CoChat
Sign Up
Cited by 78

The DOI matches its Crossref record; 55 of the 55 references it cites were found in a registry or an index.

Nutritional immunity: the impact of metals on lung immune cells and the airway microbiome during chronic respiratory disease

Healy, Claire, Munoz-Wolf, Natalia, Strydom, Janné, Faherty, Lynne, Williams, Niamh C., Kenny, Sarah, Donnelly, Seamas C., Cloonan, Suzanne M.·2021·Respiratory Research
DOI 10.1186/s12931-021-01722-yPMC PMC8082489
Open this paper in CoChat — free account

Abstract

Nutritional immunity is the sequestration of bioavailable trace metals such as iron, zinc and copper by the host to limit pathogenicity by invading microorganisms. As one of the most conserved activities of the innate immune system, limiting the availability of free trace metals by cells of the immune system serves not only to conceal these vital nutrients from invading bacteria but also operates to tightly regulate host immune cell responses and function. In the setting of chronic lung disease, the regulation of trace metals by the host is often disrupted, leading to the altered availability of these nutrients to commensal and invading opportunistic pathogenic microbes. Similarly, alterations in the uptake, secretion, turnover and redox activity of these vitally important metals has significant repercussions for immune cell function including the response to and resolution of infection. This review will discuss the intricate role of nutritional immunity in host immune cells of the lung and how changes in this fundamental process as a result of chronic lung disease may alter the airway microbiome, disease progression and the response to infection.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/s12931-021-01722-y

Cites

55 of 55 references verified0 citation errors · 0 not checkable

Statistics

Figures

Fig. 1 Macrophage Metal Metabolism. This brief summary of the metal metabolism of a generic macrophage highlights several mechanisms by which a macrophage can obtain metals. There are numerous metal transport proteins and receptors involved to ensure an adequate supply of these essential metals to the macrophage. (1) Macrophages obtain iron from various sources. Free circulating iron is first reduced from ferric to ferrous iron and then imported into the macrophage via protein transporters such as DMT1 and ZIP14. Transferrin-bound iron is bound to the transferrin receptor on the cell surface and imported via receptor-mediated endocytosis. Some macrophages also have the ability to obtain iron via erythrophagocytosis while others express receptors such as CD163 and CD64 allowing for the uptake of haemoglobin-haptoglobin and heme-hemopexin complexes, respectively. Once iron enters the macrophage it has numerous fates depending on the activation state of the cell. It can be stored in its ferrous state within the ferritin complex or utilized in the mitochondria for Fe-S cluster and heme biosynthesis. Iron is exported out of the macrophage through the only known iron export protein, ferroportin (FPN) whose expression is regulated by the hormone hepcidin. Further post-transcriptional regulation of intracellular iron levels is carried out by cytosolic regulatory proteins IRP1 and IRP2. (2) Intracellular zinc supply is mediated by two families of transport proteins; SLC39A (ZIPs) import zinc into the cell while SLC30A mediates zinc export out of the cell. (3) The copper importers Ctr1 and ATPase metal pump, ATP7A are two known copper transporters within the macrophage and gets upregulated to facilitate copper mediated host defence mechanisms
Fig. 1 Macrophage Metal Metabolism. This brief summary of the metal metabolism of a generic macrophage highlights several mechanisms by which a macrophage can obtain metals. There are numerous metal transport proteins and receptors involved to ensure an adequate supply of these essential metals to the macrophage. (1) Macrophages obtain iron from various sources. Free circulating iron is first reduced from ferric to ferrous iron and then imported into the macrophage via protein transporters such as DMT1 and ZIP14. Transferrin-bound iron is bound to the transferrin receptor on the cell surface and imported via receptor-mediated endocytosis. Some macrophages also have the ability to obtain iron via erythrophagocytosis while others express receptors such as CD163 and CD64 allowing for the uptake of haemoglobin-haptoglobin and heme-hemopexin complexes, respectively. Once iron enters the macrophage it has numerous fates depending on the activation state of the cell. It can be stored in its ferrous state within the ferritin complex or utilized in the mitochondria for Fe-S cluster and heme biosynthesis. Iron is exported out of the macrophage through the only known iron export protein, ferroportin (FPN) whose expression is regulated by the hormone hepcidin. Further post-transcriptional regulation of intracellular iron levels is carried out by cytosolic regulatory proteins IRP1 and IRP2. (2) Intracellular zinc supply is mediated by two families of transport proteins; SLC39A (ZIPs) import zinc into the cell while SLC30A mediates zinc export out of the cell. (3) The copper importers Ctr1 and ATPase metal pump, ATP7A are two known copper transporters within the macrophage and gets upregulated to facilitate copper mediated host defence mechanismsCC BY · PubMed Central
Fig. 2 Host Bactericidal Immune Defence Facilitated by Trace Metals. Metals play a pivotal role in contributing to the host immune response during bacterial infection. They can be used by immune cells to either mediate metal toxicity to rapidly kill the bacteria or be sequestered away in order to deprive the bacteria of essential metals in order to limit bacterial growth and replication. Whether the metals are sequestered or used to facilitate toxicity mechanisms is highly dependent on the nature of the bacterial infection. (1) Intracellular bacteria are mainly located within the phagosome of their host cell. Here they release siderophores allowing them to scavenge iron within the cell. In response, the host limits bacterial iron supply by exporting iron out of the infected phagosome via the NRAMP1 transporter. Furthermore, the host employs toxicity mechanisms by which both zinc and copper are pumped into the infected phagosome via their respective transporters in order to limit bacterial growth and replication. (2) Extracellular bacteria produce numerous different proteins to mediate metal acquisition from the host. The majority produce siderophores, which vary between bacterial species. However, they all function to supply the bacteria with an adequate amount of iron. The host also employs mechanisms to limit the amount of metals available to the bacteria in the extracellular space. Iron is sequestered by the upregulation of hepcidin resulting in the degradation of FPN which reduces the amount of iron exported from the cell. Furthermore, the iron importer DMT1 is also upregulated in both macrophages and neutrophils. Several metal binding proteins have also been shown to be produced mainly by neutrophils to bind extracellular metals. Lipocalin2, produced in secondary granules of neutrophils, binds bacterial siderophores and shuttles them away from the bacteria to the host cell. S100 proteins such as Calprotectin that binds zinc and manganese, and Calgranulin C binding zinc and copper also sequester these metals out of the extracellular space
Fig. 2 Host Bactericidal Immune Defence Facilitated by Trace Metals. Metals play a pivotal role in contributing to the host immune response during bacterial infection. They can be used by immune cells to either mediate metal toxicity to rapidly kill the bacteria or be sequestered away in order to deprive the bacteria of essential metals in order to limit bacterial growth and replication. Whether the metals are sequestered or used to facilitate toxicity mechanisms is highly dependent on the nature of the bacterial infection. (1) Intracellular bacteria are mainly located within the phagosome of their host cell. Here they release siderophores allowing them to scavenge iron within the cell. In response, the host limits bacterial iron supply by exporting iron out of the infected phagosome via the NRAMP1 transporter. Furthermore, the host employs toxicity mechanisms by which both zinc and copper are pumped into the infected phagosome via their respective transporters in order to limit bacterial growth and replication. (2) Extracellular bacteria produce numerous different proteins to mediate metal acquisition from the host. The majority produce siderophores, which vary between bacterial species. However, they all function to supply the bacteria with an adequate amount of iron. The host also employs mechanisms to limit the amount of metals available to the bacteria in the extracellular space. Iron is sequestered by the upregulation of hepcidin resulting in the degradation of FPN which reduces the amount of iron exported from the cell. Furthermore, the iron importer DMT1 is also upregulated in both macrophages and neutrophils. Several metal binding proteins have also been shown to be produced mainly by neutrophils to bind extracellular metals. Lipocalin2, produced in secondary granules of neutrophils, binds bacterial siderophores and shuttles them away from the bacteria to the host cell. S100 proteins such as Calprotectin that binds zinc and manganese, and Calgranulin C binding zinc and copper also sequester these metals out of the extracellular spaceCC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 55 references

