Abstract
The transcription factor NF-κB is a central mediator of inflammation with multiple links to thrombotic processes. In this review, we focus on the role of NF-κB signaling in cell types within the vasculature and the circulation that are involved in thrombo-inflammatory processes. All these cells express NF-κB, which mediates important functions in cellular interactions, cell survival and differentiation, as well as expression of cytokines, chemokines, and coagulation factors. Even platelets, as anucleated cells, contain NF-κB family members and their corresponding signaling molecules, which are involved in platelet activation, as well as secondary feedback circuits. The response of endothelial cells to inflammation and NF-κB activation is characterized by the induction of adhesion molecules promoting binding and transmigration of leukocytes, while simultaneously increasing their thrombogenic potential. Paracrine signaling from endothelial cells activates NF-κB in vascular smooth muscle cells and causes a phenotypic switch to a “synthetic” state associated with a decrease in contractile proteins. Monocytes react to inflammatory situations with enforced expression of tissue factor and after differentiation to macrophages with altered polarization. Neutrophils respond with an extension of their life span—and upon full activation they can expel their DNA thereby forming so-called neutrophil extracellular traps (NETs), which exert antibacterial functions, but also induce a strong coagulatory response. This may cause formation of microthrombi that are important for the immobilization of pathogens, a process designated as immunothrombosis. However, deregulation of the complex cellular links between inflammation and thrombosis by unrestrained NET formation or the loss of the endothelial layer due to mechanical rupture or erosion can result in rapid activation and aggregation of platelets and the manifestation of thrombo-inflammatory diseases. Sepsis is an important example of such a disorder caused by a dysregulated host response to infection finally leading to severe coagulopathies. NF-κB is critically involved in these pathophysiological processes as it induces both inflammatory and thrombotic responses.
Highlights
Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology
Neutrophils respond with an extension of their life span—and upon full activation they can expel their DNA thereby forming so-called neutrophil extracellular traps (NETs), which exert antibacterial functions, and induce a strong coagulatory response
Chronic inflammation causes a phenotypic switch of vascular smooth muscle cells from a contractile to a synthetic phenotype, which is associated with secretion of pro-inflammatory mediators and which can result in a macrophage-like state [5]
Summary
Il-1β, TNFα [25, 26], IL-12 [27], IL-17 [28], IL-33 [29], Lymphotoxin-β [30], GM-CSF [31]. Most of the NF-κB-activating signaling pathways converge at the level of IκB kinases (IKKα and IKKβ), which upon activation phosphorylate the inhibitory molecules of the IκB family or the inhibitory domains of p100 and p105 on two adjacent serine residues This triggers another type of polyubiquitination, which is characterized by linkage of ubiquitin moieties via lysine-48 (K48) and catalyzed by E3ligases of the CRL (Cullin-Ring ligase) type, named SCFtype (for the key components Skp, Cullin, and F-box protein) [80, 81]. The major biological function of NF-κB is to change cellular programs in all different kinds of stress situations, so that the various cell types can respond to the stress in a way that the organism can cope with the threat, activate defense mechanisms and eliminate or escape the endangering factors with the final aim to re-gain the original physiological state [83] This major biological function of NF-κB signaling explains the various types of target genes that are upregulated or induced after NFκB activation. Important NF-κB target genes in the context of inflammation include various enzymes such as cyclooxygenases and lipoxygenases catalyzing the formation of prostaglandins and leukotrienes, as well as NO synthases, which are important
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