Skip to main content
SpringerLink
Log in

Atypical antiinflammatory activation of microglia induced by apoptotic neurons

Possible role of phosphatidylserine-phosphatidylserine receptor interaction

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

In the central nervous system (CNS), apoptosis plays an important role during development and is a primary pathogenic mechanism in several adult neurodegenerative diseases. A main feature of apoptotic cell death is the efficient and fast removal of dying cells by macrophages and nonprofessional phagocytes, without eliciting inflammation in the surrounding tissue. Apoptotic cells undergo several membrane changes, including the externalization of so-called “eat me” signals whose cognate receptors are present on professional phagocytes. Among these signals, the aminophospholipid phosphatidylserine (PS) appears to have a crucial and unique role in preventing the classical pro-inflammatory activation of macrophages, thus ensuring the silent and safe removal of apoptotic cells. Although extensively studied in the peripheral organs, the process of recognition and removal of apoptotic cells in the brain has only recently begun to be unraveled. Here, we summarize the evidence suggesting that upon interaction with PS-expressing apoptotic neurons, microglia may no longer promote the inflammatory cascade, but rather facilitate the elimination of damaged neurons through antiinflammatory and neuroprotective functions. We propose that the anti-inflammatory microglial phenotype induced through the activation of the specific PS receptor (PtdSerR), expressed by resting and activated microglial cells, could be relevant to the final outcome of neurodegenerative diseases, in which apoptosis seems to play a crucial role.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Perry V. H., Andersson P. B., and Gordon S. (1993) Macrophages and inflammation in the central nervous system. Trends Neurosci. 16, 268–273.

    Article  PubMed  CAS  Google Scholar 

  2. Perry V. H., Bolton S. J., Anthony D. C., and Betmouni S. (1998) The contribution of inflammation to acute and chronic neurodegeneration. Res. Immunol. 149, 721–725.

    Article  PubMed  CAS  Google Scholar 

  3. Kreutzberg G. W. (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19, 312–318.

    Article  PubMed  CAS  Google Scholar 

  4. Streit W. J. (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40, 133–139.

    Article  PubMed  Google Scholar 

  5. Minghetti L. and Levi G. (1998) Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide. Prog. Neurobiol. 54, 99–125.

    Article  PubMed  CAS  Google Scholar 

  6. Zhang J. and Rivest S. (2001) Anti-inflammatory effects of prostaglandin E2 in the central nervous system in response to brain injury and circulating lipopolysaccharide. J. Neurochem. 76, 855–864.

    Article  PubMed  CAS  Google Scholar 

  7. Mirza B., Hadberg H., Thomsen P., and Moos T. (2000) The absence of reactive astrocytosis is indicative of a unique inflammatory process in Parkinson’s disease. Neuroscience 95, 425–432.

    Article  PubMed  CAS  Google Scholar 

  8. Perry V. H., Cunningham C., and Boche D. (2002) Atypical inflammation in the central nervous system in prion disease. Curr. Opin. Neurol. 15, 349–354.

    Article  PubMed  Google Scholar 

  9. Minghetti L., Greco A., Cardone F., et al. (2000) Increased brain synthesis of prostaglandin E2 and F2-isoprostane in human and experimental transmissible spongiform encephalopathies. J. Neuropathol. Exp. Neurol. 59, 866–871.

    PubMed  CAS  Google Scholar 

  10. Minghetti L., Cardone F., Greco A., et al. (2002) Increased CSF levels of prostaglandin E(2) in variant Creutzfeldt-Jakob disease. Neurology 58, 127–129.

    PubMed  CAS  Google Scholar 

  11. Bellamy C. O., Malcomson R. D., Harrison D. J., and Wyllie A. H. (1995) Cell death in health and disease: the biology and regulation of apoptosis. Semin. Cancer Biol. 6, 3–16.

    Article  PubMed  CAS  Google Scholar 

  12. Savill J., Dransfield I., Gregory C., and Haslett C. (2002) A blast from the past: clearance of apoptotic cells regulates immune responses. Nat. Rev. Immunol. 2, 965–975.

    Article  PubMed  CAS  Google Scholar 

  13. Peiser L. and Gordon S. (2001) The function of scavenger receptors expressed by macrophages and their role in the regulation of inflammation. Microbes Infect. 3, 149–159.