Research works printed but not linked: 507

  1. Cornelis P, Dingemans J. Pseudomonas aeruginosa adapts its iron uptake strategies in function of the type of infections. Front Cell Infect Microbiol. 2013;3:75. · DOI
  2. Bachman MA, et al. Klebsiella pneumoniae yersiniabactin promotes respiratory tract infection through evasion of lipocalin 2. Infect Immun. 2011;79(8):3309–16. · DOI
  3. Pidcock KA, et al. Iron acquisition by Haemophilus influenzae. Infect Immun. 1988;56(4):721–5. · DOI
  4. Phelan JJ, et al. Modulating Iron for Metabolic Support of TB Host Defense. Front Immunol. 2018; 9(2296). · DOI
  5. Smith DJ, et al. Targeting iron uptake to control Pseudomonas aeruginosa infections in cystic fibrosis. Eur Respir J. 2013;42(6):1723–36. · DOI
  6. Babu U, Failla ML. Respiratory burst and candidacidal activity of peritoneal macrophages are impaired in copper-deficient rats. J Nutr. 1990;120(12):1692–9. · DOI
  7. Macomber L, Imlay JA. The iron-sulfur clusters of dehydratases are primary intracellular targets of copper toxicity. Proc Natl Acad Sci U S A. 2009;106(20):8344–9. · DOI · Paper page
  8. Urban CF, et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog. 2009;5(10):e1000639. · DOI
  9. Guillin OM, et al. Selenium, selenoproteins and viral infection. Nutrients, 2019; 11(9). · DOI
  10. O’Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16(9):553–65. · DOI · Paper page
  11. O’Beirne SL, et al. Alveolar macrophage immunometabolism and lung function impairment in smoking and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2020;201(6):735–9. · DOI
  12. Fricker M, Gibson PG. Macrophage dysfunction in the pathogenesis and treatment of asthma. Eur Respir J. 2017;50(3):1700196. · DOI
  13. Bruscia EM, Bonfield TL. Cystic fibrosis lung immunity: the role of the macrophage. J Innate Immun. 2016;8(6):550–63. · DOI
  14. Ardain A, Marakalala MJ, Leslie A. Tissue-resident innate immunity in the lung. Immunology. 2020;159(3):245–56. · DOI
  15. Guilliams M, et al. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J Exp Med. 2013;210(10):1977–92. · DOI
  16. van de Laar L, et al. Yolk sac macrophages, fetal liver, and adult monocytes can colonize an empty niche and develop into functional tissue-resident macrophages. Immunity. 2016;44(4):755–68. · DOI
  17. Snelgrove RJ, et al. A critical function for CD200 in lung immune homeostasis and the severity of influenza infection. Nat Immunol. 2008;9(9):1074–83. · DOI
  18. Byrne AJ, et al. Pulmonary macrophages: key players in the innate defence of the airways. Thorax. 2015;70(12):1189–96. · DOI
  19. Neupane AS, et al. Patrolling alveolar macrophages conceal bacteria from the immune system to maintain homeostasis. Cell. 2020;183(1):110-125.e11. · DOI
  20. Bourdonnay E, et al. Transcellular delivery of vesicular SOCS proteins from macrophages to epithelial cells blunts inflammatory signaling. J Exp Med. 2015;212(5):729–42. · DOI
  21. Levine AM, et al. GM-CSF–deficient mice are susceptible to pulmonary group B streptococcal infection. J Clin Investig. 1999;103(4):563–9. · DOI
  22. Gonzalez-Juarrero M, et al. Disruption of granulocyte macrophage-colony stimulating factor production in the lungs severely affects the ability of mice to control Mycobacterium tuberculosis infection. J Leukoc Biol. 2005;77(6):914–22. · DOI
  23. Schneider C, et al. Alveolar macrophages are essential for protection from respiratory failure and associated morbidity following influenza virus infection. PLoS Pathog. 2014;10(4):e1004053. · DOI
  24. Yu X, et al. The cytokine TGF-β promotes the development and homeostasis of alveolar macrophages. Immunity. 2017;47(5):903-912.e4. · DOI
  25. Puttur F, Gregory LG, Lloyd CM. Airway macrophages as the guardians of tissue repair in the lung. Immunol Cell Biol. 2019;97(3):246–57. · DOI
  26. Gibbings SL, et al. Three unique interstitial macrophages in the murine lung at steady state. Am J Respir Cell Mol Biol. 2017;57(1):66–76. · DOI
  27. Schyns J, et al. Non-classical tissue monocytes and two functionally distinct populations of interstitial macrophages populate the mouse lung. Nat Commun. 2019;10(1):3964. · DOI
  28. Janssen WJ, et al. Fas determines differential fates of resident and recruited macrophages during resolution of acute lung injury. Am J Respir Crit Care Med. 2011;184(5):547–60. · DOI
  29. Mould KJ, et al. Cell origin dictates programming of resident versus recruited macrophages during acute lung injury. Am J Respir Cell Mol Biol. 2017;57(3):294–306. · DOI
  30. Machiels B, et al. A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes. Nat Immunol. 2017;18(12):1310–20. · DOI
  31. Byrne AJ, et al. Dynamics of human monocytes and airway macrophages during healthy aging and after transplant. J Exp Med, 2020; 217(3). · DOI
  32. Guilliams M, et al. Establishment and maintenance of the macrophage niche. Immunity. 2020;52(3):434–51. · DOI · Paper page
