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Immunological Mechanisms and Therapies in Brain Injuries and Stroke pp 121–134Cite as

Ion Transporters in Microglial Function: New Therapeutic Targets for Neuroinflammation in Ischemic Stroke?

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Part of the book series: Springer Series in Translational Stroke Research ((SSTSR,volume 6))

Abstract

Microglia are the macrophage immune cells in the CNS and monitor extracellular microenvironment in healthy brains. They can be rapidly activated under pathological conditions and move to a lesion site following chemotactic gradients and unfold their phagocytotic activities to clear tissue debris, damaged cells, or microbes. A growing body of studies illustrated the importance of ion transporters in regulating activation and migration of microglia and peripheral immune cells in cerebral ischemic conditions. This chapter summarized roles of Na+/H+ exchanger, Na+/Ca2+ exchanger, and K+/Cl− cotransporters in regulation of pHi, Ca2+-spiking events, cell volume, and membrane signal molecule expression during microglia/peripheral immune cell migration, adhesion, and activation. In light of the detrimental effects of excessive pro-inflammatory response on ischemic brain injury, targeting ion transporters may be a new therapeutic strategy to minimize neuroinflammatory reactions after ischemic stroke.

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Abbreviations

NHE:

Na+/H+ exchanger

NCX:

Na+/Ca2+ exchange

MCAO:

Middle cerebral artery occlusion

NOX:

NADPH oxidase

OGD:

Oxygen and glucose deprivation

pHi:

Intracellular pH

ROS:

Reactive oxygen species

[Ca2+]i :

Intracellular Ca2+

[Na+]i :

Intracellular Na+

KCC:

K+–Cl− cotransporters

IL:

Interleukin

TNF-α:

Tumor necrosis factor alpha

ATP:

Adenosine triphosphate

References

  1. Ling EA, Wong WC (1993) The origin and nature of ramified and ameboid microglia: a historical review and current concepts. Glia 7:9–18

    Article  CAS  PubMed  Google Scholar 

  2. Moore S, Thanos S (1996) The concept of microglia in relation to central nervous system disease and regeneration. Prog Neurobiol 48:441–460

    Article  CAS  PubMed  Google Scholar 

  3. Graeber MB, Streit WJ (2010) Microglia: biology and pathology. Acta Neuropathol 119(1):89–105

    Article  PubMed  Google Scholar 

  4. Jin R, Yang G, Li G (2010) Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 87(5):779–89

    Article  CAS  PubMed  Google Scholar 

  5. Tambuyzer BR, Ponsaerts P, Nouwen EJ (2009) Microglia: gatekeepers of central nervous system immunology. J Leukoc Biol 85:352–370

    Article  CAS  PubMed  Google Scholar 

  6. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553

    Article  CAS  PubMed  Google Scholar 

  7. Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, Gao Y, Chen J (2012) Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43(11):3063–70

    Article  CAS  PubMed  Google Scholar 

  8. Harrigan TJ, Abdullaev IF, Jourd’heuil D, Mongin AA (2008) Activation of microglia with zymosan promotes excitatory amino acid release via volume-regulated anion channels: the role of NADPH oxidases. J Neurochem 106:2449–2462

    Article  CAS  PubMed  Google Scholar 

  9. Yenari MA, Kauppinen TM, Swanson RA (2010) Microglial activation in stroke: therapeutic targets. Neurotherapeutics 7(4):378–91

    Article  CAS  PubMed  Google Scholar 

  10. Lalancette-Hebert M, Gowing G, Simard A, Weng YC, Kriz J (2007) Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci 27(10):2596–605

    Article  CAS  PubMed  Google Scholar 

  11. Mongin AA (2007) Disruption of ionic and cell volume homeostasis in cerebral ischemia: the perfect storm. Pathophysiology 14(3–4):183–93

    Article  CAS  PubMed  Google Scholar 

  12. Shi Y, Kim D, Caldwell M, Sun D (2013) The role of Na+/H+ exchanger isoform 1 in inflammatory responses: maintaining H+ homeostasis of immune cells. Adv Exp Med Biol 961:411–8

