Abstract: Introduction: Neutrophil extracellular trap (NET) formation was recently identified as a novel mechanism to kill pathogens. However, excessive NET formation in sepsis can injure host tissues. We have recently shown that parenteral vitamin C (VitC) is protective in sepsis. Whether VitC alters NETosis is unknown. Methods: We used Gulo−/− mice as they lack the ability to synthesize VitC. Sepsis was induced by intraperitoneal infusion of a fecal stem solution (abdominal peritonitis, FIP). Some VitC deficient Gulo−/− mice received an infusion of ascorbic acid (AscA, 200 mg/kg) 30 min after induction of FIP. NETosis was assessed histologically and by quantification for circulating free DNA (cf-DNA) in serum. Autophagy, histone citrullination, endoplasmic reticulum (ER) stress, NFκB activation and apoptosis were investigated in peritoneal PMNs. Results: Sepsis produced significant NETs in the lungs of VitC deficient Gulo−/− mice and increased circulating cf-DNA. This was attenuated in the VitC sufficient Gulo−/− mice and in VitC deficient Gulo−/− mice infused with AscA. Polymorphonuclear neutrophils (PMNs) from VitC deficient Gulo−/− mice demonstrated increased activation of ER stress, autophagy, histone citrullination, and NFκB activation, while apoptosis was inhibited. VitC also significantly attenuated PMA induced NETosis in PMNs from healthy human volunteers.
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Mohammed, B.M.; Fisher, B.J.; Kraskauskas, D.; Farkas, D.; Brophy, D.F.; Fowler, A.A.; Natarajan, R. Vitamin C: A Novel Regulator of Neutrophil Extracellular Trap Formation. Nutrients 2013, 5, 3131-3150.
Mohammed BM, Fisher BJ, Kraskauskas D, Farkas D, Brophy DF, Fowler AA, Natarajan R. Vitamin C: A Novel Regulator of Neutrophil Extracellular Trap Formation. Nutrients. 2013; 5(8):3131-3150.
Mohammed, Bassem M.; Fisher, Bernard J.; Kraskauskas, Donatas; Farkas, Daniela; Brophy, Donald F.; Fowler, Alpha A.; Natarajan, Ramesh. 2013. "Vitamin C: A Novel Regulator of Neutrophil Extracellular Trap Formation." Nutrients 5, no. 8: 3131-3150.