    Article  PubMed  CAS  Google Scholar 

  14. Sambrano G. R. and Steinberg D. (1995) Recognition of oxidatively damaged and apoptotic cells by an oxidized low density lipoprotein receptor on mouse peritoneal macrophages: role of membrane phosphatidylserine. Proc. Natl. Acad. Sci. USA 92, 1396–1400.

    Article  PubMed  CAS  Google Scholar 

  15. Gershov D., Kim S., Brot N., and Elkon K. B. (2000) C-Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity. J. Exp. Med. 192, 1353–1364.

    Article  PubMed  CAS  Google Scholar 

  16. Nauta A. J., Daha M. R., Kooten C., and Roos A. (2003) Recognition and clearance of apoptotic cells: a role for complement and pentraxins. Trends Immunol. 24, 148–154.

    Article  PubMed  CAS  Google Scholar 

  17. Gregory C. D. (2000) CD14-dependent clearance of apoptotic cells: relevance to the immune system. Curr. Opin. Immunol. 12, 27–34.

    Article  PubMed  CAS  Google Scholar 

  18. Savill J., Fadok V., Henson P., and Haslett C. (1993) Phagocyte recognition of cells undergoing apoptosis. Immunol. Today 14, 131–136.

    Article  PubMed  CAS  Google Scholar 

  19. Henson P. M., Bratton D. L., and Fadok V. A. (2001) Apoptotic cell removal. Curr. Biol. 11, R795–805.

    Article  PubMed  CAS  Google Scholar 

  20. Mozzi R., Buratta S., and Goracci G. (2003) Metabolism and functions of phosphatidylserine in mammalian brain. Neurochem. Res. 28, 195–214.

    Article  PubMed  CAS  Google Scholar 

  21. Schlegel R. A. and Williamson P. (2001) Phosphatidylserine, a death knell. Cell Death Differ. 8, 551–563.

    Article  PubMed  CAS  Google Scholar 

  22. Fadok V. A., Xue D., and Henson P. (2001) If phosphatidylserine is the death knell, a new phosphatidylserine-specific receptor is the bell ringer. Cell Death Differ. 8, 582–587.

    Article  PubMed  CAS  Google Scholar 

  23. Hoffmann P. R., de Cathelineau A. M., Ogden C. A., et al. (2001) Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells. J. Cell. Biol. 155, 649–659.

    Article  PubMed  CAS  Google Scholar 

  24. Fadok V. A., Bratton D. L., Konowal A., Freed P. W., Westcott J. Y., and Henson P. M. (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokines production through autocrine/paracrine mechanisms involving TGF-β, PGE2, and PAF. J. Clin. Invest. 4, 890–898.

    Google Scholar 

  25. Yuan J. and Yankner B. A. (2000) Apoptosis in the nervous system. Nature 407, 802–809.

    Article  PubMed  CAS  Google Scholar 

  26. Gray F., Chretien F., Adle-Biassette H., et al. (1999) Neuronal apoptosis in Creutzfeldt-Jakob disease. J. Neuropathol. Exp. Neurol. 58, 321–328.

    Article  PubMed  CAS  Google Scholar 

  27. Friedlander R. M. (2003) Apoptosis and caspases in neurodegenerative diseases. N. Engl. J. Med. 348, 1365–1375.

    Article  PubMed  CAS  Google Scholar 

  28. Smith M. E. (2001) Phagocytic properties of microglia in vitro: implications for a role in multiple sclerosis and EAE. Microsc. Res. Tech. 54, 81–94.

    Article  PubMed  CAS  Google Scholar 

  29. Webster S. D., Park, M., Fonseca M. I., and Tenner A. J. (2000) Structural and functional evidence for microglial expression of C1qR(P), the C1q receptor that enhances phagocytosis. J. Leukoc. Biol. 67, 109–116.

    PubMed  CAS  Google Scholar 

  30. van Beek J., Elward K., Gasque P. (2003) Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection. Ann. NY Acad. Sci. 992, 56–71.

    PubMed  Google Scholar 

  31. Bamberger M. E., and Landreth G. E. (2001) Microglial interaction with beta-amyloid: implications for the pathogenesis of Alzheimer’s disease. Microsc. Res. Tech. 15, 59–70.

