Advertisement

Neurochemical Research

, Volume 34, Issue 1, pp 109–117 | Cite as

Role of Ciliary Neurotrophic Factor in Microglial Phagocytosis

  • Tsung-I. Lee
  • Chung-Shi Yang
  • Kuan-Ming Fang
  • Shun-Fen Tzeng
Original Paper

Abstract

Microglia, CNS-resident macrophages, serve as scavengers to remove cellular debris and facilitate tissue remodeling in the developing and injured CNS. Little is known as what and how microenvironmental factors mediate the phagocytotic ability of microglia. Our previous study has indicated that treatment with glial cell line-derived neurotrophic factor (GDNF) increased the phagocytotic activity of primary rat microglia possibly through the upregulation of α5 integrin. In the present study, ciliary neurotrophic factor (CNTF), which has been reported to be produced by glia, was shown to have stimulatory effect on the phagocytosis of primary rat microglia and mouse microglial cell line BV2. Ca2+ imaging analysis and the application of intracellular calcium chelator BAPTA-AM revealed that CNTF-induced increase in microglial phagocytosis was mediated by a calcium signaling pathway. Furthermore, treatment with CNTF led to an increase in the expression of αv integrin, which has been reported to be involved in the phagocytosis of the apoptotic cells. In summary, we have provided evidence that CNTF can increase microglial phagocytosis through a calcium-mediated pathway. Our results also suggest that the upregulation of αv integrin by CNTF could be involved in the increased phagocytotic activity of microglia.

Keywords

Microglia Phagocytosis CNTF Calcium αv Integrin 

Notes

Acknowledgements

The authors thank Ms. Hsin-I. Lin for assistance with the cell culture. This study was supported in part by grants from the National Science Council (NSC 94–2321-B-006-121; NSC94-2120-M260-003) of Taiwan.