  33. Winn NC, Volk KM, Hasty AH. Regulation of tissue iron homeostasis: the macrophage “ferrostat”. JCI Insight, 2020; 5(2). · DOI
  34. Roth-Walter F, et al. Linking iron-deficiency with allergy: role of molecular allergens and the microbiome. Metallomics. 2017;9(12):1676–92. · DOI
  35. Ghio AJ, et al. DMT1 expression is increased in the lungs of hypotransferrinemic mice. Am J Physiol-Lung Cell Mol Physiol. 2003;284(6):L938–44. · DOI
  36. Wygrecka M, et al. Shedding of low-density lipoprotein receptor–related protein-1 in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2011;184(4):438–48. · DOI
  37. Beker Aydemir T, et al. Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose homeostasis during the innate immune response (Endotoxemia). PLoS ONE. 2012;7(10):e48679. · DOI
  38. Pisu D, et al. Dual RNA-Seq of Mtb-infected macrophages in vivo reveals ontologically distinct host-pathogen interactions. Cell Rep. 2020;30(2):335-350.e4. · DOI
  39. Wesselius LJ, Flowers CH, Skikne BS. Alveolar macrophage content of isoferritins and transferrin: comparison of nonsmokers and smokers with and without chronic airflow obstruction. Am Rev Respir Dis. 1992;145(2_pt_1):311–6. · DOI
  40. Neves J, et al. Disruption of the hepcidin/ferroportin regulatory system causes pulmonary iron overload and restrictive lung disease. EBioMedicine. 2017;20:230–9. · DOI
  41. Lim D, et al. The hepcidin-ferroportin axis controls the iron content of Salmonella-containing vacuoles in macrophages. Nat Commun. 2018;9(1):2091. · DOI · Paper page
  42. Nguyen NB, et al. Hepcidin expression and iron transport in alveolar macrophages. Am J Physiol Lung Cell Mol Physiol. 2006;291(3):L417–25. · DOI · Paper page
  43. Perez E, et al. Hepcidin is essential for alveolar macrophage function and is disrupted by smoke in a murine chronic obstructive pulmonary disease model. J Immunol. 2020;205(9):2489–98. · DOI
  44. Brown BL, et al. Structure of the mitochondrial aminolevulinic acid synthase, a key heme biosynthetic enzyme. Structure. 2018;26(4):580–9. · DOI
  45. Knutson MD, et al. Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin 1 overexpression and down-regulated by hepcidin. Proc Natl Acad Sci USA. 2005;102(5):1324–8. · DOI · Paper page
  46. van den Heuvel MM, et al. Regulation of CD163 on human macrophages: cross-linking of CD163 induces signaling and activation. J Leukoc Biol. 1999;66(5):858–66. · DOI
  47. Simões RL, et al. Proinflammatory responses of heme in alveolar macrophages: repercussion in lung hemorrhagic episodes. Mediators Inflamm. 2013;2013:946878. · DOI
  48. Stocker R, et al. Bilirubin is an antioxidant of possible physiological importance. Science. 1987;235(4792):1043–6. · DOI · Paper page
  49. Vitali SH, et al. Heme oxygenase-1 dampens the macrophage sterile inflammasome response and regulates its components in the hypoxic lung. Am J Physiol Lung Cell Mol Physiol. 2020;318(1):L125-l134. · DOI
  50. Oberle S, et al. The antioxidant defense protein ferritin is a novel and specific target for pentaerithrityl tetranitrate in endothelial cells. Biochem Biophys Res Commun. 1999;261(1):28–34. · DOI
  51. Flo TH, et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature. 2004;432(7019):917–21. · DOI · Paper page
  52. Agoro R, Mura C. Inflammation-induced up-regulation of hepcidin and down-regulation of ferroportin transcription are dependent on macrophage polarization. Blood Cells Mol Dis. 2016;61:16–25. · DOI
  53. Poss KD, Tonegawa S. Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci. 1997;94(20):10919–24. · DOI · Paper page
  54. Agoro R, et al. Cell iron status influences macrophage polarization. PLoS ONE. 2018;13(5):e0196921. · DOI
  55. Artyomov MN, Sergushichev A, Schilling JD. Integrating immunometabolism and macrophage diversity. Semin Immunol. 2016;28(5):417–24. · DOI
  56. Russell DG, Huang L, Vanderven BC. Immunometabolism at the interface between macrophages and pathogens. Nat Rev Immunol. 2019;19(5):291–304. · DOI
  57. Pain D, Dancis A. Roles of Fe–S proteins: from cofactor synthesis to iron homeostasis to protein synthesis. Curr Opin Genet Dev. 2016;38:45–51. · DOI
  58. Canal F, et al. Regulation of the cysteine desulfurase Nfs1 and the scaffold protein IscU in macrophages stimulated with interferon-γ and lipopolysaccharide. Arch Biochem Biophys. 2007;465(1):282–92. · DOI
  59. Drapier JC, Hibbs JB Jr. Differentiation of murine macrophages to express nonspecific cytotoxicity for tumor cells results in L-arginine-dependent inhibition of mitochondrial iron-sulfur enzymes in the macrophage effector cells. J Immunol. 1988;140(8):2829–38. · DOI
  60. Pereira M, et al. Acute iron deprivation reprograms human macrophage metabolism and reduces inflammation in vivo. Cell Rep. 2019;28(2):498-511.e5. · DOI
  61. Salvin SB, et al. The effect of dietary zinc and prothymosin alpha on cellular immune responses of RF/J mice. Clin Immunol Immunopathol. 1987;43(3):281–8. · DOI
