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European Journal of Nutrition

Erschienen in:

07.07.2017 | Original Contribution

Cellular zinc homeostasis modulates polarization of THP-1-derived macrophages

verfasst von: Laura Dierichs, Veronika Kloubert, Lothar Rink

Erschienen in: European Journal of Nutrition | Ausgabe 6/2018

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Abstract

Purpose

Polarization of macrophages by environmental stimuli leads to the characteristic of different phenotypes that exhibit distinct functions, ranging in a continuous spectrum from pro-inflammatory M1 up to immunoregulatory and wound-healing M2 macrophages. Diseases like cancer, allergic asthma or diabetes are associated with an M1/M2 imbalance. Owing to the importance of the essential trace element zinc for the immune system and its involvement in signal transduction as a second messenger, we investigated the impact of zinc on M1 and M2 polarization of macrophages in vitro.

Methods

A polarization model with human THP-1 cells was established and validated with previously described markers using quantitative real-time PCR, Western blot and flow cytometry. Intracellular free Zn²⁺ was determined with FluoZin-3-AM.

Results

Whereas pSTAT1 and HLA-DR or pSTAT6 and Dectin-1 distinguish between M1 and M2 macrophages, respectively, CD86 and CD206 failed. Depending on the used markers, both zinc supplementation in physiological dose (50 µM) and zinc deficiency promote M1 polarization of THP-1-derived macrophages. Furthermore, zinc supplementation strongly inhibits M2 polarization.

Conclusion

For the first time, we show a modulating effect of zinc for the polarization of human macrophages. The strong inhibitory effect of zinc supplementation on M2 polarization indicates a relevance regarding M2-dominated diseases like allergic asthma or cancer. All in all, zinc achieves a great potential for modulating macrophage polarization.

Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11:723–737. doi:10.1038/nri3073 CrossRefPubMedPubMedCentral

Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM (2000) M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 164:6166–6173. doi:10.4049/jimmunol.164.12.6166 CrossRefPubMed

Murray PJ, Allen JE, Fisher EA, Gordon S, Goerdt S, Hamilton JA, Ivashkiv LB, Lawrence T (2014) Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41:14–20. doi:10.1016/j.immuni.2014.06.008.Macrophage CrossRefPubMedPubMedCentral

Martinez FO, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 6:1–13. doi:10.12703/P6-13 CrossRef

Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Investig 122:787–795. doi:10.1172/JCI59643DS1 CrossRefPubMedPubMedCentral

Italiani P, Boraschi D (2014) From monocytes to M1/M2 macrophages: phenotypical vs. functional differentiation. Front Immunol 5:1–22. doi:10.3389/fimmu.2014.00514 CrossRef

Spiller KL, Wrona EA, Romero-Torres S, Pallotta I, Graney PL, Witherel CE, Panicker LM, Feldman RA, Urbanska AM, Santambrogio L, Vunjak-Novakovic G, Freytes DO (2015) Differential gene expression in human, murine, and cell line-derived macrophages upon polarization. Exp Cell Res. doi:10.1016/j.yexcr.2015.10.017 CrossRefPubMed

Maret W, Sandstead HH (2006) Zinc requirements and the risks and benefits of zinc supplementation. J Trace Elem Med Biol 20:3–18. doi:10.1016/j.jtemb.2006.01.006 CrossRefPubMed

Haase H, Rink L (2014) Multiple impacts of zinc on immune function. Metallomics 6:1175–1180. doi:10.1039/c3mt00353a CrossRefPubMed

10.

Ibs K-H, Rink L (2003) Zinc-altered immune function. J Nutr 133:1452S–1456SCrossRefPubMed

11.

Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT, Tsui C, Hurley P, Chien M, Chai S, Hitotsumatsu O, McNally E, Pickart C, Ma A (2004) The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol 5:1052–1060. doi:10.1038/ni1110 CrossRefPubMed

12.

von Bülow V, Rink L, Haase H (2005) Zinc-mediated inhibition of cyclic nucleotide phosphodiesterase activity and expresssion supresses TNF-alpha and IL-1Beta production in monocytes by elevation of guanosine 3′,5′-cyclic monophosphate. J Immunol 175:4697–4705. doi:10.4049/jimmunol.175.7.4697 CrossRef

13.