    Article  PubMed  Google Scholar 

  13. Orlowski J, Grinstein S (2004) Diversity of the mammalian sodium/proton exchanger SLC9 gene family. Pflugers Arch 447:549–565

    Article  CAS  PubMed  Google Scholar 

  14. Fliegel L (2005) The Na+/H+ exchanger isoform 1. Int J Biochem Cell Biol 37:33–37

    Article  CAS  PubMed  Google Scholar 

  15. Zachos NC, Tse M, Donowitz M (2005) Molecular physiology of intestinal Na+/H+ exchange. Annu Rev Physiol 67:411–443

    Article  CAS  PubMed  Google Scholar 

  16. Brett CL, Wei Y, Donowitz M, Rao R (2002) Human Na+/H+ exchanger isoform 6 is found in recycling endosomes of cells, not in mitochondria. Am J Physiol Cell Physiol 282:C1031–C1041

    Article  CAS  PubMed  Google Scholar 

  17. Numata M, Orlowski J (2001) Molecular cloning and characterization of a novel (Na+, K+)/H+ exchanger localized to the trans-Golgi network. J Biol Chem 276:17387–17394

    Article  CAS  PubMed  Google Scholar 

  18. De Vito P (2006) The sodium/hydrogen exchanger: a possible mediator of immunity. Cell Immunol 240:69–85

    Article  PubMed  Google Scholar 

  19. Rotin D, Grinstein S (1989) Impaired cell volume regulation in Na+–H+ exchange-deficient mutants. Am J Physiol 257:C1158–C1165

    CAS  PubMed  Google Scholar 

  20. Denker SP, Huang DC, Orlowski J, Furthmayr H, Barber DL (2000) Direct binding of the Na-H exchanger NHE1 to ERM proteins regulates the cortical cytoskeleton and cell shape independently of H+ translocation. Mol Cell 6:1425–1436

    Article  CAS  PubMed  Google Scholar 

  21. Denker SP, Barber DL (2002) Cell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1. J Cell Biol 159(6):1087–96

    Article  CAS  PubMed  Google Scholar 

  22. Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87(1):245–313

    Article  CAS  PubMed  Google Scholar 

  23. Henderson LM, Chappell JB, Jones OT (1988) Internal pH changes associated with the activity of NADPH oxidase of human neutrophils. Further evidence for the presence of an H+ conducting channel. Biochem J 251:563–567

    CAS  PubMed  Google Scholar 

  24. Liu Y, Kintner DB, Chanana V, Algharabli J, Chen X, Gao Y, Chen J, Ferrazzano P, Olson JK, Sun D (2010) Activation of microglia depends on Na+/H+ exchange-mediated H+ homeostasis. J Neurosci 30:15210–15220

    Article  CAS  PubMed  Google Scholar 

  25. Shi Y, Chanana V, Watters JJ, Ferrazzano P, Sun D (2011) Role of sodium/hydrogen exchanger isoform 1 in microglial activation and proinflammatory responses in ischemic brains. J Neurochem 119:124–135

    Article  CAS  PubMed  Google Scholar 

  26. Honda S, Sasaki Y, Ohsawa K, Imai Y, Nakamura Y, Inoue K, Kohsaka S (2001) Extracellular ATP or ADP induce chemotaxis of cultured microglia through Gi/o-coupled P2Y receptors. J Neurosci 21:1975–1982

    CAS  PubMed  Google Scholar 

  27. Ifuku M, Farber K, Okuno Y, Yamakawa Y, Miyamoto T, Nolte C, Merrino VF, Kita S, Iwamoto T, Komuro I, Wang B, Cheung G, Ishikawa E, Ooboshi H, Bader M, Wada K, Kettenmann H, Noda M (2007) 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