  62. Nowak JE, et al. Prophylactic zinc supplementation reduces bacterial load and improves survival in a murine model of sepsis. Pediatr Crit Care Med. 2012;13(5):e323–9. · DOI
  63. Wirth JJ, Fraker PJ, Kierszenbaum F. Zinc requirement for macrophage function: effect of zinc deficiency on uptake and killing of a protozoan parasite. Immunology. 1989;68(1):114–9.
  64. Hamon R, et al. Zinc and zinc transporters in macrophages and their roles in efferocytosis in COPD. PLoS ONE. 2014;9(10):e110056. · DOI
  65. Gao H, et al. Metal transporter Slc39a10 regulates susceptibility to inflammatory stimuli by controlling macrophage survival. Proc Natl Acad Sci U S A. 2017;114(49):12940–5. · DOI
  66. Neyrolles O, Mintz E, Catty P. Zinc and copper toxicity in host defense against pathogens: Mycobacterium tuberculosis as a model example of an emerging paradigm. Front Cell Infect Microbiol. 2013;3:89. · DOI · Paper page
  67. Crocker A, et al. Interaction of nutrition and infection: effect of copper deficiency on resistance to Trypanosoma lewisi. J Natl Med Assoc. 1992;84(8):697–706.
  68. Wagner D, et al. Elemental analysis of Mycobacterium avium-, Mycobacterium tuberculosis-, and Mycobacterium smegmatis-containing phagosomes indicates pathogen-induced microenvironments within the host cell’s endosomal system. J Immunol. 2005;174(3):1491–500. · DOI
  69. Shen Q, et al. Macrophage activation by IFN-γ triggers restriction of phagosomal copper from intracellular pathogens. PLoS Pathog. 2018;14(11):e1007444. · DOI
  70. Jabado N, et al. Natural resistance to intracellular infections: natural resistance-associated macrophage protein 1 (Nramp1) functions as a pH-dependent manganese transporter at the phagosomal membrane. J Exp Med. 2000;192(9):1237–48. · DOI · Paper page
  71. Davidsson L, et al. Identification of transferrin as the major plasma carrier protein for manganese introduced orally or intravenously or after in vitro addition in the rat. J Nutr. 1989;119(10):1461–4. · DOI
  72. Lee BC, et al. Selenoprotein MsrB1 promotes anti-inflammatory cytokine gene expression in macrophages and controls immune response in vivo. Sci Rep. 2017;7(1):5119–5119. · DOI
  73. Nelson SM, Lei X, Prabhu KS. Selenium levels affect the IL-4-induced expression of alternative activation markers in murine macrophages. J Nutr. 2011;141(9):1754–61. · DOI
  74. Carlson BA, et al. Role of selenium-containing proteins in T-cell and macrophage function. Proc Nutr Soc. 2010;69(3):300–10. · DOI
  75. Naik SH, et al. Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo. Nat Immunol. 2007;8(11):1217–26. · DOI
  76. Guilliams M, Lambrecht BN, Hammad H. Division of labor between lung dendritic cells and macrophages in the defense against pulmonary infections. Mucosal Immunol. 2013;6(3):464–73. · DOI
  77. Sichien D, et al. Development of conventional dendritic cells: from common bone marrow progenitors to multiple subsets in peripheral tissues. Mucosal Immunol. 2017;10(4):831–44. · DOI
  78. Hoffmann FM, et al. Distribution and Interaction of Murine Pulmonary Phagocytes in the Naive and Allergic Lung. Front Immunol. 2018. 9. · DOI
  79. Cella M, et al. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med. 1999;5(8):919–23. · DOI
  80. Van Pottelberge GR, et al. Plasmacytoid dendritic cells in pulmonary lymphoid follicles of patients with COPD. Eur Respir J. 2010;36(4):781–91. · DOI
  81. De Heer HJ, et al. Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J Exp Med. 2004;200(1):89–98. · DOI
  82. Verna G, et al. Iron overload mimicking conditions skews bone marrow dendritic cells differentiation into MHCII(low)CD11c(+)CD11b(+)F4/80(+) cells. Int J Mol Sci. 2020; 21(4). · DOI
  83. Kramer JL, et al. Differentiation of functional dendritic cells and macrophages from human peripheral blood monocyte precursors is dependent on expression of p21 (WAF1/CIP1) and requires iron. Br J Haematol. 2002;117(3):727–34. · DOI
  84. Kitamura H, et al. Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function. Nat Immunol. 2006;7(9):971–7. · DOI
  85. Jenne CN, et al. Neutrophils recruited to sites of infection protect from virus challenge by releasing neutrophil extracellular traps. Cell Host Microbe. 2013;13(2):169–80. · DOI
  86. Kumawat K, et al. LAIR-1 limits neutrophilic airway inflammation. Front Immunol. 2019;10:842. · DOI
  87. Casulli J, et al. CD200R deletion promotes a neutrophil niche for Francisella tularensis and increases infectious burden and mortality. Nat Commun. 2019;10(1):1–9. · DOI
  88. Griffiths JS, et al. Differential susceptibility of Dectin-1 isoforms to functional inactivation by neutrophil and fungal proteases. FASEB J. 2018;32(6):3385–97. · DOI
  89. Giacalone VD, et al. Neutrophil adaptations upon recruitment to the lung: new concepts and implications for homeostasis and disease. Int J Mol Sci. 2020; 21(3). · DOI
