Vitamin C and Neutrophil Function: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Nutrition & Dietetics
Contributor:
Anitra Carr

Vitamin C is known to support immune function and is accumulated by neutrophils to millimolar intracellular concentrations suggesting an important role for the vitamin in these cells.

  • vitamin C
  • ascorbic acid
  • neutrophils
  • polymorphonuclear leukocytes
  • migration
  • chemotaxis
  • apoptosis
  • phagocytosis
  • oxidative burst

1. Introduction

Neutrophils are a vital component of the innate immune system, providing a first line of defense against invading pathogens [1]. Following microbial invasion, neutrophils migrate to the site of infection in response to pathogen- and host-derived pro-inflammatory mediators, known as chemotaxis [1]. The neutrophils then proceed to phagocytose, kill and digest the invading pathogens via both oxidative and enzymatic mechanisms [2]. Spent neutrophils subsequently undergo a process of programmed cell death which results in recognition and clearance of the cells by macrophages [3]. Effective clearance of neutrophils from inflammatory loci is vital for resolution of the pro-inflammatory response as release of necrotic cell contents results in tissue damage [4]. Chromatin released from neutrophils, known as neutrophil extracellular traps, comprises both oxidative and proteolytic enzymes, and has been implicated in host tissue damage and various pathologies [5].
Defective neutrophil function is observed in a number of conditions, such as chronic granulomatous disease and Chédiak-Higashi syndrome, which result in recurrent infections [6][7]. Patients with recurrent infections and sepsis can also present with dysfunctional neutrophils, sometimes referred to as immune paralysis due to the inability of the cells to migrate appropriately [8]. It is noteworthy that patients with severe infections and sepsis present with depleted vitamin C status [9][10]. Vitamin C is known to have pleiotropic roles in the immune system, through its antioxidant and enzyme cofactor activities, including potentially supporting neutrophil function [11]. Preclinical studies indicate that neutrophils isolated from scorbutic guinea pigs exhibit attenuated chemotaxis, phagocytosis, oxidant production and microbial killing compared with control animals, and supplementation with vitamin C reversed the dysfunctional activities [12][13][14]. Vitamin C-deficient gulonolactone oxidase (Gulo) knockout mice exhibit dysfunctional neutrophil cell death and diminished uptake by macrophages [15], and vitamin C supplementation can decrease neutrophil extracellular traps formation in septic Gulo knockout mice [16].
Although mean plasma vitamin C concentrations are typically around 50 µmol/L, neutrophils accumulate millimolar intracellular vitamin C concentrations against a concentration gradient which is thought to indicate an important role for the vitamin in these cells [17]. Thus, the depleted vitamin C status of neutrophils observed during infectious episodes could potentially compromise their function [18]. Numerous non-controlled studies have investigated the effects of vitamin C supplementation on the neutrophil functions of chemotaxis, phagocytosis, oxidant generation and microbial killing and predominantly showed positive effects (reviewed in [11]). A number of these studies included patients with known neutrophil dysfunction e.g., those with chronic granulomatous disease or Chédiak-Higashi syndrome, or individuals with allergic or infectious conditions. Exercise, both single bouts and prolonged training over several weeks, can produce changes in the distribution and function of various cellular and humoral components of the immune system [19]. Studies have reported high susceptibility of athletes to infections, especially upper respiratory tract infections, following heavy and intensive training as well as after marathon and ultramarathon running [20][21]. Thus, the effect of vitamin C supplementation on neutrophil function in athletes is also of interest.