    Article  CAS  PubMed  Google Scholar 

  28. Stock C, Schwab A (2009) Protons make tumor cells move like clockwork. Pflugers Arch 458:981–992

    Article  CAS  PubMed  Google Scholar 

  29. Carlier MF, Laurent V, Santolini J, Melki R, Didry D, Xia GX, Hong Y, Chua NH, Pantaloni D (1997) Actin depolymerizing factor (ADF/cofilin) enhances the rate of filament turnover: implication in actin-based motility. J Cell Biol 136:1307–1322

    Article  CAS  PubMed  Google Scholar 

  30. Ghosh M, Song X, Mouneimne G, Sidani M, Lawrence DS, Condeelis JS (2004) Cofilin promotes actin polymerization and defines the direction of cell motility. Science 304:743–746

    Article  CAS  PubMed  Google Scholar 

  31. Frantz C, Barreiro G, Dominguez L, Chen X, Eddy R, Condeelis J, Kelly MJ, Jacobson MP, Barber DL (2008) Cofilin is a pH sensor for actin free barbed end formation: role of phosphoinositide binding. J Cell Biol 183:865–879

    Article  CAS  PubMed  Google Scholar 

  32. Yonezawa N, Nishida E, Sakai H (1985) pH control of actin polymerization by cofilin. J Biol Chem 260:14410–14412

    CAS  PubMed  Google Scholar 

  33. Shi Y, Yuan H, Kim D, Chanana V, Baba A, Matsuda T, Cengiz P, Ferrazzano P, Sun D (2013) Stimulation of Na(+) / H(+) exchanger isoform 1 promotes microglial migration. PLoS One 8(8):e74201

    Google Scholar 

  34. Annunziato L, Pignataro G, Di Renzo GF (2004) Pharmacology of brain Na+/Ca2+ exchanger: from molecular biology to therapeutic perspectives. Pharmacol Rev 56:633–654

    Article  CAS  PubMed  Google Scholar 

  35. Philipson KD, Nicoll DA (2000) Sodium–calcium exchange: a molecular perspective. Annu Rev Physiol 62:111–133

    Article  CAS  PubMed  Google Scholar 

  36. Philipson KD, Nicoll DA, Ottolia M, Quednau BD, Reuter H, John S, Qiu Z (2002) The Na+/Ca2+ exchange molecule: an overview. Ann N Y Acad Sci 976:1–10

    Article  CAS  PubMed  Google Scholar 

  37. Nicoll DA, Longoni S, Philipson KD (1990) Molecular cloning and functional expression of the cardiac sarcolemmal Na+–Ca2+ exchanger. Science 250:562–565

    Article  CAS  PubMed  Google Scholar 

  38. Newell EW, Stanley EF, Schlichter LC (2007) Reversed Na+/Ca2+ exchange contributes to Ca2+ influx and respiratory burst in microglia. Channels (Austin) 1:366–376

    Google Scholar 

  39. Quednau BD, Nicoll DA, Philipson KD (1997) Tissue specificity and alternative splicing of the Na+/Ca2+ exchanger isoforms NCX1, NCX2, and NCX3 in rat. Am J Physiol 272:C1250–C1261

    CAS  PubMed  Google Scholar 

  40. Nagano T, Kawasaki Y, Baba A, Takemura M, Matsuda T (2004) Up-regulation of Na+–Ca2+ exchange activity by interferon-gamma in cultured rat microglia. J Neurochem 90:784–791

    Article  CAS  PubMed  Google Scholar 

  41. Boscia F, Gala R, Pannaccione A, Secondo A, Scorziello A, Di Renzo G, Annunziato L (2009) NCX1 expression and functional activity increase in microglia invading the infarct core. Stroke 40:3608–3617

    Article  CAS  PubMed  Google Scholar 

  42. Matsuda T, Nagano T, Takemura M, Baba A (2006) Topics on the Na+/Ca2+ exchanger: responses of Na+/Ca2+ exchanger to interferon-gamma and nitric oxide in cultured microglia. J Pharmacol Sci 102:22–26

