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Human Macrophages and Monocytes Express Functional Na+/Ca2+ Exchangers 1 and 3

  • Rosaria I. Staiano
  • Francescopaolo Granata
  • Agnese Secondo
  • Angelica Petraroli
  • Stefania Loffredo
  • Lucio Annunziato
  • Massimo Triggiani
  • Gianni MaroneEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 961)

Abstract

The Na+/Ca2+ exchanger (NCX) is a plasma membrane protein that can switch Na+ and Ca2+ in either direction to maintain the homeostasis of intracellular Ca2+. A family of three genes (NCX1, NCX2, and NCX3) has been identified in neurons and muscle cells. NCX activity has also been reported in certain immune cells (e.g., mast cells). We have examined the expression and function of these NCX isoforms in the human monocytes and lung macrophages. Monocytes were purified from peripheral blood of healthy donors. Macrophages (HLM) were isolated and purified from the lung parenchyma of patients undergoing thoracic surgery. NCX1 and NCX3, but not NCX2, were expressed in HLM and monocytes at both mRNA and protein level. Exposure to Na+-free medium induced a significant increase in intracellular calcium concentration ([Ca2+]i) in both cell types, suggesting that NCX isoforms expressed on these cells were functionally active. This response was completely abolished by the NCX inhibitor 5-(N-4-chlorobenzyl)-20,40-dimethylbenzamil (CB-DMB). In addition, incubation of macrophages with Na+-free medium induced a marked release of TNF-α. Preincubation of HLM with CB-DMB and RNAi-mediated knockdown of NCX1 blocked TNF-α release. Our results demonstrate that human macrophages and monocytes express NCX1 and NCX3 that operate in a bidirectional manner to restore [Ca2+]i to generate Ca2+ signals and to induce TNF-α production. We suggest that NCX may modulate Ca2+ homeostasis and proinflammatory functions in human macrophages and monocytes.