  90. Kuebler W, et al. Contribution of selectins to leucocyte sequestration in pulmonary microvessels by intravital microscopy in rabbits. J Physiol. 1997;501(Pt 2):375. · DOI
  91. Devi S, et al. Neutrophil mobilization via plerixafor-mediated CXCR4 inhibition arises from lung demargination and blockade of neutrophil homing to the bone marrow. J Exp Med. 2013;210(11):2321–36. · DOI
  92. Francis N, et al. Lactoferrin inhibits neutrophil apoptosis via blockade of proximal apoptotic signaling events. Biochim Biophys Acta. 2011;1813(10):1822–6. · DOI
  93. Grigorieva DV, et al. Effects of recombinant human lactoferrin on calcium signaling and functional responses of human neutrophils. Arch Biochem Biophys. 2019;675:108122. · DOI
  94. Maxwell PH, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271–5. · DOI · Paper page
  95. Sadiku P, et al. Prolyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses. J Clin Investig. 2017;127(9):3407–20. · DOI
  96. Mecklenburgh KI, et al. Involvement of a ferroprotein sensor in hypoxia-mediated inhibition of neutrophil apoptosis. Blood. 2002;100(8):3008–16. · DOI
  97. Konrad FM, et al. Heme oxygenase-1 attenuates acute pulmonary inflammation by decreasing the release of segmented neutrophils from the bone marrow. Am J Physiol Lung Cell Mol Physiol. 2014;307(9):L707–17. · DOI
  98. Cichon I, et al. Reduced neutrophil extracellular trap (NET) formation during systemic inflammation in mice with Menkes disease and Wilson disease: copper requirement for NET release. Front Immunol. 2019;10:3021. · DOI
  99. Iwata T, et al. Ceruloplasmin induces polymorphonuclear leukocyte priming in localized aggressive periodontitis. J Periodontol. 2009;80(8):1300–6. · DOI
  100. Hasan R, Rink L, Haase H. Chelation of free Zn2+ impairs chemotaxis, phagocytosis, oxidative burst, degranulation, and cytokine production by neutrophil granulocytes. Biol Trace Elem Res. 2016;171(1):79–88. · DOI
  101. Hasan R, Rink L, Haase H. Zinc signals in neutrophil granulocytes are required for the formation of neutrophil extracellular traps. Innate Immun. 2013;19(3):253–64. · DOI
  102. Kehl-Fie TE, et al. Nutrient metal sequestration by calprotectin inhibits bacterial superoxide defense, enhancing neutrophil killing of Staphylococcus aureus. Cell Host Microbe. 2011;10(2):158–64. · DOI · Paper page
  103. Isaksen B, Fagerhol MK. Calprotectin inhibits matrix metalloproteinases by sequestration of zinc. Mol Pathol: MP. 2001;54(5):289–92. · DOI
  104. Moroz OV, et al. Both Ca 2+ and Zn 2+ are essential for S100A12 protein oligomerization and function. BMC Biochem. 2009;10(1):1–18. · DOI
  105. Köse SA, Nazıroğlu M. Selenium reduces oxidative stress and calcium entry through TRPV1 channels in the neutrophils of patients with polycystic ovary syndrome. Biol Trace Elem Res. 2014;158(2):136–42. · DOI
  106. Kashiwakura J, et al. Pivotal advance: IgE accelerates in vitro development of mast cells and modifies their phenotype. J Leukoc Biol. 2008;84(2):357–67. · DOI
  107. Kirshenbaum AS, et al. Demonstration of the origin of human mast cells from CD34+ bone marrow progenitor cells. J Immunol. 1991;146(5):1410–5. · DOI
  108. Tsai M, et al. The rat c-kit ligand, stem cell factor, induces the development of connective tissue-type and mucosal mast cells in vivo. Analysis by anatomical distribution, histochemistry, and protease phenotype. J Exp Med. 1991;174(1):125–31. · DOI
  109. Suto H, et al. Mast cell-associated tnf promotes dendritic cell migration. J Immunol. 2006;176(7):4102–12. · DOI
  110. Levi-Schaffer F, et al. Mouse bone marrow-derived mast cells cocultured with fibroblasts. Morphology and stimulation-induced release of histamine, leukotriene B4, leukotriene C4, and prostaglandin D2. J Immunol. 1987;139(10):3431–41. · DOI
  111. McCurdy JD, et al. Cutting edge: distinct toll-like receptor 2 activators selectively induce different classes of mediator production from human mast cells. J Immunol. 2003;170(4):1625–9. · DOI
  112. Weller CL, et al. Chemotactic action of prostaglandin E2 on mouse mast cells acting via the PGE2 receptor 3. Proc Natl Acad Sci. 2007;104(28):11712–7. · DOI
  113. Abonia JP, et al. Constitutive homing of mast cell progenitors to the intestine depends on autologous expression of the chemokine receptor CXCR2. Blood. 2005;105(11):4308–13. · DOI
  114. Dvorak AM. Ultrastructural analysis of human mast cells and basophils. Chem Immunol. 1995;61:1–33.
  115. Kirshenbaum AS, et al. IL-3-dependent growth of basophil-like cells and mastlike cells from human bone marrow. J Immunol. 1989;142(7):2424–9. · DOI
  116. Varricchi G, et al. Human mast cells and basophils-How are they similar how are they different? Immunol Rev. 2018;282(1):8–34. · DOI
  117. Schwartz C, Eberle JU, Voehringer D. Basophils in inflammation. Eur J Pharmacol. 2016;778:90–5. · DOI