2. Current Insights on Vitamin C and Neutrophil Function

Overall, nine of the 16 RCTs included in this review reported no effect of supplementation with vitamin C alone, or in combination with other micronutrients or antioxidants, on various neutrophil functions [19][22][23][24][25][26][27][28][29]. The seven studies which did show effects of supplementation on the neutrophil functions assessed (i.e., chemotaxis, oxidative burst activity, antioxidant enzyme activity and apoptosis) were in hospitalized patients or outpatients [30][31][32][33] or athletes [34][35][36]. None of the other studies carried out with healthy volunteers showed any effects of additional supplementation.
Eight of 10 RCTs showed no effect of supplementation on neutrophil phagocytosis and/or oxidative burst activity [19][23][24][25][26][27][28][29]. The two studies that showed an effect on oxidative burst activity used combination supplements and they showed opposite effects [33][35]. Herbaczynska-Cedro et al. [33] showed decreased oxidant burst activity in acute myocardial infarction patients treated with a combination of vitamins C and E. It is well known that vitamin C can recycle vitamin E and vitamin C has been proposed to interact with vitamin E in vivo, thus they appear to work synergistically [37]. Although another study also tested a combination of vitamins C and E, they saw no effect on oxidative burst activity [25]. However, this study was carried out in smokers and it is known that smoking causes enhanced oxidative stress and smokers require significantly higher intakes of vitamin C to reach the same circulating concentrations as non-smokers [38]. In contrast, Robson et al. [35] showed an increase in oxidative burst activity in trained runners supplemented with an antioxidant combination following prolonged exercise. Since the baseline vitamin C status of the participants was already at saturating levels (i.e., 70 µmol/L), this suggests that the observed effects may have been due to other components of the antioxidant mixture, although it does not rule out vitamin C acting synergistically with these components.
Eight of the 10 RCTs investigating oxidative burst activity and/or phagocytosis were carried out in healthy participants or athletes [19][23][24][26][35][27][28][29]. However, only one of these studies assessed baseline vitamin C status, which was already saturating [35]. It should also be noted that neutrophils saturate at lower vitamin C levels than plasma [39]. Therefore, it is unlikely that supplementing healthy volunteers or athletes with additional vitamin C over and above their normal baseline levels would have an effect on neutrophil function [40]. Exercise trials can also be complicated in that, depending on the exercise intensity, the effects on the immune system can vary such that moderate exercises may have immunopotentiating effects while intense exercise is potentially immunosuppressive [41]. Although two combination trials showed positive effects of supplementation on neutrophil function in athletes [35][36], with combination studies, it is not always possible to determine which of the component(s) is having the effects, or if there are synergistic interactions occurring between the components.
Four of the RCTs administered intravenous vitamin C in hospital or outpatient settings, three of which saw an effect of the intervention on neutrophil chemotaxis and apoptosis [30][22][31][32]. Intravenous vitamin C is known to provide significantly higher plasma concentrations of vitamin C than oral administration [42]. Anderson et al. showed that administration of intravenous vitamin C (1000 mg once daily) was associated with improved neutrophil chemotaxis in asthmatic patients. Maderazo et al. [31] reported an increase in plasma vitamin C status and enhanced neutrophil chemotaxis in trauma patients administrated the combination of vitamins C and E. Ferron-Celma et al. [32] observed a decrease in pro-apoptotic enzymes and an increase in anti-apoptotic proteins in septic patients administered vitamin C alone. The forth study was carried out in healthy children undergoing elective surgery and although their baseline vitamin C levels were not assessed, these may have already been adequate [22]. Furthermore, the vitamin C was administered as a single dose only (10 mg/kg bodyweight), which is less likely to have an effect than repeated dosing [43].
There are a number of limitations of using the RCT paradigm to assess the effectiveness of nutrients such as vitamin C [44]. RCTs were specifically developed and designed to test the safety and efficacy of pharmaceutical drugs, not nutrients. For example, it is not possible to have a true placebo group in RCTs of nutrients as all of the participants will be consuming variable amounts of the nutrient of interest. Of note, a number of the assessed studies did not control for dietary intake or the participants were asked to maintain their normal diet. More than half of the RCTs included in this review did not assess baseline plasma vitamin C status, and a majority of the studies were carried out in healthy individuals, who likely already had adequate plasma vitamin C status prior to beginning the supplementation, thus negating any effect of supplementation. Only one study measured the vitamin C content of the neutrophils pre- and post-supplementation [34]. There was also variability in the analysis of the neutrophil functions, with the chemotaxis, enzyme activity, and apoptosis assays being carried out with isolated cells in buffer or culture media, and the phagocytosis and/or oxidative burst assays being carried out with either whole blood or isolated cells. Furthermore, two of the studies used only a single dose of the vitamin [22][23]. Because vitamin C is water soluble, it is cleared rapidly from circulation by the kidneys, with a half-life of approximately two hours, therefore a regular intake is required to maintain adequate levels [42]. Finally, smoking status is well known to impact on vitamin C status and requirements, due to enhanced oxidative stress [45][38], however, this was not taken into account in a majority of the studies.