References

  1. 1.
    Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394PubMedCrossRefGoogle Scholar
  2. 2.
    Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318PubMedCrossRefGoogle Scholar
  3. 3.
    Garden GA, Moller T (2006) Microglia biology in health and disease. J Neuroimmune Pharmacol 1:127–137PubMedCrossRefGoogle Scholar
  4. 4.
    Elkabes S, DiCicco-Bloom EM, Black IB (1996) Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J Neurosci 16:2508–2521PubMedGoogle Scholar
  5. 5.
    Cammer W, Zhang H (1996) Carbonic anhydrase II in microglia in forebrains of neonatal rats. J Neuroimmunol 67:131–136PubMedCrossRefGoogle Scholar
  6. 6.
    Bessis A, Bechade C, Bernard D, Roumier A (2007) Microglial control of neuronal death and synaptic properties. Glia 55:233–238PubMedCrossRefGoogle Scholar
  7. 7.
    Schwartz M (2003) Macrophages and microglia in central nervous system injury: are they helpful or harmful? J Cereb Blood Flow Metab 23:385–394PubMedCrossRefGoogle Scholar
  8. 8.
    Liu B, Hong JS (2003) Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 304:1–7PubMedCrossRefGoogle Scholar
  9. 9.
    Giulian D, Corpuz M (1993) Microglial secretion products and their impact on the nervous system. Adv Neurol 59:315–320PubMedGoogle Scholar
  10. 10.
    David S, Bouchard C, Tsatas O, Giftochristos N (1990) Macrophages can modify the nonpermissive nature of the adult mammalian central nervous system. Neuron 5:463–469PubMedCrossRefGoogle Scholar
  11. 11.
    Lin LF, Mismer D, Lile JD, Armes LG, Butler ET 3rd, Vannice JL, Collins F (1989) Purification, cloning, and expression of ciliary neurotrophic factor (CNTF). Science 246:1023–1025PubMedCrossRefGoogle Scholar
  12. 12.
    Adler R, Landa KB, Manthorpe M, Varon S (1979) Cholinergic neuronotrophic factors: intraocular distribution of trophic activity for ciliary neurons. Science 204:1434–1436PubMedCrossRefGoogle Scholar
  13. 13.
    Richardson PM (1994) Ciliary neurotrophic factor: a review. Pharmacol Ther 63:187–198PubMedCrossRefGoogle Scholar
  14. 14.
    Stankoff B, Aigrot MS, Noel F, Wattilliaux A, Zalc B, Lubetzki C (2002) Ciliary neurotrophic factor (CNTF) enhances myelin formation: a novel role for CNTF and CNTF-related molecules. J Neurosci 22:9221–9227PubMedGoogle Scholar
  15. 15.
    Mittoux V, Joseph JM, Conde F, Palfi S, Dautry C, Poyot T, Bloch J, Deglon N, Ouary S, Nimchinsky EA, Brouillet E, Hof PR, Peschanski M, Aebischer P, Hantraye P (2000) Restoration of cognitive and motor functions by ciliary neurotrophic factor in a primate model of Huntington’s disease. Hum Gene Ther 11:1177–1187PubMedCrossRefGoogle Scholar
  16. 16.
    Escartin C, Pierre K, Colin A, Brouillet E, Delzescaux T, Guillermier M, Dhenain M, Deglon N, Hantraye P, Pellerin L, Bonvento G (2007) Activation of astrocytes by CNTF induces metabolic plasticity and increases resistance to metabolic insults. J Neurosci 27:7094–7104PubMedCrossRefGoogle Scholar
  17. 17.
    Kahn MA, Ellison JA, Speight GJ, de Vellis J (1995) CNTF regulation of astrogliosis and the activation of microglia in the developing rat central nervous system. Brain Res 685:55–67PubMedCrossRefGoogle Scholar
  18. 18.
    Krady JK, Lin HW, Liberto CM, Basu A, Kremlev SG, Levison SW (2008) Ciliary neurotrophic factor and interleukin-6 differentially activate microglia. J Neurosci ResGoogle Scholar
  19. 19.
    Jutras I, Desjardins M (2005) Phagocytosis: at the crossroads of innate and adaptive immunity. Annu Rev Cell Dev Biol 21:511–527PubMedCrossRefGoogle Scholar
  20. 20.
    Witting A, Muller P, Herrmann A, Kettenmann H, Nolte C (2000) Phagocytic clearance of apoptotic neurons by Microglia/Brain macrophages in vitro: involvement of lectin-, integrin-, and phosphatidylserine-mediated recognition. J Neurochem 75:1060–1070PubMedCrossRefGoogle Scholar
  21. 21.
    Blasi E, Barluzzi R, Bocchini V, Mazzolla R, Bistoni F (1990) Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol 27:229–237PubMedCrossRefGoogle Scholar
  22. 22.
    Tzeng SF, Huang HY, Lee TI, Jwo JK (2005) Inhibition of lipopolysaccharide-induced microglial activation by preexposure to neurotrophin-3. J Neurosci Res 81:666–676PubMedCrossRefGoogle Scholar
  23. 23.
    Tzeng SF, Lee JL, Kuo JS, Yang CS, Murugan P, Ai Tai L, Chu Hwang K (2002) Effects of malonate C60 derivatives on activated microglia. Brain Res 940:61–68PubMedCrossRefGoogle Scholar
