The Role of Sterile Inflammation in Thrombosis: Consequences for Cardiovascular Disease and COVID‐19

Figures

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  Figure 1. Overview of sterile inflammation.

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  Figure 2. DAMP associated with different modes of cell death.

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  Figure 3. A simplified model of how viral nucleic acids (such as dsRNA, ssRNA, and dsDNA) activate PRRs. TLRs in endosomes and RIG-1-like receptors (RLRs) in the cytoplasm are directly activated by viral nucleic acids. This activation triggers the formation of macromolecular signaling complexes through adapter proteins like MyD88 and TRIF, as well as adapter motifs like CARD (caspase recruitment domains). These complexes initiate downstream signaling pathways (not depicted), leading to the activation of transcription factors (NF-kB, p38-MAP-kinase pathway, and interferon regulatory factor [IRF]), resulting in the expression of genes involved in inflammatory responses. Additionally, tissue factors released during viral injury can activate the NLRP3 inflammasome, which induces interleukin-1b febrile responses. PAMP refers to pathogen-associated molecular pattern. NLR3, NOD like receptor family, pyrin domain containing 3. CARD, Caspase recruitment domain; IRF, interferon regulatory factor; RLRs, RIG-1 like receptors; TLRs, Toll-like receptors.

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  Figure 4. TLR signaling pathway is essential for detecting distinct microbial patterns. All TLRs, except TLR3, trigger the production of pro-inflammatory cytokines via a MyD88–IRAK–TRAF6–NF-κB dependent signaling pathway. On the other hand, the MyD88–IRAK–TRAF6 pathway is involved in the secretion of type I interferons (IFNs) also (not shown). TLR3, leads to the secretion of pro-inflammatory cytokines such as IL-1 and TNF-α through a TRIF- and RIP1-dependent mechanism. Additionally, both TLR3 and TLR4 can engage a MyD88-independent pathway, also known as the TRIF-dependent pathway, to induce the expression of Type I interferons (IFN-α, β) and IFN-inducible proteins in response to viral infections. NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; TRAM, translocation associated membrane protein 1. AP1, activator protein 1; IL-1, interleukin-1; IRAK1, interleukin-1 receptor-associated kinase 1; IRAK4, interleukin-1 receptor associated kinase 4; IRF3, interferon regulatory factor 3; MAPK, mitogen-activated protein kinase; MyD88, myeloid differentiation primary response 88; RIP1, receptor interacting serine/threonine-protein kinase 1; TAK1, transforming growth factor…

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  Figure 5. Passive release of HMGB1 during different modes of cell death.

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  Figure 6. Structural organization of human HMGB1.

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  Figure 7. Endothelial cells become activated in response to an inflammatory stimulus, which causes vWF and its propeptide vWFpp (yellow in color) to be released in massive quantities from Weibel–Palade bodies (WPBs) (A). vWF and vWFpp levels are consequently higher than in the basal state (B), and measuring the VWFpp/VWF ratio may aid in differentiating between acute and chronic inflammation.

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  Figure 8. Regeneration of skeletal muscles by appropriate levels of S100b protein after acute muscle injury.

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  Figure 9. Molecular mechanism implied in immunothrombosis/thromboinflammation. Upon activation of immune cells, tissue factor (TF) is decrypted and released from these cells. This activation also triggers pyroptosis via the NLRP3 inflammasome. Consequently, thrombin is generated, which leads to platelet activation and NETosis. These events enhance fibrin formation and increase the release of proinflammatory cytokines.

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  Figure 10. Thrombosis and inflammation: The processes of hemostasis and thrombosis are closely interconnected. Key cytokines such as TNFα, IL-1, and IL-6 can contribute to a prothrombotic environment.

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  Figure 11. Hypoxia is crucial in the inflammatory process. In chronic inflammation, the oxygen demand in affected tissues increases while the oxygen supply decreases, resulting in tissue hypoxia. This oxygen shortage leads to heightened activity of hypoxia-inducible factors (HIF) in both resident and infiltrating immune cells. The elevated HIF activity then alters the function of these immune cells, affecting the overall inflammatory response and its severity.

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  Figure 12. Hypoxia links thrombosis risk factors to blood clot formation. When these risk factors induce hypoxia, it activates both HIF-dependent and independent signaling pathways, which then trigger the expression of hypoxia-regulated genes involved in coagulation and fibrinolysis. Targeting these hypoxia-regulated genes could offer a promising strategy for preventing thrombosis.