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Vitamin C: A Novel Regulator of Neutrophil Extracellular Trap Formation
Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, VA 23298, USA
Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
Division of Pulmonary Disease and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
* Author to whom correspondence should be addressed.
Received: 13 May 2013; in revised form: 30 July 2013 / Accepted: 5 August 2013 / Published: 9 August 2013
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.
Keywords: vitamin C; sepsis; neutrophils; NETosis; cell free DNA; nuclear factor κB
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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.