  24. 24.
    McCarthy KD, de Vellis J (1980) Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol 85:890–902PubMedCrossRefGoogle Scholar
  25. 25.
    Chang YP, Fang KM, Lee TI, Tzeng SF (2006) Regulation of microglial activities by glial cell line derived neurotrophic factor. J Cell Biochem 97:501–511PubMedCrossRefGoogle Scholar
  26. 26.
    Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K, Shinozaki Y, Ohsawa K, Tsuda M, Joshi BV, Jacobson KA, Kohsaka S, Inoue K (2007) UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature 446:1091–1095PubMedCrossRefGoogle Scholar
  27. 27.
    Schrijvers DM, Martinet W, De Meyer GR, Andries L, Herman AG, Kockx MM (2004) Flow cytometric evaluation of a model for phagocytosis of cells undergoing apoptosis. J Immunol Methods 287:101–108PubMedCrossRefGoogle Scholar
  28. 28.
    Hsiao HY, Mak OT, Yang CS, Liu YP, Fang KM, Tzeng SF (2007) TNF-alpha/IFN-gamma-induced iNOS expression increased by prostaglandin E2 in rat primary astrocytes via EP2-evoked cAMP/PKA and intracellular calcium signaling. Glia 55:214–223PubMedCrossRefGoogle Scholar
  29. 29.
    Boran MS, Baltrons MA, Garcia A (2008) The ANP-cGMP-protein kinase G pathway induces a phagocytic phenotype but decreases inflammatory gene expression in microglial cells. Glia 56:394–411PubMedCrossRefGoogle Scholar
  30. 30.
    Bocchini V, Artault JC, Rebel G, Dreyfus H, Massarelli R (1988) Phagocytosis of polystyrene latex beads by rat brain microglia cell cultures is increased by treatment with gangliosides. Dev Neurosci 10:270–276PubMedCrossRefGoogle Scholar
  31. 31.
    Dersch P, Isberg RR (2000) An immunoglobulin superfamily-like domain unique to the Yersinia pseudotuberculosis invasin protein is required for stimulation of bacterial uptake via integrin receptors. Infect Immun 68:2930–2938PubMedCrossRefGoogle Scholar
  32. 32.
    Isberg RR, Hamburger Z, Dersch P (2000) Signaling and invasin-promoted uptake via integrin receptors. Microbes Infect 2:793–801PubMedCrossRefGoogle Scholar
  33. 33.
    Albert ML, Kim JI, Birge RB (2000) Alphavbeta5 integrin recruits the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells. Nat Cell Biol 2:899–905PubMedCrossRefGoogle Scholar
  34. 34.
    Leitinger B, McDowall A, Stanley P, Hogg N (2000) The regulation of integrin function by Ca(2+). Biochim Biophys Acta 1498:91–98PubMedCrossRefGoogle Scholar
  35. 35.
    Jaconi ME, Lew DP, Carpentier JL, Magnusson KE, Sjogren M, Stendahl O (1990) Cytosolic free calcium elevation mediates the phagosome-lysosome fusion during phagocytosis in human neutrophils. J Cell Biol 110:1555–1564PubMedCrossRefGoogle Scholar
  36. 36.
    Bloch J, Bachoud-Levi AC, Deglon N, Lefaucheur JP, Winkel L, Palfi S, Nguyen JP, Bourdet C, Gaura V, Remy P, Brugieres P, Boisse MF, Baudic S, Cesaro P, Hantraye P, Aebischer P, Peschanski M (2004) Neuroprotective gene therapy for Huntington’s disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor: results of a phase I study. Hum Gene Ther 15:968–975PubMedCrossRefGoogle Scholar
  37. 37.
    Hashimoto M, Nitta A, Fukumitsu H, Nomoto H, Shen L, Furukawa S (2005) Involvement of glial cell line-derived neurotrophic factor in activation processes of rodent macrophages. J Neurosci Res 79:476–487PubMedCrossRefGoogle Scholar
  38. 38.
    McPhillips K, Janssen WJ, Ghosh M, Byrne A, Gardai S, Remigio L, Bratton DL, Kang JL, Henson P (2007) TNF-alpha inhibits macrophage clearance of apoptotic cells via cytosolic phospholipase A2 and oxidant-dependent mechanisms. J Immunol 178:8117–8126PubMedGoogle Scholar
  39. 39.
    Koenigsknecht J, Landreth G (2004) Microglial phagocytosis of fibrillar beta-amyloid through a beta1 integrin-dependent mechanism. J Neurosci 24:9838–9846PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Tsung-I. Lee
    • 1
  • Chung-Shi Yang
    • 2
    • 3
    • 4
  • Kuan-Ming Fang
    • 1
  • Shun-Fen Tzeng
    • 1
  1. 1.Department of Life SciencesNational Cheng Kung UniversityTainan CityTaiwan
  2. 2.Center for Nanomedicine ResearchNational Health Research InstitutesZhunanTaiwan
  3. 3.Department of Applied ChemistryNational Chi-Nan UniversityPuliTaiwan
  4. 4.Graduate Institute of Biomedicine and Biomedical TechnologyNational Chi-Nan UniversityPuliTaiwan

Personalised recommendations