3. Conclusions

Overall, 44% of the RCTs assessed in this review showed effects of vitamin C supplementation on various neutrophil functions. The studies were very heterogeneous, comprising different participant cohorts (athletes, hospitalized patents or healthy volunteers) and different dosing regimens (oral or intravenous, monotherapy or multi-supplements, synthetic or food-derived, and from one-off to many months in duration). There were also a number of limitations inherent in the design of many of these RCTs. Unlike drug trials, evidence indicates that RCTs of vitamin C supplementation will be more likely to have a positive effect in participants who are suboptimal or deficient in the vitamin at baseline [44]. Therefore, future RCTs should incorporate prescreening of potential participants for low vitamin C status or utilize cohorts known to have low vitamin status, such as hospitalized patients. The effects of vitamin C administration on more recently discovered functions of neutrophils, such as the formation of neutrophil extracellular traps, should also be explored in future studies based on promising in vitro and preclinical data [16]. Meta-analyses have indicated that vitamin C intakes of at least 200 mg/day can decrease the risk of acquiring respiratory infections [46][47], however, gram doses of vitamin C are required once an infection has taken hold, due to increased requirements for the vitamin [10][48]. Therefore, future RCTs should also comprise appropriate vitamin C dosing for the specific cohort under investigation.

This entry is adapted from the peer-reviewed paper 10.3390/nu11092102

References

  1. Ley, K.; Hoffman, H.M.; Kubes, P.; Cassatella, M.A.; Zychlinsky, A.; Hedrick, C.C.; Catz, S.D. Neutrophils: New insights and open questions. Sci. Immunol. 2018, 3, eaat4579.
  2. Borregaard, N. Neutrophils, from marrow to microbes. Immunity 2010, 33, 657–670.
  3. McCracken, J.M.; Allen, L.A. Regulation of human neutrophil apoptosis and lifespan in health and disease. J. Cell Death 2014, 7, 15–23.
  4. Weiss, S.J. Tissue destruction by neutrophils. N. Engl. J. Med. 1989, 320, 365–376.
  5. Papayannopoulos, V. Neutrophil extracellular traps in immunity and disease. Nat. Rev. Immunol. 2017, 18, 134–147.
  6. Roos, D. Chronic granulomatous disease. Br. Med. Bull. 2016, 118, 50–63.
  7. Introne, W.; Boissy, R.E.; Gahl, W.A. Clinical, molecular, and cell biological aspects of Chediak-Higashi syndrome. Mol. Genet. Metab. 1999, 68, 283–303.
  8. Alves-Filho, J.C.; Spiller, F.; Cunha, F.Q. Neutrophil paralysis in sepsis. Shock 2010, 34 (Suppl. 1), 15–21.
  9. Carr, A.C.; Rosengrave, P.C.; Bayer, S.; Chambers, S.; Mehrtens, J.; Shaw, G.M. Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Crit. Care 2017, 21, 300.
  10. Carr, A.C. Vitamin C in pneumonia and sepsis. In Vissers; Chen, M.Q., Ed.; Oxidative Stress and Disease; Boca Raton Taylor and Francis Group: Boca Raton, FL, USA, 2019; in press.
  11. Carr, A.C.; Maggini, S. Vitamin C and immune function. Nutrients 2017, 9, 1211.
  12. Goldschmidt, M.C. Reduced bactericidal activity in neutrophils from scorbutic animals and the effect of ascorbic acid on these target bacteria in vivo and in vitro. Am. J. Clin. Nutr. 1991, 54 (Suppl. 6), 1214S–1220S.
  13. Shilotri, P.G. Glycolytic, hexose monophosphate shunt and bactericidal activities of leukocytes in ascorbic acid deficient guinea pigs. J. Nutr. 1977, 107, 1507–1512.