Keywords

Monocytes Macrophages Na+/Ca2+ exchanger Ca2+-signaling Cytokines 

References

  1. A. Alfonso, J. Lago, M.A. Botana, M.R. Vieytes, L.M. Botana, Characterization of the Na+/Ca2+ exchanger on rat mast cells. Evidence for a functional role on the regulation of the cellular response. Cell. Physiol. Biochem. 9, 53–71 (1999)PubMedCrossRefGoogle Scholar
  2. P. Allavena, A. Mantovani, Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment. Clin. Exp. Immunol. 167, 195–205 (2012)PubMedCrossRefGoogle Scholar
  3. E. Aneiros, S. Philipp, A. Lis, M. Freichel, A. Cavalie, Modulation of Ca2+ signaling by Na+/Ca2+ exchangers in mast cells. J. Immunol. 174, 119–130 (2005)PubMedGoogle Scholar
  4. L. Annunziato, G. Pignataro, G.F. Di Renzo, Pharmacology of brain Na+/Ca2+ exchanger: from molecular biology to therapeutic perspectives. Pharmacol. Rev. 56, 633–654 (2004)PubMedCrossRefGoogle Scholar
  5. M. Balasubramanyam, C. Rohowsky-Kochan, J.P. Reeves, J.P. Gardner, Na+/Ca2+ exchange-mediated calcium entry in human lymphocytes. J. Clin. Invest. 94, 2002–2008 (1994)PubMedCrossRefGoogle Scholar
  6. S.K. Biswas, L. Gangi, S. Paul, T. Schioppa, A. Saccani, M. Sironi, B. Bottazzi, A. Doni, B. Vincenzo, F. Pasqualini, L. Vago, M. Nebuloni, A. Mantovani, A. Sica, A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation). Blood 107, 2112–2122 (2006)PubMedCrossRefGoogle Scholar
  7. S.K. Biswas, A. Mantovani, Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11, 889–896 (2010)PubMedCrossRefGoogle Scholar
  8. M.P. Blaustein, W.J. Lederer, Sodium/calcium exchange: its physiological implications. Physiol. Rev. 79, 763–854 (1999)PubMedGoogle Scholar
  9. R.A. Bouwman, K. Salic, F.G. Padding, E.C. Eringa, B.J. van Beek-Harmsen, T. Matsuda, A. Baba, R.J. Musters, W.J. Paulus, J.J. de Lange, C. Boer, Cardioprotection via activation of protein kinase C-delta depends on modulation of the reverse mode of the Na+/Ca2+ exchanger. Circulation 114, I226–I232 (2006)PubMedCrossRefGoogle Scholar
  10. E. Donnadieu, A. Trautmann, Is there a Na+/Ca2+ exchanger in macrophages and in lymphocytes? Pflugers Arch. 424, 448–455 (1993)PubMedCrossRefGoogle Scholar
  11. D.K. Fogg, C. Sibon, C. Miled, S. Jung, P. Aucouturier, D.R. Littman, A. Cumano, F. Geissmann, A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311, 83–87 (2006)PubMedCrossRefGoogle Scholar
  12. S. Gordon, P.R. Taylor, Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 5, 953–964 (2005)PubMedCrossRefGoogle Scholar
  13. F. Granata, A. Frattini, S. Loffredo, R.I. Staiano, A. Petraroli, D. Ribatti, R. Oslund, M.H. Gelb, G. Lambeau, G. Marone, M. Triggiani, Production of vascular endothelial growth factors from human lung macrophages induced by group IIA and group X secreted phospholipases A2. J. Immunol. 184, 5232–5241 (2010)PubMedCrossRefGoogle Scholar
  14. M. Ifuku, K. Farber, Y. Okuno, Y. Yamakawa, T. Miyamoto, C. Nolte, V.F. Merrino, S. Kita, T. Iwamoto, I. Komuro, B. Wang, G. Cheung, E. Ishikawa, H. Ooboshi, M. Bader, K. Wada, H. Kettenmann, M. Noda, Bradykinin-induced microglial migration mediated by B1-bradykinin receptors depends on Ca2+ influx via reverse-mode activity of the Na+/Ca2+ exchanger. J. Neurosci. 27, 13065–13073 (2007)PubMedCrossRefGoogle Scholar
  15. U. Johansson, C. Lawson, M. Dabare, D. Syndercombe-Court, A.C. Newland, G.L. Howells, M.G. Macey, Human peripheral blood monocytes express protease receptor-2 and respond to receptor activation by production of IL-6, IL-8, and IL-1{beta}. J. Leukoc. Biol. 78, 967–975 (2005)PubMedCrossRefGoogle Scholar
  16. M. Kurowska-Stolarska, B. Stolarski, P. Kewin, G. Murphy, C.J. Corrigan, S. Ying, N. Pitman, A. Mirchandani, B. Rana, N. van Rooijen, M. Shepherd, C. McSharry, I.B. McInnes, D. Xu, F.Y. Liew, IL-33 amplifies the polarization of alternatively activated macrophages that contribute to airway inflammation. J. Immunol. 183, 6469–6477 (2009)PubMedCrossRefGoogle Scholar