    Article  CAS  PubMed  Google Scholar 

  43. Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394

    Article  CAS  PubMed  Google Scholar 

  44. Ito D, Tanaka K, Suzuki S, Dembo T, Fukuuchi Y (2001) Enhanced expression of Iba1, ionized calcium-binding adapter molecule 1, after transient focal cerebral ischemia in rat brain. Stroke 32:1208–1215

    Article  CAS  PubMed  Google Scholar 

  45. Zierler S, Frei E, Grissmer S, Kerschbaum HH (2008) Chloride influx provokes lamellipodium formation in microglial cells. Cell Physiol Biochem 21:55–62

    Article  CAS  PubMed  Google Scholar 

  46. Leis JA, Bekar LK, Walz W (2005) Potassium homeostasis in the ischemic brain. Glia 50:407–416

    Article  PubMed  Google Scholar 

  47. Faff L, Ohlemeyer C, Kettenmann H (1996) Intracellular pH regulation in cultured microglial cells from mouse brain. J Neurosci Res 46:294–304

    Article  CAS  PubMed  Google Scholar 

  48. Schwab A (2001) Function and spatial distribution of ion channels and transporters in cell migration. Am J Physiol Renal Physiol 280:F739–F747

    CAS  PubMed  Google Scholar 

  49. Schwab A (2001) Ion channels and transporters on the move. News Physiol Sci 16:29–33

    CAS  PubMed  Google Scholar 

  50. Weinstein JR, Koerner IP, Moller T (2010) Microglia in ischemic brain injury. Future Neurol 5:227–246

    Article  CAS  PubMed  Google Scholar 

  51. Schilling M, Besselmann M, Muller M, Strecker JK, Ringelstein EB, Kiefer R (2005) Predominant phagocytic activity of resident microglia over hematogenous macrophages following transient focal cerebral ischemia: an investigation using green fluorescent protein transgenic bone marrow chimeric mice. Exp Neurol 196:290–297

    Article  CAS  PubMed  Google Scholar 

  52. Bernardes-Silva M, Anthony DC, Issekutz AC, Perry VH (2001) Recruitment of neutrophils across the blood–brain barrier: the role of E- and P-selectins. J Cereb Blood Flow Metab 21:1115–1124

    Article  CAS  PubMed  Google Scholar 

  53. Martins PS, Kallas EG, Neto MC, Dalboni MA, Blecher S, Salomao R (2003) Upregulation of reactive oxygen species generation and phagocytosis, and increased apoptosis in human neutrophils during severe sepsis and septic shock. Shock 20:208–212

    Article  CAS  PubMed  Google Scholar 

  54. Robinson JM (2008) Reactive oxygen species in phagocytic leukocytes. Histochem Cell Biol 130:281–297

    Article  CAS  PubMed  Google Scholar 

  55. Fukushima T, Waddell TK, Grinstein S, Goss GG, Orlowski J, Downey GP (1996) Na+/H+ exchange activity during phagocytosis in human neutrophils: role of Fcgamma receptors and tyrosine kinases. J Cell Biol 132:1037–1052

    Article  CAS  PubMed  Google Scholar 

  56. Hayashi H, Aharonovitz O, Alexander RT, Touret N, Furuya W, Orlowski J, Grinstein S (2008) Na+/H+ exchange and pH regulation in the control of neutrophil chemokinesis and chemotaxis. Am J Physiol Cell Physiol 294:C526–C534

    Article  CAS  PubMed  Google Scholar 

  57. Kaba NK, Schultz J, Law FY, Lefort CT, Martel-Gallegos G, Kim M, Waugh RE, Arreola J, Knauf PA (2008) Inhibition of Na+/H+ exchanger enhances low pH-induced L-selectin shedding and beta2-integrin surface expression in human neutrophils. Am J Physiol Cell Physiol 295:C1454–C1463

    Article  CAS  PubMed  Google Scholar 

  58. Donnadieu E, Trautmann A (1993) Is there a Na+/Ca2+ exchanger in macrophages and in lymphocytes? Pflugers Arch 424:448–455