  14. Shilotri, P.G. Phagocytosis and leukocyte enzymes in ascorbic acid deficient guinea pigs. J. Nutr. 1977, 107, 1513–1516.
  15. Vissers, M.C.; Wilkie, R.P. Ascorbate deficiency results in impaired neutrophil apoptosis and clearance and is associated with up-regulation of hypoxia-inducible factor 1alpha. J. Leukoc. Biol. 2007, 81, 1236–1244.
  16. Mohammed, B.M.; Fisher, B.J.; Kraskauskas, D.; Farkas, D.; Brophy, D.; Natarajan, R. Vitamin C: A novel regulator of neutrophil extracellular trap formation. Nutrients 2013, 5, 3131–3151.
  17. Washko, P.W.; Wang, Y.; Levine, M. Ascorbic acid recycling in human neutrophils. J. Biol. Chem. 1993, 268, 15531–15535.
  18. Hume, R.; Weyers, E. Changes in leucocyte ascorbic acid during the common cold. Scott. Med. J. 1973, 18, 3–7.
  19. Nieman, D.C.; Henson, D.A.; Butterworth, D.E.; Warren, B.J.; Davis, J.M.; Fagoaga, O.R.; Nehlsen-Cannarella, S.L. Vitamin C supplementation does not alter the immune response to 2.5 hours of running. Int. J. Sport Nutr. 1997, 7, 173–184.
  20. Nieman, D.C.; Johanssen, L.M.; Lee, J.W.; Arabatzis, K. Infectious episodes in runners before and after the Los Angeles Marathon. J. Sports Med. Phys. Fit. 1990, 30, 316–328.
  21. Peters, E.M.; Bateman, E.D. Ultramarathon running and upper respiratory tract infections. An epidemiological survey. S. Afr. Med. J. 1983, 64, 582–584.
  22. Charlton, A.J.; Harvey, B.A.; Hatch, D.J.; Soothill, J.F. Neutrophil mobility during anaesthesia in children. A trial of ascorbate premedication. Acta Anaesthesiol. Scand. 1987, 31, 343–346.
  23. Davison, G.; Gleeson, M. Influence of acute vitamin C and/or carbohydrate ingestion on hormonal, cytokine, and immune responses to prolonged exercise. Int. J. Sport Nutr. Exerc. Metab. 2005, 15, 465–479.
  24. Davison, G.; Gleeson, M. The effect of 2 weeks vitamin C supplementation on immunoendocrine responses to 2.5 h cycling exercise in man. Eur. J. Appl. Physiol. 2006, 97, 454–461.
  25. Fuller, C.J.; May, M.A.; Martin, K.J. The effect of vitamin E and vitamin C supplementation on LDL oxidizability and neutrophil respiratory burst in young smokers. J. Am. Coll. Nutr. 2000, 19, 361–369.
  26. Krause, R.; Patruta, S.; Daxbock, F.; Fladerer, P.; Biegelmayer, C.; Wenisch, C. Effect of vitamin C on neutrophil function after high-intensity exercise. Eur. J. Clin. Investig. 2001, 31, 258–263.
  27. Hunter, D.C.; Skinner, M.A.; Wolber, F.M.; Booth, C.L.; Loh, J.M.; Wohlers, M.; Stevenson, L.M.; Kruger, M.C. Consumption of gold kiwifruit reduces severity and duration of selected upper respiratory tract infection symptoms and increases plasma vitamin C concentration in healthy older adults. Br. J. Nutr. 2012, 108, 1235–1245.
  28. Nieman, D.C.; Henson, D.A.; Sha, W. Ingestion of micronutrient fortified breakfast cereal has no influence on immune function in healthy children: A randomized controlled trial. Nutr. J. 2011, 10, 36.
  29. Wolvers, D.A.; van Herpen-Broekmans, W.M.; Logman, M.H.; van der Wielen, R.P.; Albers, R. Effect of a mixture of micronutrients, but not of bovine colostrum concentrate, on immune function parameters in healthy volunteers: A randomized placebo-controlled study. Nutr. J. 2006, 5, 28.
  30. Anderson, R.; Hay, I.; van Wyk, H.A.; Theron, A. Ascorbic acid in bronchial asthma. S. Afr. Med. J. 1983, 63, 649–652.
  31. Maderazo, E.G.; Woronick, C.L.; Hickingbotham, N.; Jacobs, L.; Bhagavan, H.N. A randomized trial of replacement antioxidant vitamin therapy for neutrophil locomotory dysfunction in blunt trauma. J. Trauma 1991, 31, 1142–1150.
