BioChem - DOS

TF-FVIIa PAR2-β-Arrestin Signaling Sustains Organ Dysfunction in Coxsackievirus B3 Infection of Mice

Arteriosclerosis, thrombosis, and vascular biology

Kespohl, Meike; Goetzke, Carl Christoph; Althof, Nadine; Bredow, Clara; Kelm, Nicolas; Pinkert, Sandra; Bukur, Thomas; Bukur, Valesca; Grunz, Kristin; Kaur, Dilraj; Heuser, Arnd; Mü lleder, Michael; Sauter, Martina; Klingel, Karin; Weiler, Hartmut; Berndt, Nikolaus; Gaida, Matthias M.; Ruf, Wolfram; Beling, Antje

<P>BACKGROUND:<P>Accumulating evidence implicates the activation of G-protein-coupled PARs (protease-activated receptors) by coagulation proteases in the regulation of innate immune responses.</P></P><P>METHODS:<P>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.</P></P><P>RESULTS:<P>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 &beta;-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 &beta;-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.</P></P><P>CONCLUSIONS:<P>These data provide insights into a TF-FVIIa signaling axis through PAR2-&beta;-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.</P></P>

2024

Ovid Technologies Wolters Kluwer -American Heart Association

1079-5642

1524-4636

44

4

pp.843-865

10.1161/atvbaha.123.320157

http://click.ndsl.kr/servlet/OpenAPIDetailView?keyValue=05787966&target=NART&cn=NART129302297