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| Item Type: | Article |
|---|---|
| Title: | TF-FVIIa PAR2-β-arrestin in mouse signaling sustains organ dysfunction in coxsackievirus B3 infection |
| Creators Name: | Kespohl, M., Goetzke, C.C., Althof, N., Bredow, C., Kelm, N., Pinkert, S., Bukur, T., Bukur, V., Grunz, K., Kaur, D., Heuser, A., Mülleder, M., Sauter, M., Klingel, K., Weiler, H., Berndt, N., Gaida, M.M., Ruf, W. and Beling, A. |
| Abstract: | BACKGROUND: Accumulating evidence implicates the activation of G-protein-coupled PARs (protease-activated receptors) by coagulation proteases in the regulation of innate immune responses. METHODS: Using mouse models with genetic alterations of the PAR2 signaling platform, we have explored contributions of PAR2 signaling to infection with coxsackievirus B3, a single-stranded RNA virus provoking multiorgan tissue damage, including the heart. RESULTS: We show that PAR2 activation sustains correlates of severe morbidity-hemodynamic compromise, aggravated hypothermia, and hypoglycemia-despite intact control of the virus. Following acute viral liver injury, canonical PAR2 signaling impairs the restoration process associated with exaggerated type I IFN (interferon) signatures in response to viral RNA recognition. Metabolic profiling in combination with proteomics of liver tissue shows PAR2-dependent reprogramming of liver metabolism, increased lipid droplet storage, and gluconeogenesis. PAR2-sustained hypodynamic compromise, reprograming of liver metabolism, as well as imbalanced IFN responses are prevented in β-arrestin coupling-deficient PAR2 C-terminal phosphorylation mutant mice. Thus, wiring between upstream proteases and immune-metabolic responses results from biased PAR2 signaling mediated by intracellular recruitment of β-arrestin. Importantly, blockade of the TF (tissue factor)-FVIIa (coagulation factor VIIa) complex capable of PAR2 proteolysis with the NAPc2 (nematode anticoagulant protein c2) mitigated virus-triggered pathology, recapitulating effects seen in protease cleavage-resistant PAR2 mice. CONCLUSIONS: These data provide insights into a TF-FVIIa signaling axis through PAR2-β-arrestin coupling that is a regulator of inflammation-triggered tissue repair and hemodynamic compromise in coxsackievirus B3 infection and can potentially be targeted with selective coagulation inhibitors. |
| Keywords: | Heart Failure, Infections, Inflammation, Myocarditis, Proteomics, Animals, Mice |
| Source: | Arteriosclerosis Thrombosis and Vascular Biology |
| ISSN: | 1079-5642 |
| Publisher: | American Heart Association |
| Volume: | 44 |
| Number: | 4 |
| Page Range: | 843-865 |
| Date: | April 2024 |
| Official Publication: | https://doi.org/10.1161/ATVBAHA.123.320157 |
| PubMed: | View item in PubMed |
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