Coagulation takes center stage in inflammation

Akassoglou, Katerina

doi:10.1182/blood-2014-11-609222

Cited by 10 publications

(10 citation statements)

References 8 publications

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“…It is possible that in addition to fibrinogen, other plasma proteins might play a role in brain pathology. In particular, other components of the coagulation cascade involved in fibrin formation and clot stabilization, such as thrombin, factors X, XII and XIII could be involved in inflammatory responses 49 . Future studies will elucidate the relative contribution of blood proteins to brain inflammation and neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation

et al. 2015

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Autoimmunity and macrophage recruitment into the central nervous system (CNS) are critical determinants of neuroinflammatory diseases. However, the mechanisms that drive immunological responses targeted to the CNS remain largely unknown. Here we show that fibrinogen, a central blood coagulation protein deposited in the CNS after blood–brain barrier disruption, induces encephalitogenic adaptive immune responses and peripheral macrophage recruitment into the CNS leading to demyelination. Fibrinogen stimulates a unique transcriptional signature in CD11b+ antigen-presenting cells inducing the recruitment and local CNS activation of myelin antigen-specific Th1 cells. Fibrinogen depletion reduces Th1 cells in the multiple sclerosis model, experimental autoimmune encephalomyelitis. Major histocompatibility complex (MHC) II-dependent antigen presentation, CXCL10- and CCL2-mediated recruitment of T cells and macrophages, respectively, are required for fibrinogen-induced encephalomyelitis. Inhibition of the fibrinogen receptor CD11b/CD18 protects from all immune and neuropathologic effects. Our results show that the final product of the coagulation cascade is a key determinant of CNS autoimmunity.

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Section: Discussionmentioning

confidence: 99%

Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation

et al. 2015

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“…Emerging evidence from the fields of neuroscience, immunology, and vascular biology have aimed the spotlight on fibrin and the fibrinolytic system for their pleiotropic functions in neurological diseases. Although current evidence points to fibrin as a major contributor to neuroinflammation and neurodegeneration, it is possible that other components of the coagulation cascade are activated upon neurologic disease and play a role in CNS diseases via fibrin-dependent and potentially fibrin-independent mechanisms (Akassoglou, 2015 ). For example, a novel molecular probe for thrombin identified increased thrombin activity in animal models of stroke (Chen et al, 2012 ) and MS (Davalos et al, 2014 ).…”

Section: Future Directionsmentioning

confidence: 99%

Breaking boundaries—coagulation and fibrinolysis at the neurovascular interface

Bardehle

Rafalski

Akassoglou

2015

Front. Cell. Neurosci.

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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.

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“…Fibrinogen plays a causative role in nervous system disease as a regulator of inflammation (Akassoglou et al, 2004;Adams et al, 2007a,b;Akassoglou, 2015), remyelination (Akassoglou et al, 2002), and neurodegeneration (Schachtrup et al, 2007). Fibrin, the final product of the coagulation cascade, is a result of thrombin-mediated conversion of fibrinogen to an insoluble fibrin network (Akassoglou, 2015).…”

Section: Discussionmentioning

confidence: 98%

“…Fibrin, the final product of the coagulation cascade, is a result of thrombin-mediated conversion of fibrinogen to an insoluble fibrin network (Akassoglou, 2015).…”

Section: Discussionmentioning

confidence: 99%