  17. T. Lawrence, G. Natoli, Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat. Rev. Immunol. 11, 750–761 (2011)PubMedCrossRefGoogle Scholar
  18. B. Linck, Z. Qiu, Z. He, Q. Tong, D.W. Hilgemann, K.D. Philipson, Functional comparison of the three isoforms of the Na+/Ca2+ exchanger (NCX1, NCX2, NCX3). Am. J. Physiol. 274, C415–C423 (1998)PubMedGoogle Scholar
  19. H. Liu, H. Zhang, H.J. Forman, Silica induces macrophage cytokines through phosphatidylcholine-specific phospholipase C with hydrogen peroxide. Am. J. Respir. Cell Mol. Biol. 36, 594–599 (2007)PubMedCrossRefGoogle Scholar
  20. J. Lytton, Na+/Ca2+ exchangers: three mammalian gene families control Ca2+ transport. Biochem. J. 406, 365–382 (2007)PubMedCrossRefGoogle Scholar
  21. A. Mantovani, A. Sica, S. Sozzani, P. Allavena, A. Vecchi, M. Locati, The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686 (2004)PubMedCrossRefGoogle Scholar
  22. F.O. Martinez, S. Gordon, M. Locati, A. Mantovani, Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J. Immunol. 177, 7303–7311 (2006)PubMedGoogle Scholar
  23. F.O. Martinez, L. Helming, S. Gordon, Alternative activation of macrophages: an immunologic functional perspective. Annu. Rev. Immunol. 27, 451–483 (2009)PubMedCrossRefGoogle Scholar
  24. M. Mayne, C.P. Holden, A. Nath, J.D. Geiger, Release of calcium from inositol 1,4,5-trisphosphate receptor-regulated stores by HIV-1 Tat regulates TNF-alpha production in human macrophages. J. Immunol. 164, 6538–6542 (2000)PubMedGoogle Scholar
  25. D.M. Mosser, J.P. Edwards, Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008)PubMedCrossRefGoogle Scholar
  26. O.H. Petersen, Stimulus-secretion coupling: cytoplasmic calcium signals and the control of ion channels in exocrine acinar cells. J. Physiol. 448, 1–51 (1992)PubMedGoogle Scholar
  27. K.D. Philipson, D.A. Nicoll, Sodium-calcium exchange: a molecular perspective. Annu. Rev. Physiol. 62, 111–133 (2000)PubMedCrossRefGoogle Scholar
  28. H.A. Praetorius, U.G. Friis, J. Praetorius, T. Johansen, Evidence for a Na+/Ca2+ exchange mechanism in rat peritoneal mast cells. Pflugers Arch. 437, 86–93 (1998)PubMedCrossRefGoogle Scholar
  29. G. Raes, L. Brys, B.K. Dahal, J. Brandt, J. Grooten, F. Brombacher, G. Vanham, W. Noel, P. Bogaert, T. Boonefaes, A. Kindt, R. Van den Bergh, P.J. Leenen, P. De Baetselier, G.H. Ghassabeh, Macrophage galactose-type C-type lectins as novel markers for alternatively activated macrophages elicited by parasitic infections and allergic airway inflammation. J. Leukoc. Biol. 77, 321–327 (2005)PubMedCrossRefGoogle Scholar
  30. D.E. Roberts, A. McNicol, R. Bose, Mechanism of collagen activation in human platelets. J. Biol. Chem. 279, 19421–19430 (2004)PubMedCrossRefGoogle Scholar
  31. F. Rogister, D. Laeckmann, P. Plasman, F. Van Eylen, M. Ghyoot, C. Maggetto, J. Liegeois, J. Geczy, A. Herchuelz, J. Delarge, B. Masereel, Novel inhibitors of the sodium-calcium exchanger: benzene ring analogues of N-guanidino substituted amiloride derivatives. Eur. J. Med. Chem. 36, 597–614 (2001)PubMedCrossRefGoogle Scholar
  32. E. Rumpel, U. Pilatus, A. Mayer, I. Pecht, Na+-dependent Ca2+ transport modulates the secretory response to the Fcepsilon receptor stimulus of mast cells. Biophys. J. 79, 2975–2986 (2000)PubMedCrossRefGoogle Scholar
  33. L. Santacruz-Toloza, M. Ottolia, D.A. Nicoll, K.D. Philipson, Functional analysis of a disulfide bond in the cardiac Na+-Ca2+ exchanger. J. Biol. Chem. 275, 182–188 (2000)PubMedCrossRefGoogle Scholar
  34. R. Schmitt, D.H. Ellison, N. Farman, B.C. Rossier, R.F. Reilly, W.B. Reeves, I. Oberbaumer, R. Tapp, S. Bachmann, Developmental expression of sodium entry pathways in rat nephron. Am. J. Physiol. 276, F367–F381 (1999)PubMedGoogle Scholar
  35. A. Secondo, R.I. Staiano, A. Scorziello, R. Sirabella, F. Boscia, A. Adornetto, V. Valsecchi, P. Molinaro, L.M. Canzoniero, G. Di Renzo, L. Annunziato, BHK cells transfected with NCX3 are more resistant to hypoxia followed by reoxygenation than those transfected with NCX1 and NCX2: possible relationship with mitochondrial membrane potential. Cell Calcium 42, 521–535 (2007)PubMedCrossRefGoogle Scholar