  118. Brunner T, Heusser CH, Dahinden CA. Human peripheral blood basophils primed by interleukin 3 (IL-3) produce IL-4 in response to immunoglobulin E receptor stimulation. J Exp Med. 1993;177(3):605–11. · DOI
  119. Arinobu Y, et al. Developmental checkpoints of the basophil/mast cell lineages in adult murine hematopoiesis. Proc Natl Acad Sci. 2005;102(50):18105–10. · DOI
  120. Cohen M, et al. Lung single-cell signaling interaction map reveals basophil role in macrophage imprinting. Cell. 2018;175(4):1031-1044.e18. · DOI
  121. Lamkhioued B, et al. Increased expression of eotaxin in bronchoalveolar lavage and airways of asthmatics contributes to the chemotaxis of eosinophils to the site of inflammation. J Immunol. 1997;159(9):4593–601. · DOI
  122. Stevens WW, et al. Detection and quantitation of eosinophils in the murine respiratory tract by flow cytometry. J Immunol Methods. 2007;327(1–2):63–74. · DOI
  123. Mesnil C, et al. Lung-resident eosinophils represent a distinct regulatory eosinophil subset. J Clin Investig. 2016;126(9):3279–95. · DOI
  124. Yi S, et al. Eosinophil recruitment is dynamically regulated by interplay among lung dendritic cell subsets after allergen challenge. Nat Commun. 2018;9(1):3879. · DOI
  125. Drake MG, et al. Human and mouse eosinophils have antiviral activity against parainfluenza virus. Am J Respir Cell Mol Biol. 2016;55(3):387–94. · DOI
  126. Palma-Carlos AG, Palma-Carlos ML, Costa AC. “Minor” hemoglobinopathies: a risk factor for asthma. Eur Ann Allergy Clin Immunol. 2005;37(5):177–82.
  127. Wu Z, Holwill SD, Oliveira DB. Desferrioxamine modulates chemically induced T helper 2-mediated autoimmunity in the rat. Clin Exp Immunol. 2004;135(2):194–9. · DOI
  128. Maazi H, et al. Iron administration reduces airway hyperreactivity and eosinophilia in a mouse model of allergic asthma. Clin Exp Immunol. 2011;166(1):80–6. · DOI
  129. Arnhold J, Furtmüller PG, Obinger C, Redox properties of myeloperoxidase. 2003, Redox Rep. p. 179–186. · DOI · Paper page
  130. Ten RM, et al. Molecular cloning of the human eosinophil peroxidase. Evidence for the existence of a peroxidase multigene family. J Exp Med. 1989;169(5):1757–69. · DOI
  131. Voehringer D, van Rooijen N, Locksley RM. Eosinophils develop in distinct stages and are recruited to peripheral sites by alternatively activated macrophages. J Leukoc Biol. 2007;81(6):1434–44. · DOI · Paper page
  132. Sumbayev VV, et al. Involvement of hypoxia-inducible factor-1 (HiF-1α) in IgE-mediated primary human basophil responses. Eur J Immunol. 2009;39(12):3511–9. · DOI
  133. Ünal M, et al. Serum levels of antioxidant vitamins, copper, zinc and magnesium in children with chronic rhinosinusitis. J Trace Elem Med Biol. 2004;18(2):189–92. · DOI
  134. Guo C-H, et al. Role of certain trace minerals in oxidative stress, inflammation, CD4/CD8 lymphocyte ratios and lung function in asthmatic patients. Ann Clin Biochem. 2011;48(4):344–51. · DOI
  135. Ariaee N, et al. Trace elements status in sera of patients with allergic asthma. Rep Biochem Mol Biol. 2016;5(1):20–5.
  136. Ho LH, et al. Labile zinc and zinc transporter ZnT4 in mast cell granules: role in regulation of caspase activation and NF-kappaB translocation. J Immunol. 2004;172(12):7750–60. · DOI
  137. Ugajin T, et al. Zinc-binding metallothioneins are key modulators of IL-4 production by basophils. Mol Immunol. 2015;66(2):180–8. · DOI
  138. Richter M, et al. Zinc status modulates bronchopulmonary eosinophil infiltration in a murine model of allergic inflammation. Chest. 2003;123(3 Suppl):446s. · DOI
  139. Lu H, et al. Zinc suppressed the airway inflammation in asthmatic rats: effects of zinc on generation of eotaxin, MCP-1, IL-8, IL-4, and IFN-γ. Biol Trace Elem Res. 2012;150(1–3):314–21. · DOI
  140. Öhrvik H, et al. Ctr2 regulates mast cell maturation by affecting the storage and expression of tryptase and proteoglycans. J Immunol. 2015;195(8):3654–64. · DOI
  141. Simoni Y, et al. Human innate lymphoid cell subsets possess tissue-type based heterogeneity in phenotype and frequency. Immunity. 2018;48(5):1060. · DOI
  142. Yudanin NA, et al. Spatial and temporal mapping of human innate lymphoid cells reveals elements of tissue specificity. Immunity. 2019;50(2):505–19. · DOI
  143. Kärre K, et al. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature. 1986;319(6055):675–8. · DOI
  144. Hart OM, et al. TLR7/8-mediated activation of human NK cells results in accessory cell-dependent IFN-γ production. J Immunol. 2005;175(3):1636–42. · DOI
  145. Kumar P, et al. IL-22 from conventional NK cells is epithelial regenerative and inflammation protective during influenza infection. Mucosal Immunol. 2013;6(1):69–82. · DOI
  146. Marquardt N, et al. Human lung natural killer cells are predominantly comprised of highly differentiated hypofunctional CD69− CD56dim cells. J Allergy Clin Immunol. 2017;139(4):1321–30. · DOI