    Article  CAS  PubMed  Google Scholar 

  59. Balasubramanyam M, Rohowsky-Kochan C, Reeves JP, Gardner JP (1994) Na+/Ca2+ exchange-mediated calcium entry in human lymphocytes. J Clin Invest 94:2002–2008

    Article  CAS  PubMed  Google Scholar 

  60. Tintinger GR, Anderson R (2004) 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

    Article  CAS  PubMed  Google Scholar 

  61. Gordon S (2007) The macrophage: past, present and future. Eur J Immunol 37(Suppl 1):S9–17

    Article  CAS  PubMed  Google Scholar 

  62. Hume DA, Ross IL, Himes SR, Sasmono RT, Wells CA, Ravasi T (2002) The mononuclear phagocyte system revisited. J Leukoc Biol 72:621–627

    CAS  PubMed  Google Scholar 

  63. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686

    Article  CAS  PubMed  Google Scholar 

  64. Fogg DK, Sibon C, Miled C, Jung S, Aucouturier P, Littman DR, Cumano A, Geissmann F (2006) A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311:83–87

    Article  CAS  PubMed  Google Scholar 

  65. Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964

    Article  CAS  PubMed  Google Scholar 

  66. Cathcart MK (2004) Regulation of superoxide anion production by NADPH oxidase in monocytes/macrophages: contributions to atherosclerosis. Arterioscler Thromb Vasc Biol 24:23–28

    Article  CAS  PubMed  Google Scholar 

  67. Tapper H (1996) The secretion of preformed granules by macrophages and neutrophils. J Leukoc Biol 59:613–622

    CAS  PubMed  Google Scholar 

  68. Staiano RI, Granata F, Secondo A, Petraroli A, Loffredo S, Frattini A, Annunziato L, Marone G, Triggiani M (2009) Expression and function of Na+/Ca2+ exchangers 1 and 3 in human macrophages and monocytes. Eur J Immunol 39:1405–1418

    Article  CAS  PubMed  Google Scholar 

  69. Secondo A, Staiano RI, Scorziello A, Sirabella R, Boscia F, Adornetto A, Valsecchi V, Molinaro P, Canzoniero LM, Di RG, Annunziato L (2007) 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

    Article  CAS  PubMed  Google Scholar 

  70. Watanabe N, Suzuki J, Kobayashi Y (1996) Role of calcium in tumor necrosis factor-alpha production by activated macrophages. J Biochem 120:1190–1195

    Article  CAS  PubMed  Google Scholar 

  71. Liu H, Zhang H, Forman HJ (2007) Silica induces macrophage cytokines through phosphatidylcholine-specific phospholipase C with hydrogen peroxide. Am J Respir Cell Mol Biol 36:594–599

    Article  CAS  PubMed  Google Scholar 

  72. Mayne M, Holden CP, Nath A, Geiger JD (2000) 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

    CAS  PubMed  Google Scholar 

  73. Zhou X, Yang W, Li J (2006) 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

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment

This work was supported by NIH grants R01NS 48216 and R01NS 38118 (D. Sun).

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Authors and Affiliations

  1. Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA

    Hui Yuan, Yejie Shi & Dandan Sun

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  1. Hui Yuan
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  2. Yejie Shi
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  3. Dandan Sun
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Correspondence to Dandan Sun .

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Editors and Affiliations

  1. University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Jun Chen

  2. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Xiaoming Hu

  3. Molecular Microbiology & Immunology, Oregon Health & Sciences University, Portland, Oregon, USA

    Mary Stenzel-Poore

  4. Loma Linda University, Loma Linda, California, USA

    John H. Zhang

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Yuan, H., Shi, Y., Sun, D. (2014). Ion Transporters in Microglial Function: New Therapeutic Targets for Neuroinflammation in Ischemic Stroke?. In: Chen, J., Hu, X., Stenzel-Poore, M., Zhang, J. (eds) Immunological Mechanisms and Therapies in Brain Injuries and Stroke. Springer Series in Translational Stroke Research, vol 6. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8915-3_8

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  • DOI: https://doi.org/10.1007/978-1-4614-8915-3_8

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