  36. E. Shumilina, S.M. Huber, F. Lang, Ca2+ signaling in the regulation of dendritic cell functions. Am. J. Physiol. Cell Physiol. 300, C1205–C1214 (2011)PubMedCrossRefGoogle Scholar
  37. J.R. Sierra, S. Corso, L. Caione, V. Cepero, P. Conrotto, A. Cignetti, W. Piacibello, A. Kumanogoh, H. Kikutani, P.M. Comoglio, L. Tamagnone, S. Giordano, Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages. J. Exp. Med. 205, 1673–1685 (2008)PubMedCrossRefGoogle Scholar
  38. L. Simchowitz, E.J. Cragoe Jr., Na+-Ca2+ exchange in human neutrophils. Am. J. Physiol. 254, C150–C164 (1988)PubMedGoogle Scholar
  39. D.M. Sosnoski, C.V. Gay, NCX3 is a major functional isoform of the sodium-calcium exchanger in osteoblasts. J. Cell. Biochem. 103, 1101–1110 (2008)PubMedCrossRefGoogle Scholar
  40. R.I. Staiano, F. Granata, A. Secondo, A. Petraroli, S. Loffredo, A. Frattini, L. Annunziato, G. Marone, M. Triggiani, Expression and function of Na+/Ca2+ exchangers 1 and 3 in human macrophages and monocytes. Eur. J. Immunol. 39, 1405–1418 (2009)PubMedCrossRefGoogle Scholar
  41. M.J. Sweet, B.P. Leung, D. Kang, M. Sogaard, K. Schulz, V. Trajkovic, C.C. Campbell, D. Xu, F.Y. Liew, A novel pathway regulating lipopolysaccharide-induced shock by ST2/T1 via inhibition of Toll-like receptor 4 expression. J. Immunol. 166, 6633–6639 (2001)PubMedGoogle Scholar
  42. G.R. Tintinger, R. Anderson, Counteracting effects of NADPH oxidase and the Na+/Ca2+ exchanger on membrane repolarisation and store-operated uptake of Ca2+ by chemoattractant-activated human neutrophils. Biochem. Pharmacol. 67, 2263–2271 (2004)PubMedCrossRefGoogle Scholar
  43. M. Torroella-Kouri, R. Silvera, D. Rodriguez, R. Caso, A. Shatry, S. Opiela, D. Ilkovitch, R.A. Schwendener, V. Iragavarapu-Charyulu, Y. Cardentey, N. Strbo, D.M. Lopez, Identification of a subpopulation of macrophages in mammary tumor-bearing mice that are neither M1 nor M2 and are less differentiated. Cancer Res. 69, 4800–4809 (2009)PubMedCrossRefGoogle Scholar
  44. M. Triggiani, M. Gentile, A. Secondo, F. Granata, A. Oriente, M. Taglialatela, L. Annunziato, G. Marone, Histamine induces exocytosis and IL-6 production from human lung macrophages through interaction with H1 receptors. J. Immunol. 166, 4083–4091 (2001)PubMedGoogle Scholar
  45. M. Triggiani, A. Petraroli, S. Loffredo, A. Frattini, F. Granata, P. Morabito, R.I. Staiano, A. Secondo, L. Annunziato, G. Marone, Differentiation of monocytes into macrophages induces the upregulation of histamine H1 receptor. J. Allergy Clin. Immunol. 119, 472–481 (2007)PubMedCrossRefGoogle Scholar
  46. M.C. Wacholtz, E.J. Cragoe Jr., P.E. Lipsky, A Na+-dependent Ca2+ exchanger generates the sustained increase in intracellular Ca2+ required for T cell activation. J. Immunol. 149, 1912–1920 (1992)PubMedGoogle Scholar
  47. X. Zhou, W. Yang, J. Li, Ca2+- and protein kinase C-dependent signaling pathway for nuclear factor-kappaB activation, inducible nitric-oxide synthase expression, and tumor necrosis factor-alpha production in lipopolysaccharide-stimulated rat peritoneal macrophages. J. Biol. Chem. 281, 31337–31347 (2006)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Rosaria I. Staiano
    • 1
  • Francescopaolo Granata
    • 1
  • Agnese Secondo
    • 2
  • Angelica Petraroli
    • 1
  • Stefania Loffredo
    • 1
  • Lucio Annunziato
    • 2
  • Massimo Triggiani
    • 1
    • 3
  • Gianni Marone
    • 1
    • 3
    Email author
  1. 1.Division of Clinical Immunology and Allergy, School of MedicineUniversity of Naples Federico IINaplesItaly
  2. 2.Division of Pharmacology, Department of Neuroscience, School of MedicineUniversity of Naples Federico IINaplesItaly
  3. 3.Center for Basic and Clinical Immunology Research (CISI)NaplesItaly

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