  147. Fehniger TA, et al. Differential cytokine and chemokine gene expression by human NK cells following activation with IL-18 or IL-15 in combination with IL-12: implications for the innate immune response. J Immunol. 1999;162(8):4511–20. · DOI
  148. Yamamoto Y, et al. Lung-resident natural killer cells control pulmonary tumor growth in mice. Cancer Sci. 2018;109(9):2670–6. · DOI
  149. Marquardt N, et al. Unique transcriptional and protein-expression signature in human lung tissue-resident NK cells. Nat Commun. 2019;10(1):3841. · DOI
  150. Michel T, et al. Mouse lung and spleen natural killer cells have phenotypic and functional differences, in part influenced by macrophages. PLoS ONE. 2012;7(12):e51230. · DOI
  151. Cong J, Wei H. Natural killer cells in the lungs. Front Immunol. 2019;10:1416. · DOI
  152. Cooper GE, et al. Human CD49a(+) lung natural killer cell cytotoxicity in response to influenza a virus. Front Immunol. 2018;9:1671. · DOI
  153. Orange JS. Human natural killer cell deficiencies and susceptibility to infection. Microbes Infect. 2002;4(15):1545–58. · DOI
  154. Augustin A, Kubo RT, Sim GK. Resident pulmonary lymphocytes expressing the gamma/delta T-cell receptor. Nature. 1989;340(6230):239–41. · DOI
  155. Cheng M, Hu S. Lung-resident gammadelta T cells and their roles in lung diseases. Immunology. 2017;151(4):375–84. · DOI · Paper page
  156. Barlow JL, McKenzie ANJ. Innate lymphoid cells of the lung. Annu Rev Physiol. 2019;81:429–52. · DOI
  157. Trottein F, Paget C. Natural killer T cells and mucosal-associated invariant t cells in lung infections. Front Immunol. 2018;9:1750. · DOI
  158. Metelitsa LS, et al. Human NKT cells mediate antitumor cytotoxicity directly by recognizing target cell CD1d with bound ligand or indirectly by producing IL-2 to activate NK cells. J Immunol. 2001;167(6):3114–22. · DOI
  159. Lee YJ, et al. Tissue-specific distribution of iNKT cells impacts their cytokine response. Immunity. 2015;43(3):566–78. · DOI
  160. Thanabalasuriar A, et al. iNKT cell emigration out of the lung vasculature requires neutrophils and monocyte-derived dendritic cells in inflammation. Cell Rep. 2016;16(12):3260–72. · DOI
  161. Gold MC, et al. Human mucosal associated invariant T cells detect bacterially infected cells. PLoS Biol. 2010;8(6):e1000407. · DOI
  162. Marçais A, et al. The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat Immunol. 2014;15(8):749–57. · DOI
  163. Keating SE, et al. Metabolic reprogramming supports IFN-γ production by CD56bright NK Cells. J Immunol. 2016;196(6):2552–60. · DOI
  164. Damiens E, et al. Effects of human lactoferrin on NK cell cytotoxicity against haematopoietic and epithelial tumour cells. Biochim Biophys Acta. 1998;1402(3):277–87. · DOI
  165. Hua Y, et al. Iron overload may promote alteration of NK cells and hematopoietic stem/progenitor cells by JNK and P38 pathway in myelodysplastic syndromes. Int J Hematol. 2017;106(2):248–57. · DOI
  166. Sottile R, et al. Iron and ferritin modulate MHC class I expression and NK cell recognition. Front Immunol. 2019;10:224. · DOI
  167. Kumar S, et al. Zinc-induced polymerization of killer-cell Ig-like receptor into filaments promotes its inhibitory function at cytotoxic immunological synapses. Mol Cell. 2016;62(1):21–33. · DOI
  168. Muzzioli M, et al. Zinc improves the development of human CD34+ cell progenitors towards NK cells and increases the expression of GATA-3 transcription factor in young and old ages. Biogerontology. 2009;10(5):593–604. · DOI
  169. Wessels I, Maywald M, Rink L. Zinc as a gatekeeper of immune function. Nutrients, 2017; 9(12). · DOI
  170. Mace EM, et al. A dual role for talin in NK cell cytotoxicity: activation of LFA-1-mediated cell adhesion and polarization of NK cells. J Immunol. 2009;182(2):948–56. · DOI
  171. Lv M, et al. Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy. Cell Res. 2020;30(11):966–79. · DOI · Paper page
  172. Kiremidjian-Schumacher L, et al. Supplementation with selenium augments the functions of natural killer and lymphokine-activated killer cells. Biol Trace Elem Res. 1996;52(3):227–39. · DOI
  173. Brekelmans P, et al. Inhibition of proliferation and differentiation during early T cell development by anti-transferrin receptor antibody. Eur J Immunol. 1994;24(11):2896–902. · DOI
  174. Mincheva-Nilsson L, Hammarstrom S, Hammarstrom ML. Activated human gamma delta T lymphocytes express functional lactoferrin receptors. Scand J Immunol. 1997;46(6):609–18. · DOI
  175. Vargas Buonfiglio LG, et al. Airway surface liquid from smokers promotes bacterial growth and biofilm formation via iron-lactoferrin imbalance. Respir Res. 2018;19(1):42. · DOI
  176. Reuben A, et al. The hemochromatosis protein HFE 20 years later: an emerging role in antigen presentation and in the immune system. Immun Inflamm Dis. 2017;5(3):218–32. · DOI
  177. French JD, et al. Gammadelta T lymphocyte homeostasis is negatively regulated by beta2-microglobulin. J Immunol. 2009;182(4):1892–900. · DOI