Prasad AS, Bao B, Beck FWJ, Kucuk O, Sarkar FH (2004) Antioxidant effect of zinc in humans. Free Radic Biol Med 37:1182–1190. doi:10.1016/j.freeradbiomed.2004.07.007 CrossRefPubMed

14.

Haase H, Ober-Blobaum JL, Engelhardt G, Hebel S, Heit A, Heine H, Rink L (2008) Zinc signals are essential for lipopolysaccharide-induced signal transduction in monocytes. J Immunol 181:6491–6502. doi:10.4049/jimmunol.181.9.6491 CrossRefPubMed

15.

Haase H, Rink L (2009) Functional significance of zinc-related signaling pathways in immune cells. Annu Rev Nutr 29:133–152. doi:10.1146/annurev-nutr-080508-141119 CrossRefPubMed

16.

Mazzatti DJ, Uciechowski P, Hebel S, Engelhardt G, White AJ, Powell JR, Rink L, Haase H (2008) Effects of long-term zinc supplementation and deprivation on gene expression in human THP-1 mononuclear cells. J Trace Elem Med Biol 22:325–336. doi:10.1016/j.jtemb.2008.06.002 CrossRefPubMed

17.

Haase H, Hebel S, Engelhardt G, Rink L (2006) Flow cytometric measurement of labile zinc in peripheral blood mononuclear cells. Anal Biochem 352:222–230. doi:10.1016/j.ab.2006.02.009 CrossRefPubMed

18.

Kapral M, Wawszczyk J, Sosnicki S, Weglarz L (2015) Down-regulation of inducible nitric oxide synthase expression by inositol hexaphosphate in human colon cancer cells. Acta Pol Pharm 72:705–711PubMed

19.

Faneyte IF, Kristel PM, van de Vijver MJ (2001) Determining MDR1/P-glycoprotein expression in breast cancer. Int J Cancer 93:114–122. doi:10.1002/1097-0215(20010701)93:1<114:AID-IJC1309>3.0.CO;2-J CrossRefPubMed

20.

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408. doi:10.1006/meth.2001.1262 CrossRefPubMed

21.

Dubben S, Hönscheid A, Winkler K, Rink L, Haase H (2010) Cellular zinc homeostasis is a regulator in monocyte differentiation of HL-60 cells by 1 alpha,25-dihydroxyvitamin D3. J Leukoc Biol 87:833–844. doi:10.1189/jlb.0409241 CrossRefPubMed

22.

Haase H, Rink L (2007) Signal transduction in monocytes: the role of zinc ions. Biometals 20:579–585. doi:10.1007/s10534-006-9029-8 CrossRefPubMed

23.

Jantsch J, Schatz V, Friedrich D, Schröder A, Kopp C, Siegert I, Maronna A, Wendelborn D, Linz P, Binger KJ, Gebhardt M, Heinig M, Neubert P, Fischer F, Teufel S, David JP, Neufert C, Cavallaro A, Rakova N, Küper C, Beck FX, Neuhofer W, Muller DN, Schuler G, Uder M, Bogdan C, Luft FC, Titze J (2015) Cutaneous Na+ storage strengthens the antimicrobial barrier function of the skin and boosts macrophage-driven host defense. Cell Metab 21:493–501. doi:10.1016/j.cmet.2015.02.003 CrossRefPubMedPubMedCentral

24.

Binger KJ, Gebhardt M, Heinig M, Rintisch C, Schroeder A, Neuhofer W, Hilgers K, Manzel A, Schwartz C, Kleinewietfeld M, Voelkl J, Schatz V, Linker RA, Lang F, Voehringer D, Wright MD, Hubner N, Dechend R, Jantsch J, Titze J, Müller DN (2015) High salt reduces the activation of IL-4 and IL-13 stimulated macrophages. J Clin Invest 125:1–3. doi:10.1172/JCI80919 CrossRef

25.

