup et al., 2010) and Schwann cells (Akassoglou et al., 2002; reviewed in Davalos and Akassoglou, 2012; Ryu et al., 2009). Thus, fibrinogen acts as a molecular switch linking the PA system to activation of cell intrinsic signaling pathways involved in immune response and CNS homeostasis/neuronal functions (Figure 1).

Bottom Line: In particular, we focus on novel functions of fibrin-the final product of the coagulation cascade and the main substrate of plasmin-in the activation of immune responses and trafficking of immune cells into the brain.We also comment on the suitability of the coagulation and fibrinolytic systems as potential biomarkers and drug targets in diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD) and stroke.Studying coagulation and fibrinolysis as major molecular pathways that regulate cellular functions at the NVU has the potential to lead to the development of novel strategies for the detection and treatment of neurologic diseases.

View Article: PubMed Central - PubMed

Affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco San Francisco, CA, USA.

ABSTRACT
Blood proteins at the neurovascular unit (NVU) are emerging as important molecular determinants of communication between the brain and the immune system. Over the past two decades, roles for the plasminogen activation (PA)/plasmin system in fibrinolysis have been extended from peripheral dissolution of blood clots to the regulation of central nervous system (CNS) functions in physiology and disease. In this review, we discuss how fibrin and its proteolytic degradation affect neuroinflammatory, degenerative and repair processes. In particular, we focus on novel functions of fibrin-the final product of the coagulation cascade and the main substrate of plasmin-in the activation of immune responses and trafficking of immune cells into the brain. We also comment on the suitability of the coagulation and fibrinolytic systems as potential biomarkers and drug targets in diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD) and stroke. Studying coagulation and fibrinolysis as major molecular pathways that regulate cellular functions at the NVU has the potential to lead to the development of novel strategies for the detection and treatment of neurologic diseases.

No MeSH data available.


Related in: MedlinePlus