  32. Ferron-Celma, I.; Mansilla, A.; Hassan, L.; Garcia-Navarro, A.; Comino, A.M.; Bueno, P.; Ferrón, J.A. Effect of vitamin C administration on neutrophil apoptosis in septic patients after abdominal surgery. J. Surg. Res. 2009, 153, 224–230.
  33. Herbaczynska-Cedro, K.; Ko-W, B.; Cedro, K.; Wasek, W.; Panczenko-Kresowska, B.; Wartanowicz, M. Supplementation with vitamins C and E suppresses leukocyte oxygen free radical production in patients with myocardial infarction. Eur. Heart J. 1995, 16, 1044–1049.
  34. Sureda, A.; Batle, J.M.; Tauler, P.; Aguilo, A.; Cases, N.; Tur, J.A.; Pons, A. Hypoxia/reoxygenation and vitamin C intake influence NO synthesis and antioxidant defenses of neutrophils. Free Radic. Biol. Med. 2004, 37, 1744–1755.
  35. Robson, P.J.; Bouic, P.J.; Myburgh, K.H. Antioxidant supplementation enhances neutrophil oxidative burst in trained runners following prolonged exercise. Int. J. Sport Nutr. Exerc. Metab. 2003, 13, 369–381.
  36. Tauler, P.; Aguilo, A.; Fuentespina, E.; Tur, J.A.; Pons, A. Diet supplementation with vitamin, E.; vitamin C and beta-carotene cocktail enhances basal neutrophil antioxidant enzymes in athletes. Pflügers Arch. 2002, 443, 791–797.
  37. Bruno, R.S.; Leonard, S.W.; Atkinson, J.; Montine, T.J.; Ramakrishnan, R.; Bray, T.M.; Traber, M.G. Faster plasma vitamin E disappearance in smokers is normalized by vitamin C supplementation. Free Radic. Biol. Med. 2006, 40, 689–697.
  38. Schectman, G.; Byrd, J.C.; Hoffmann, R. Ascorbic acid requirements for smokers: Analysis of a population survey. Am. J. Clin. Nutr. 1991, 53, 1466–1470.
  39. Levine, M.; Conry-Cantilena, C.; Wang, Y.; Welch, R.W.; Washko, P.W.; Dhariwal, K.R.; Park, J.B.; Lazarev, A.; Graumlich, J.F.; King, J.; et al. Vitamin C pharmacokinetics in healthy volunteers: Evidence for a recommended dietary allowance. Proc. Natl. Acad. Sci. USA 1996, 93, 3704–3709.
  40. Bozonet, S.M.; Carr, A.C. The role of physiological vitamin C concentrations on key functions of neutrophils isolated from healthy individuals. Nutrients 2019, 11, 1363.
  41. Hoffman-Goetz, L.; Pedersen, B.K. Exercise and the immune system: A model of the stress response? Immunol. Today 1994, 15, 382–387.
  42. Padayatty, S.J.; Sun, H.; Wang, Y.; Riordan, H.D.; Hewitt, S.M.; Katz, A.; Wesley, R.A.; Levine, M. Vitamin C pharmacokinetics: Implications for oral and intravenous use. Ann. Intern. Med. 2004, 140, 533–537.
  43. Carr, A.C. Duration of intravenous vitamin C therapy is a critical consideration. Crit. Care Resusc. 2019, 21, 220–221.
  44. Lykkesfeldt, J.; Poulsen, H.E. Is vitamin C supplementation beneficial? Lessons learned from randomised controlled trials. Br. J. Nutr. 2010, 103, 1251–1259.
  45. Lykkesfeldt, J.; Loft, S.; Nielsen, J.B.; Poulsen, H.E. Ascorbic acid and dehydroascorbic acid as biomarkers of oxidative stress caused by smoking. Am. J. Clin. Nutr. 1997, 65, 959–963.
  46. Hemilä, H.; Chalker, E. Vitamin C for preventing and treating the common cold. Cochrane Database Syst. Rev. 2013, 1, CD000980.
  47. Hemilä, H.; Louhiala, P. Vitamin C for preventing and treating pneumonia. Cochrane Database Syst. Rev. 2013, Cd005532.
  48. Ran, L.; Zhao, W.; Wang, J.; Wang, H.; Zhao, Y.; Tseng, Y.; Bu, H. Extra dose of vitamin C based on a daily supplementation shortens the common cold: A meta-analysis of 9 randomized controlled trials. BioMed Res. Int. 2018, 2018, 1837634.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
ScholarVision Creations
Feedback