Fukada T, Yamasaki S, Nishida K, Murakami M, Hirano T (2011) Zinc homeostasis and signaling in health and diseases. J Biol Inorg Chem 16:1123–1134. doi:10.1007/s00775-011-0797-4 CrossRefPubMedPubMedCentral

26.

Moshage H (1997) Cytokines and the hepatic acute phase response. J Pathol 181:257–266. doi:10.1002/(SICI)1096-9896(199703)181:3<257:AID-PATH756>3.0.CO;2-U CrossRefPubMed

27.

Day DA, Tuite MF (1998) Post-transcriptional gene regulatory mechanisms in eukaryotes: an overview. J Endocrinol 157:361–371CrossRefPubMed

28.

Laskar A, Eilertsen J, Li W, Yuan X-M (2013) SPION primes THP1 derived M2 macrophages towards M1-like macrophages. Biochem Biophys Res Commun 441:737–742. doi:10.1016/j.bbrc.2013.10.115 CrossRefPubMed

29.

Kahmann L, Uciechowski P, Warmuth S, Plümäkers B, Gressner AM, Malavolta M, Mocchegiani E, Rink L (2008) Zinc supplementation in the elderly reduces spontaneous inflammatory cytokine release and restores T cell functions. Rejuvenation Res 11:227–237. doi:10.1089/rej.2007.0613 CrossRefPubMed

30.

Kitamura H, Morikawa H, Kamon H, Iguchi M, Hojyo S, Fukada T, Yamashita S, Kaisho T, Akira S, Murakami M, Hirano T (2006) Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function. Nat Immunol 7:971–977. doi:10.1038/ni1373 CrossRefPubMed

31.

Subramanian Vignesh K, Landero Figueroa JA, Porollo A, Caruso JA, Deepe GS (2013) Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival. Immunity 39:697–710. doi:10.1016/j.immuni.2013.09.006 CrossRefPubMed

32.

Haase H (2013) An element of life: competition for zinc in hostpathogen interaction. Immunity 39:623–624. doi:10.1016/j.immuni.2013.09.009 CrossRefPubMed

33.

Kloubert V, Rink L (2015) Zinc as a micronutrient and its preventive role of oxidative damage in cells. Food Funct 6:3195–3204. doi:10.1039/C5FO00630A CrossRefPubMed

34.

Draijer C, Robbe P, Boorsma CE, Hylkema MN, Melgert BN (2013) Characterization of macrophage phenotypes in three murine models of house-dust-mite-induced asthma. Mediat Inflamm 2013:1–11. doi:10.1155/2013/632049 CrossRef

35.

Zhang M, He Y, Sun X, Li Q, Wang W, Zhao A, Di W (2014) A high M1/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients. J Ovarian Res 7:1–16. doi:10.1186/1757-2215-7-19 CrossRef

36.

Gumulec J, Masarik M, Adam V, Eckschlager T, Provaznik I, Kizek R (2014) Serum and tissue zinc in epithelial malignancies: a meta-analysis. PLoS One 9:1–11. doi:10.1371/journal.pone.0099790 CrossRef

37.

Maywald M, Rink L (2016) Zinc supplementation induces CD4 + CD25 + Foxp3+ antigen-specific regulatory T cells and suppresses IFN-g production by upregulation of Foxp3 and KLF-10 and downregulation of IRF-1. Eur J Nutr. doi:10.1007/s00394-016-1228-7 CrossRefPubMed

Titel: Cellular zinc homeostasis modulates polarization of THP-1-derived macrophages
verfasst von: Laura Dierichs
Veronika Kloubert
Lothar Rink
Publikationsdatum: 07.07.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: European Journal of Nutrition / Ausgabe 6/2018
Print ISSN: 1436-6207
Elektronische ISSN: 1436-6215
DOI: https://doi.org/10.1007/s00394-017-1491-2

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