Abstract
The emerging concept of a crosstalk between hemostasis, inflammation, and immune system prompt recent works on coagulation cascade in multiple sclerosis (MS). Studies on MS pathology identified several coagulation factors since the beginning of the disease pathophysiology: fibrin deposition with breakdown of blood brain barrier, and coagulation factors within active plaques may exert pathogenic role, especially through the innate immune system. Studies on circulating coagulation factors showed complex imbalance involving several components of hemostasis cascade (thrombin, factor X, factor XII). To analyze the role of the coagulation process in connection with other pathogenic pathways, we implemented a systematic matching of genome-wide association studies (GWAS) data with an informative and unbiased network of coagulation pathways. Using MetaCore (version 6.35 build 69300, 2018) we analyzed the connectivity (i.e., direct and indirect interactions among two networks) between the network of the coagulation process and the network resulting from feeding into MetaCore the MS GWAS data. The two networks presented a remarkable over-connectivity: 958 connections vs. 561 expected by chance; z-score = 17.39; p-value < 0.00001. Moreover, genes coding for cluster of differentiation 40 (CD40) and plasminogen activator, urokinase (PLAU) shared both networks, pointed to an integral interplay between coagulation cascade and main pathogenic immune effectors. In fact, CD40 pathways is especially operative in B cells, that are currently a major therapeutic target in MS field. The potential interaction of PLAU with a signal of paramount importance for B cell pathogenicity, such as CD40, suggest new lines of research and pave the way to implement new therapeutic targets.
Highlights
Recent studies focused on the role of coagulation cascade in neuroinflammation and neurodegenerative disease, considering new suggestions on a crosstalk between hemostasis, inflammation and immune system [1]
A recent review discussed the role of fibrinogen in some neurological diseases, with an emphasis on the cellular targets and the fibrinogen-induced signal transduction pathways in the central nervous system (CNS): fibrinogen has a pleiotropic role in the activation of inflammation and pathologies that share, as common change, the increased blood-brain barrier (BBB) permeability
In particular we considered genes that were reported in 19 multiple sclerosis (MS) genome-wide association studies (GWAS) studies [23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41] filed in the GWAS Catalog; such list (Supplementary Table 1) contains 398 genes, that were either reported as associated to MS in the aforementioned studies, or that were originally reported as hits on non-well specified regions, later mapped to better characterized regions and genes
Summary
Recent studies focused on the role of coagulation cascade in neuroinflammation and neurodegenerative disease, considering new suggestions on a crosstalk between hemostasis, inflammation and immune system [1]. In vivo experiments with antagonists of the coagulation factors identified (hirudin or recombinant activated protein C) were capable of ameliorating animal models of MS and suppressing pathogenic immune effectors, confirming the impact of dysregulated coagulation factors on demyelinating processes and suggesting potential therapeutic targets [9].
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