    Article  Google Scholar 

  32. Husemann J., Loike J. D., Anankov R., Febbraio M., and Silverstein S. C. (2002) Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia 40, 195–205.

    Article  PubMed  Google Scholar 

  33. Witting A., Muller P., Herrmann A., Kettenmann H., and 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 

  34. Marzolo M. P., von Bernhardi R., and Inestrosa N. C. (1999) Mannose receptor is present in a functional state in rat microglial cells. J. Neurosci. Res. 58, 387–395.

    Article  PubMed  CAS  Google Scholar 

  35. Linehan S. A., Martinez-Pomares L., Stahl P. D., and Gordon S. (1999) Mannose receptor and its putative ligands in normal murine lymphoid and nonlymphoid organs: In situ expression of mannose receptor by selected macrophages, endothelial cells, perivascular microglia, and mesangial cells, but not dendritic cells. J. Exp. Med. 189, 1961–1972.

    Article  PubMed  CAS  Google Scholar 

  36. Zimmer H., Riese S., and Regnier-Vigouroux A. (2003) Functional characterization of mannose receptor expressed by immunocompetent mouse microglia. Glia 42, 89–100.

    Article  PubMed  Google Scholar 

  37. Walton M., Sirimanne E., Reutelingsperger C., Williams C., Gluckman P., and Dragunow M. (1997) Annexin V labels apoptotic neurons following hypoxia-ischemia. Neuroreport 8, 3871–3875.

    Article  PubMed  CAS  Google Scholar 

  38. Rimon G., Bazenet C. E., Philpott K. L., and Rubin L. L. (1997) Increased surface phosphatidylserine is an early marker of neuronal apoptosis. J. Neurosci. Res. 48, 563–570.

    Article  PubMed  CAS  Google Scholar 

  39. Das P., Estephan R., and Banerjee P. (2003) Apoptosis is associated with an inhibition of aminophospholipid translocase (APTL) in CNS-derived HN2–5 and HOG cells and phosphatidylserine is a recognition molecule in microglial uptake of the apoptotic HN2–5 cells. Life Science 72, 2617–2627.

    Article  CAS  Google Scholar 

  40. Maiese K. and Vincent A. M. (2000) Membrane asymmetry and DNA degradation: functionally distinct determinants of neuronal programmed cell death. J. Neurosci. Res. 59, 568–580.

    Article  PubMed  CAS  Google Scholar 

  41. Adayev T., Estephan R., Meserole S., Mazza B., Yurkow E. J., and Banerjee P. (1998) Externalization of phosphatidylserine may not be an early signal of apoptosis in neuronal cells, but only the phosphatidylserine-displaying apoptotic cells are phagocytosed by microglia. J. Neurochem. 71, 1854–1864.

    Article  PubMed  CAS  Google Scholar 

  42. Hisatomi T., Sakamoto T., Sonoda K. H., et al. (2003) Clearance of apoptotic photoreceptors: elimination of apoptotic debris into the subretinal space and macrophage-mediated phagocytosis via phosphatidylserine receptor and integrin alphavbeta3. Am. J. Pathol. 162, 1869–1879.

    PubMed  CAS  Google Scholar 

  43. Chang G. H., Barbaro N. M., and Pieper R. O. (2000) Phosphatidylserine-dependent phagocytosis of apoptotic glioma cells by normal human microglia, astrocytes, and glioma cells. Neuro. Oncol. 2, 174–183.

    Article  PubMed  CAS  Google Scholar 

  44. De Simone R., Ajmone-Cat M. A., Nicolini A., and Minghetti L. (2002) Expression of phosphatidylserine receptor and down-regulation of pro-inflammatory molecule production by its natural ligand in rat microglial cultures. J. Neuropathol. Exp. Neurol. 61, 237–244.

    Google Scholar 

  45. Fadok V. A., Bratton D. L., Rose D. M., Pearson A., Ezekewitz R. A., and Henson P. M. (2000) A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405, 85–90.

    Article  PubMed  CAS  Google Scholar 

  46. Chan A., Seguin R., Magnus T., Papadimitriou C., Toyka K. V., Antel J. P., and Gold R. (2003) Phagocytosis of apoptotic inflammatory cells by microglia and its therapeutic implications: Termination of CNS autoimmune inflammation and modulation by interferon-beta. Glia 43, 231–242.

