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Role of Ciliary Neurotrophic Factor in Microglial Phagocytosis

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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.

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References

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

    Article  PubMed  CAS  Google Scholar 

  2. Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318

    Article  PubMed  CAS  Google Scholar 

  3. Garden GA, Moller T (2006) Microglia biology in health and disease. J Neuroimmune Pharmacol 1:127–137

    Article  PubMed  Google Scholar 

  4. Elkabes S, DiCicco-Bloom EM, Black IB (1996) Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J Neurosci 16:2508–2521

    PubMed  CAS  Google Scholar 

  5. Cammer W, Zhang H (1996) Carbonic anhydrase II in microglia in forebrains of neonatal rats. J Neuroimmunol 67:131–136

    Article  PubMed  CAS  Google Scholar 

  6. Bessis A, Bechade C, Bernard D, Roumier A (2007) Microglial control of neuronal death and synaptic properties. Glia 55:233–238

    Article  PubMed  Google Scholar 

  7. Schwartz M (2003) Macrophages and microglia in central nervous system injury: are they helpful or harmful? J Cereb Blood Flow Metab 23:385–394

    Article  PubMed  Google Scholar 

  8. Liu B, Hong JS (2003) Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 304:1–7

    Article  PubMed  CAS  Google Scholar 

  9. Giulian D, Corpuz M (1993) Microglial secretion products and their impact on the nervous system. Adv Neurol 59:315–320

    PubMed  CAS  Google Scholar 

  10. David S, Bouchard C, Tsatas O, Giftochristos N (1990) Macrophages can modify the nonpermissive nature of the adult mammalian central nervous system. Neuron 5:463–469

    Article  PubMed  CAS  Google Scholar 

  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 246:1023–1025

    Article  PubMed  CAS  Google Scholar 

  12. Adler R, Landa KB, Manthorpe M, Varon S (1979) Cholinergic neuronotrophic factors: intraocular distribution of trophic activity for ciliary neurons. Science 204:1434–1436

    Article  PubMed  CAS  Google Scholar 

  13. Richardson PM (1994) Ciliary neurotrophic factor: a review. Pharmacol Ther 63:187–198

    Article  PubMed  CAS  Google Scholar 

  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 22:9221–9227

    PubMed  CAS  Google Scholar 

  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 11:1177–1187

    Article  PubMed  CAS  Google Scholar 

  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 27:7094–7104

    Article  PubMed  CAS  Google Scholar 

  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 685:55–67

    Article  PubMed  CAS  Google Scholar 

  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 Res

  19. Jutras I, Desjardins M (2005) Phagocytosis: at the crossroads of innate and adaptive immunity. Annu Rev Cell Dev Biol 21:511–527

    Article  PubMed  CAS  Google Scholar 

  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 75:1060–1070

    Article  PubMed  CAS  Google Scholar 

  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 27:229–237

    Article  PubMed  CAS  Google Scholar 

  22. Tzeng SF, Huang HY, Lee TI, Jwo JK (2005) Inhibition of lipopolysaccharide-induced microglial activation by preexposure to neurotrophin-3. J Neurosci Res 81:666–676

    Article  PubMed  CAS  Google Scholar 

  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 940:61–68

    Article  PubMed  CAS  Google Scholar 

  24. McCarthy KD, de Vellis J (1980) Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol 85:890–902

    Article  PubMed  CAS  Google Scholar 

  25. Chang YP, Fang KM, Lee TI, Tzeng SF (2006) Regulation of microglial activities by glial cell line derived neurotrophic factor. J Cell Biochem 97:501–511

    Article  PubMed  CAS  Google Scholar 

  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 446:1091–1095

    Article  PubMed  CAS  Google Scholar 

  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 287:101–108

    Article  PubMed  CAS  Google Scholar 

  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 55:214–223

    Article  PubMed  Google Scholar 

  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 56:394–411

    Article  PubMed  Google Scholar 

  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 10:270–276

    Article  PubMed  CAS  Google Scholar 

  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 68:2930–2938

    Article  PubMed  CAS  Google Scholar 

  32. Isberg RR, Hamburger Z, Dersch P (2000) Signaling and invasin-promoted uptake via integrin receptors. Microbes Infect 2:793–801

    Article  PubMed  CAS  Google Scholar 

  33. Albert ML, Kim JI, Birge RB (2000) Alphavbeta5 integrin recruits the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells. Nat Cell Biol 2:899–905

    Article  PubMed  CAS  Google Scholar 

  34. Leitinger B, McDowall A, Stanley P, Hogg N (2000) The regulation of integrin function by Ca(2+). Biochim Biophys Acta 1498:91–98

    Article  PubMed  CAS  Google Scholar 

  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 110:1555–1564

    Article  PubMed  CAS  Google Scholar 

  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 15:968–975

    Article  PubMed  CAS  Google Scholar 

  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 79:476–487

    Article  PubMed  CAS  Google Scholar 

  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 178:8117–8126

    PubMed  CAS  Google Scholar 

  39. Koenigsknecht J, Landreth G (2004) Microglial phagocytosis of fibrillar beta-amyloid through a beta1 integrin-dependent mechanism. J Neurosci 24:9838–9846

    Article  PubMed  CAS  Google Scholar 

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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.

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Correspondence to Shun-Fen Tzeng.

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Special issue article in honor of Dr. George DeVries.

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Lee, TI., Yang, CS., Fang, KM. et al. Role of Ciliary Neurotrophic Factor in Microglial Phagocytosis. Neurochem Res 34, 109–117 (2009). https://doi.org/10.1007/s11064-008-9682-0

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