The newly identified thirteen-series Resolvins (RvTs) regulate phagocyte functions and accelerate resolution of infectious inflammation. Since SARS-CoV-2 elicits uncontrolled inflammation involving neutrophil extracellular traps (NETs), we tested whether stereochemically defined RvTs regulate NET formation. Using microfluidic devices capturing NETs in PMA-stimulated human whole blood, the RvTs, RvT1-RvT4, 2.5 nM each, potently reduced NETs. With IL-1b-stimulated human neutrophils, each RvT dose- and time-dependently decreased NETosis giving ~50% potencies at 10 nM, compared to the known NETosis inhibitors [10 mM]. In mouse Staphylococcus aureus infection, RvTs [50 ng each] limited neutrophil infiltration, bacterial titers and NETs. Additionally, each RvT enhanced NET uptake by human macrophages; RvT2 was the most potent of the four RvTs, giving >50% increase in NET-phagocytosis. As part of the intracellular signaling mechanism, RvT2 increased cAMP and phospho-AMPK within human macrophages, and RvT2-stimulated NET uptake was abolished by PKA and AMPK inhibition. RvT2 also stimulated NET clearance by mouse macrophages in vivo. Together, these results provide evidence for novel pro-resolving functions of RvTs, namely reducing NETosis and enhancing macrophage NET clearance via a cAMP-PKA-AMPK axis. Thus, RvTs open opportunities for regulating NET-mediated collateral tissue damage during infection as well as monitoring NETs.
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