    Article  PubMed  Google Scholar 

  47. De Simone R., Ajmone-Cat M. A., Tirassa P., and Minghetti L. (2003) Apoptotic PC12 cells exposing phosphatidylserine promote the production of anti-inflammatory and neuroprotective molecules by microglial cells. J. Neuropathol. Exp. Neurol. 62, 208–216.

    PubMed  Google Scholar 

  48. Schutte B., Nuydens R., Geerts H., and Ramaekers F. (1998) Annexin V binding assay as a tool to measure apoptosis in differentiated neuronal cells. J. Neurosci. Methods 86, 63–69.

    Article  PubMed  CAS  Google Scholar 

  49. Levi G., Minghetti L., and Aloisi F. (1998) Regulation of prostanoid synthesis in microglial cells and effects of prostaglandin E2 on microglial functions. Biochimie 80, 899–904.

    Article  PubMed  CAS  Google Scholar 

  50. Akaike A., Kaneko S., Tamura Y., Nakata N., Shiomi H., Ushikubi F., and Narumiya S. (1994) Prostaglandin E2 protects cultured cortical neurons against N-methyl-d-aspartate receptor-mediated glutamate cytotoxicity. Brain Res. 14, 237–243.

    Article  Google Scholar 

  51. Kim E. J., Kwon K. J., Park J. Y., Lee S. H., Moon C. H., and Baik E. J. (2002) Neuroprotective effects of prostaglandin E2 or cAMP against microglial and neuronal free radical mediated toxicity associated with inflammation. J. Neurosci. Res. 70, 97–107.

    Article  PubMed  CAS  Google Scholar 

  52. Thery C., Dobbertin A., and Mallat M. (1994) Downregulation of in vitro neurotoxicity of brain macrophages by prostaglandin E2 and a beta-adrenergic agonist. Glia 11, 383–386.

    Article  PubMed  CAS  Google Scholar 

  53. Bezzi P., Carmignoto G., Pasti L., et al. (1998) Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 15, 281–285.

    Google Scholar 

  54. Fiebich B. L., Schleicher S., Spleiss O., Czygan M., and Hull M. (2001) Mechanisms of prostaglandin E2-induced interleukin-6 release in astrocytes: possible involvement of EP4-like receptors, p38 mitogen-activated protein kinase and protein kinase C. J. Neurochem. 5, 950–958.

    Article  Google Scholar 

  55. Takadera T., Yumoto H., Tozuka Y., and Ohyashiki T. (2002) Prostaglandin E(2) induces caspase-dependent apoptosis in rat cortical cells. Neurosci. Lett. 317, 61–64.

    Article  PubMed  CAS  Google Scholar 

  56. Khoury S. J., Hancock W. W., and Weiner H. L. (1992) Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin 4, and prostaglandin E. J. Exp. Med. 176, 1355–1364.

    Article  PubMed  CAS  Google Scholar 

  57. Walsh D. T., Perry V. H., and Minghetti L. (2000) Cyclooxygenase-2 is highly expressed in microglial-like cells in a murine model of prion disease. Glia 29, 392–396.

    Article  PubMed  CAS  Google Scholar 

  58. Roberts A. B. and Sporn M. B. (1993) Physiological actions and clinical applications of transforming growth factor-beta (TGF-β). Growth Factors. 8, 1–9.

    Article  PubMed  CAS  Google Scholar 

  59. Unsicker K. and Strelau J. (2000) Functions of transforming growth factor-beta isoforms in the nervous system. Cues based on localization and experimental in vitro and in vivo evidence. Eur. J. Biochem. 267, 6972–6975.

    Article  PubMed  CAS  Google Scholar 

  60. Krupinski J., Kumar P., Kumar S., and Kaluza J. (1996) Increased expression of TGF-beta 1 in brain tissue after ischemic stroke in humans. Stroke 27, 852–857.

    PubMed  CAS  Google Scholar 

  61. Mattson M. P., Barger S. W., Furukawa K., et al. (1997) Cellular signaling roles of TGF-β, TNF-α and β APP in brain injury responses and Alzheimer’s disease. Brain Res. Rev. 23, 47–61.