  178. de Sousa M, et al. Iron overload in β2-microglobulin-deficient mice. Immunol Lett. 1994;39(2):105–11. · DOI
  179. Maia ML, et al. Invariant natural killer T cells are reduced in hereditary hemochromatosis patients. J Clin Immunol. 2015;35(1):68–74. · DOI
  180. Huang H, et al. Acute invariant NKT cell activation triggers an immune response that drives prominent changes in iron homeostasis. Sci Rep. 2020;10(1):21026. · DOI
  181. Hwang JY, Randall TD, Silva-Sanchez A. Inducible bronchus-associated lymphoid tissue: taming inflammation in the lung. Front Immunol. 2016;7:258. · DOI
  182. Hogg JC, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(26):2645–53. · DOI
  183. Belz GT, et al. Tissue-resident lymphocytes: weaponized sentinels at barrier surfaces. F1000Res, 2020; 9. · DOI
  184. Niedzielska M, et al. Differential gene expression in human tissue resident regulatory T cells from lung, colon, and blood. Oncotarget. 2018;9(90):36166–84. · DOI
  185. Lu C, et al. Memory regulatory T cells home to the lung and control influenza A virus infection. Immunol Cell Biol. 2019;97(9):774–86. · DOI
  186. Ichikawa T, et al. CD103(hi) Treg cells constrain lung fibrosis induced by CD103(lo) tissue-resident pathogenic CD4 T cells. Nat Immunol. 2019;20(11):1469–80. · DOI
  187. Weiss G. Modification of iron regulation by the inflammatory response. Best Pract Res Clin Haematol. 2005;18(2):183–201. · DOI · Paper page
  188. Brock JH. The effect of iron and transferrin on the response of serum-free cultures of mouse lymphocytes to concanavalin A and lipopolysaccharide. Immunology. 1981;43(2):387–92.
  189. Mateos F, Brock JH, Perez-Arellano JL. Iron metabolism in the lower respiratory tract. Thorax. 1998;53(7):594–600. · DOI · Paper page
  190. Stoffel NU, et al. Iron deficiency anemia at time of vaccination predicts decreased vaccine response and iron supplementation at time of vaccination increases humoral vaccine response: a birth cohort study and a randomized trial follow-up study in Kenyan infants. Front Immunol. 2020;11:1313. · DOI · Paper page
  191. Frost JN, et al. Hepcidin-mediated hypoferremia disrupts immune responses to vaccination and infection. Med. 2021;2(2):164-179.e12. · DOI
  192. Jabara HH, et al. A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nat Genet. 2016;48(1):74–8. · DOI · Paper page
  193. Ehrlich R, Lemonnier FA. HFE–a novel nonclassical class I molecule that is involved in iron metabolism. Immunity. 2000;13(5):585–8. · DOI
  194. Roy M, et al. Supplementation with selenium and human immune cell functions. I. Effect on lymphocyte proliferation and interleukin 2 receptor expression. Biol Trace Elem Res. 1994;41(1–2):103–14. · DOI
  195. Elmadfa I, Meyer AL. The role of the status of selected micronutrients in shaping the immune function. Endocr Metab Immune Disord Drug Targets. 2019;19(8):1100–15. · DOI
  196. Budden KF, et al. Functional effects of the microbiota in chronic respiratory disease. Lancet Respir Med. 2019;7(10):907–20. · DOI
  197. Dickson RP, et al. Changes in the lung microbiome following lung transplantation include the emergence of two distinct Pseudomonas species with distinct clinical associations. PLoS ONE. 2014;9(5):e97214. · DOI
  198. Andrei A, et al. Cu Homeostasis in Bacteria: The Ins and Outs. Membranes (Basel), 2020; 10(9). · DOI · Paper page
  199. Dostal A, et al. Low iron availability in continuous in vitro colonic fermentations induces strong dysbiosis of the child gut microbial consortium and a decrease in main metabolites. FEMS Microbiol Ecol. 2013;83(1):161–75. · DOI · Paper page
  200. Tompkins GR, et al. The effects of dietary ferric iron and iron deprivation on the bacterial composition of the mouse intestine. Curr Microbiol. 2001;43(1):38–42. · DOI

200 of 507 shown

Cited by

Sorted by citations

See all 78

Metadata

Authors
Healy, C., Munoz-Wolf, N., Strydom, J., Faherty, L., Williams, N. C., Kenny, S., Donnelly, S. C., & Cloonan, S. M.
ORCID
Cloonan, Suzanne M.
Venue
Respiratory Research
Publisher
Springer Science and Business Media LLC
Published
2021-04-29
Volume
22
Issue
1
ISSN
1465-993X
DOI
10.1186/s12931-021-01722-y
PMC
PMC8082489
Cited by
78
References
55
Language
en
Licence
Funders
  • Science Foundation Ireland (FRL4862</)
  • Health Research Board (EIA-2019-004)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Nutritional immunity: the impact of metals on lung immune cells and the airway microbiome during chronic respiratory disease. https://app.cochat.ai/papers/10.1186/s12931-021-01722-y
The paper
Healy, C., Munoz-Wolf, N., Strydom, J., Faherty, L., Williams, N. C., Kenny, S., Donnelly, S. C., & Cloonan, S. M. (2021). Nutritional immunity: the impact of metals on lung immune cells and the airway microbiome during chronic respiratory disease. Respiratory Research. https://doi.org/10.1186/s12931-021-01722-y