Fibrinogen Signal Transduction as a Mediator and Therapeutic Target in Inflammation:Lessons from Multiple Sclerosis

Abstract

The blood protein fibrinogen as a ligand for integrin and non-integrin receptors functions as the molecular nexus of coagulation, inflammation and immunity. Studies in animal models and in human disease have demonstrated that extravascular fibrinogen that is deposited in tissues upon vascular rupture is not merely a marker, but a mediator of diseases with an inflammatory component, such as rheumatoid arthritis, multiple sclerosis, sepsis, myocardial infarction and bacterial infection. The present article focuses on the recent discoveries of specific cellular targets and receptors for fibrinogen within tissues that have extended the role of fibrinogen from a coagulation factor to a regulator of inflammation and immunity. Fibrinogen has the potential for selective drug targeting that would target its proinflammatory properties without affecting its beneficial effects in hemostasis, since it interacts with different receptors to mediate blood coagulation and inflammation. Strategies to target receptors for fibrinogen and fibrin within the tissue microenvironment could reveal selective and disease-specific agents for therapeutic intervention in a variety of human diseases associated with fibrin deposition.

Bone Marrow-Derived Mast Cells Accumulate in the Central Nervous System During Inflammation but Are Dispensable for Experimental Autoimmune Encephalomyelitis Pathogenesis

“…Although our results suggest that mast cells are dispensable for development of disease, we do not discount the ability of mast cells to augment local tissue inflammation; this report is consistent with previous studies detecting mast cells associated with inflammatory infiltrate in both multiple sclerosis and EAE tissue, as well as products of activated mast cells in the cerebrospinal fluid of multiple sclerosis patients (32,33). Specifically, disruption of the blood brain barrier is well documented in these diseases and serum factors such as fibrinogen are reported to stimulate mast cells leading to degranulation (34). It is easy to conceive of a scenario in which the appropriate chemotactic stimulus is present in the context of inflamed CNS tissue whereby mast cells are recruited to the damage site, exposed to serum factors (including fibrinogen), and induced to degranulate, adding to the inflammatory milieu in the tissue and cerebrospinal fluid.…”

Reactive Astrogliosis Causes the Development of Spontaneous Seizures

“…Serum factors are deposited in the brain parenchyma after blood-brain barrier breakdown and this alone can generate inflammation and astrogliosis and trigger seizures (Seiffert et al, 2004;Adams et al, 2007;Schachtrup et al, 2010;Heinemann et al, 2012;Janigro, 2012). One effect of albumin deposition is astrocytic TGFRII activation, which can then lead to downregulation of Kir4.1 and Glt-1 through a TGF-␤-mediated mechanism (Frigerio et al, 2012).…”

The Effect of Sibutramine, a Serotonin-Norepinephrine Reuptake Inhibitor, on Platelets and Fibrin Networks of Male Sprague-Dawley Rats: A Descriptive Study

“…The coagulation cascade is the vital component that maintains the balance required for hemostasis by activating platelets and forming a hemostatic platelet plug as well as stabilizing fibrin networks, contributing to blood clot formation [27,28]. Laboratory-based investigations of fibrin structures, platelet morphology, and the fibrin clot in general has become a popular and powerful research tool as these structural findings could differ in and provide essential information on various diseased states possibly contributing to the discovery of new therapeutic targets [29,30].…”