    Article  PubMed  CAS  Google Scholar 

  62. Baker C. A., Lu Z. Y., Zaitsev I., and Manuelidis L. (1999) Microglial activation varies in different models of Creutzfeldt-Jakob disease. J. Virol. 73, 5089–5097.

    PubMed  CAS  Google Scholar 

  63. Cunningham C., Boche D., and Perry V. H. (2002) Transforming growth factor-β1, the dominant cytokine in murine prion disease: influence on inflammatory cytokine synthesis and alteration of vascular extracellular matrix. Neuropathol. Appl. Neurobiol. 28, 107–119.

    Article  PubMed  CAS  Google Scholar 

  64. Elkabes S., Di Cicco-Bloom E. M., and Black I. B. (1996) Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J. Neurosci. 16, 2508–2521.

    PubMed  CAS  Google Scholar 

  65. Sofroniew M. V., Howe C. L., and Mobley W. C. (2001) Nerve growth factor signaling, neuroprotection, and neural repair. Annu. Rev. Neurosci. 24, 1217–1281.

    Article  PubMed  CAS  Google Scholar 

  66. Lindholm D., Heumann R., Meyer M., and Thoenen H. (1987) Interleukin-1 regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve. Nature 330, 658–659.

    Article  PubMed  CAS  Google Scholar 

  67. Crutcher K. A., Scott S. A., Liang S., Everson W. V., and Weingartner J. (1993) Detection of NGF-like activity in human brain tissue: increased levels in Alzheimer’s disease. J. Neurosci. 13, 2540–2550.

    PubMed  CAS  Google Scholar 

  68. Polazzi E., Gianni T., and Contestabile A. (2001) Microglial cells protect cerebellar granule neurons from apoptosis: evidence for reciprocal signaling. Glia 36, 271–280.

    Article  PubMed  CAS  Google Scholar 

  69. Bruce-Keller A. J. (1999) Microglial-neuronal interactions in synaptic damage and recovery. J. Neurosci. Res. 58, 191–201.

    Article  PubMed  CAS  Google Scholar 

  70. Chamak B. and Mallat M. (1991) Fibronectin and laminin regulate the in vitro differentiation of microglial cells. Neuroscience 4, 513–527.

    Article  Google Scholar 

  71. Reyes-Reyes M., Mora N., Gonzalez G., and Rosales C. (2002) beta1 and beta2 integrins activate different signalling pathways in monocytes. Biochem. J. 363, 273–280.

    Article  PubMed  CAS  Google Scholar 

  72. Moore K. J., El Khoury J., Medeiros L. A., Terada K., Geula C., Luster A. D., and Freeman M. W. (2002) A CD36-initiated signaling cascade mediates inflammatory effects of beta-amyloid. J. Biol. Chem. 277, 47,373–47,379.

    CAS  Google Scholar 

  73. Leverrier Y. and Ridley A. J. (2001) Requirement for Rho GTPases and PI 3-kinases during apoptotic cell phagocytosis by macrophages. Curr. Biol. 11, 195–199.

    Article  PubMed  CAS  Google Scholar 

  74. Caron E. and Hall A. (1998) Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases. Science 282, 1717–1721.

    Article  PubMed  CAS  Google Scholar 

  75. Todt J. C., Hu B., Punturieri A., Sonstein J., Polak T., and Curtis J. L. (2002) Activation of protein kinase C βII by the stereo-specific phosphatidylserine receptor is required for phagocytosis of apoptotic thymocytes by resident murine tissue macrophages. J. Biol. Chem. 277, 35,906–35,914.

    Article  CAS  Google Scholar 

  76. Ajmone-Cat M. A., De Simone R., Nicolini A., and Minghetti L. (2003) Effects of phosphatidylserine on p38 mitogen activated protein kinase, cyclic AMP responding element binding protein and nuclear factor-kappaB activation in resting and activated microglial cells. J. Neurochem. 84, 413–416.

    Article  PubMed  CAS  Google Scholar 

  77. Pahl H. L. (1999) Activators and target genes of Rel/NF-κB transcription factors. Oncogene 18, 6853–6866.

    Article  PubMed  CAS  Google Scholar 

  78. O’Neill L. A. and Kaltschmidt C. (1997) NF-κB: a crucial transcription factor for glial and neuronal cell function. Trends Neurosci. 20, 252–258.

    Article  PubMed  CAS  Google Scholar 

  79. McDonald P. P., Fadok V. A., Bratton D., and Henson P. M. (1999) Transcriptional and translational regulation of inflammatory mediator production by endogenous TGF-β in macrophages that have ingested apoptotic cells. J. Immunol. 163, 6164–6172.

    PubMed  CAS  Google Scholar 

  80. Hu B., Punturieri A., Todt J., Sonstein J., Polak T., and Curtis J. L. (2002) Recognition and phagocytosis of apoptotic T cells by resident murine tissue macrophages require multiple signal transduction events. J. Leukoc. Biol. 71, 881–889.

    PubMed  CAS  Google Scholar 

  81. Mayr B. and Montminy M. (2001) Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat. Rev. Mol. Cell. Biol. 2, 599–609.

    Article  PubMed  CAS  Google Scholar 

  82. Koistinaho M. and Koistinaho J. (2002) Role of p38 and p44/42 mitogen-activated protein kinases in microglia. Glia 40, 175–183.

    Article  PubMed  Google Scholar 

  83. Ono K. and Han J. (2000) The p38 signal transduction pathway: activation and function. Cell Signal. 12, 1–13.

    Article  PubMed  CAS  Google Scholar 

  84. Nagata K., Ohashi K., Nakano T., Arita H., Zong C, Hanafusa H., and Mizuno K. (1996) Identification of the product of growth arrest-specific gene 6 as a common ligand for Axl, Sky, and Mer receptor tyrosine kinases. J. Biol. Chem. 271, 30,022–30,027.

    CAS  Google Scholar 

  85. Nakano T., Ishimoto Y., Kishino J., Umeda M., Inoue K., Nagata K., et al. (1997) Cell adhesion to phosphatidylserine mediated by a product of growth arrest-specific gene 6. J. Biol. Chem. 272, 29,411–29,414.

    CAS  Google Scholar 

  86. Scott R. S., McMahon E. J., Pop S. M., et al. (2001) Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411, 207–211.

    Article  PubMed  CAS  Google Scholar 

  87. Camenisch T. D., Koller B. H., Earp H. S., and Matsushima G. K. (1999) A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock. J. Immunol. 162, 3498–3503.

    PubMed  CAS  Google Scholar 

  88. Azuma Y., Inami Y., and Matsumoto K. (2002) Alterations in cell surface phosphatidylserine and sugar chains during apoptosis and their time-dependent role in phagocytosis by macrophages. Biol. Pharm. Bull. 25, 1277–1281.

    Article  PubMed  CAS  Google Scholar 

  89. Kagan V. E., Borisenko G. G., Serinkan B. F., et al. (2003) Appetizing rancidity of apoptotic cells for macrophages: oxidation, externalization, and recognition of phosphatidylserine. Am. J. Physiol. Lung. Cell. Mol. Physiol. 285, L1–17.

    PubMed  CAS  Google Scholar 

  90. Kagan V. E., Gleiss B., Tyurina Y. Y., et al. (2002) A role for oxidative stress in apoptosis: oxidation and externalization of phosphatidylserine is required for macrophage clearance of cells undergoing Fas-mediated apoptosis. J. Immunol. 169, 487–499.

    PubMed  CAS  Google Scholar 

  91. Vincent A. M. and Maiese K. (1999) Direct temporal analysis of apoptosis induction in living adherent neurons. J. Histochem. Cytochem. 47, 661–672.

    PubMed  CAS  Google Scholar 

  92. Polazzi E. and Contestabile A. (2002) Reciprocal interactions between microglia and neurons: from survival to neuropathology. Rev. Neurosci. 13, 221–242.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Italy

    Roberta De Simone, Maria Antonietta Ajmone-Cat & Luisa Minghetti

Authors
  1. Roberta De Simone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Antonietta Ajmone-Cat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luisa Minghetti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luisa Minghetti.

Rights and permissions

Reprints and permissions

About this article

Cite this article

De Simone, R., Ajmone-Cat, M.A. & Minghetti, L. Atypical antiinflammatory activation of microglia induced by apoptotic neurons. Mol Neurobiol 29, 197–212 (2004). https://doi.org/10.1385/MN:29:2:197

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/MN:29:2:197

Index Entries

Search

Navigation