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PMID: 19300439 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Acid sphingomyelinase activity triggers microparticle release from glial cells.

The EMBO journal ·Vol. 28 ·No. 8 ·2009-04-22 ·Pages 1043-54

Bianco F, Perrotta C, Novellino L, Francolini M, Riganti L, Menna E, Saglietti L, Schuchman EH, Furlan R, Clementi E, Matteoli M, Verderio C

Abstract

We have earlier shown that microglia, the immune cells of the CNS, release microparticles from cell plasma membrane after ATP stimulation. These vesicles contain and release IL-1beta, a crucial cytokine in CNS inflammatory events. In this study, we show that microparticles are also released by astrocytes and we get insights into the mechanism of their shedding. We show that, on activation of the ATP receptor P2X7, microparticle shedding is associated with rapid activation of acid sphingomyelinase, which moves to plasma membrane outer leaflet. ATP-induced shedding and IL-1beta release are markedly reduced by the inhibition of acid sphingomyelinase, and completely blocked in glial cultures from acid sphingomyelinase knockout mice. We also show that p38 MAPK cascade is relevant for the whole process, as specific kinase inhibitors strongly reduce acid sphingomyelinase activation, microparticle shedding and IL-1beta release. Our results represent the first demonstration that activation of acid sphingomyelinase is necessary and sufficient for microparticle release from glial cells and define key molecular effectors of microparticle formation and IL-1beta release, thus, opening new strategies for the treatment of neuroinflammatory diseases.

MeSH Terms
Adenosine Triphosphate/analogs & derivatives,metabolism Adrenergic Uptake Inhibitors/metabolism Affinity Labels/metabolism Animals Brain/cytology,metabolism,pathology Cell-Derived Microparticles/enzymology,ultrastructure Cells, Cultured Enzyme Activation Imipramine/metabolism Interleukin-1beta/metabolism Mice Mice, Knockout Models, Biological Neuroglia/cytology,metabolism Particle Size Receptors, Purinergic P2/metabolism Receptors, Purinergic P2X7 Signal Transduction/physiology Sphingomyelin Phosphodiesterase/genetics,metabolism p38 Mitogen-Activated Protein Kinases/metabolism src-Family Kinases/metabolism
Chemicals
Adrenergic Uptake Inhibitors Affinity Labels Interleukin-1beta P2rx7 protein, mouse Receptors, Purinergic P2 Receptors, Purinergic P2X7 3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate Adenosine Triphosphate src-Family Kinases p38 Mitogen-Activated Protein Kinases Sphingomyelin Phosphodiesterase Imipramine
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Bianco Fabio
CNR Institute of Neuroscience and Department of Medical Pharmacology, University of Milano, Milano, Italy.
Perrotta Cristiana
Novellino Luisa
Francolini Maura
Riganti Loredana
Menna Elisabetta
Saglietti Laura
Schuchman Edward H
Furlan Roberto
Clementi Emilio
Matteoli Michela
Verderio Claudia
References (62)
62 references, click to expand
  1. Protective effect of the interleukin-1 receptor antagonist (IL-1ra) on experimental allergic encephalomyelitis in rats.
    J Neuroimmunol. 1995 Sep;61(2):241-5 PMID: 7593560
  2. Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I.
    Nat Cell Biol. 2001 Apr;3(4):339-45 PMID: 11283606
  3. Production and release of neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia.
    J Neurosci. 2004 Jan 7;24(1):1-7 PMID: 14715932
  4. Exosomes are released by cultured cortical neurones.
    Mol Cell Neurosci. 2006 Apr;31(4):642-8 PMID: 16446100
  5. Activation of acid sphingomyelinase and its inhibition by the nitric oxide/cyclic guanosine 3',5'-monophosphate pathway: key events in Escherichia coli-elicited apoptosis of dendritic cells.
    J Immunol. 2004 Oct 1;173(7):4452-63 PMID: 15383576
  6. Are second messengers crucial for opening the pore associated with P2X7 receptor?
    Am J Physiol Cell Physiol. 2005 Feb;288(2):C260-71 PMID: 15469955
  7. Pannexin-1 couples to maitotoxin- and nigericin-induced interleukin-1beta release through a dye uptake-independent pathway.
    J Biol Chem. 2007 Jan 26;282(4):2386-94 PMID: 17121814
  8. Alveolar lipoproteinosis in an acid sphingomyelinase-deficient mouse model of Niemann-Pick disease.
    Am J Physiol Lung Cell Mol Physiol. 2003 Mar;284(3):L518-25 PMID: 12495943
  9. Combined treatment of acute EAE in Lewis rats with TNF-binding protein and interleukin-1 receptor antagonist.
    Exp Neurol. 1998 Feb;149(2):455-63 PMID: 9500957
  10. ATP-mediated cytotoxicity in microglial cells.
    Neuropharmacology. 1997 Sep;36(9):1295-301 PMID: 9364484
  11. Pulmonary involvement in Niemann-Pick disease: case report and literature review.
    Respir Med. 2000 Dec;94(12):1241-51 PMID: 11192962
  12. P2X(7) receptors: properties and relevance to CNS function.
    Glia. 2006 Nov 15;54(7):738-46 PMID: 17006902
  13. Exosomal transfer of proteins and RNAs at synapses in the nervous system.
    Biol Direct. 2007 Nov 30;2:35 PMID: 18053135
  14. Biophysics of sphingolipids I. Membrane properties of sphingosine, ceramides and other simple sphingolipids.
    Biochim Biophys Acta. 2006 Dec;1758(12):1902-21 PMID: 17070498
  15. Caspase-1-dependent processing of pro-interleukin-1beta is cytosolic and precedes cell death.
    J Cell Sci. 2007 Mar 1;120(Pt 5):772-81 PMID: 17284521
  16. CD95 signaling via ceramide-rich membrane rafts.
    J Biol Chem. 2001 Jun 8;276(23):20589-96 PMID: 11279185
  17. Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells.
    Blood. 2004 Nov 15;104(10):3257-66 PMID: 15284116
  18. Ceramide triggers budding of exosome vesicles into multivesicular endosomes.
    Science. 2008 Feb 29;319(5867):1244-7 PMID: 18309083
  19. Intracellular transport and metabolism of sphingomyelin.
    Biochim Biophys Acta. 1991 Mar 12;1082(2):113-25 PMID: 2007175
  20. Neurons produce FGF2 and VEGF and secrete them at least in part by shedding extracellular vesicles.
    J Cell Mol Med. 2007 Nov-Dec;11(6):1384-94 PMID: 18205708
  21. Caspase-1 regulates the inflammatory process leading to autoimmune demyelination.
    J Immunol. 1999 Sep 1;163(5):2403-9 PMID: 10452974
  22. Essential role for Ca2+ in regulation of IL-1beta secretion by P2X7 nucleotide receptor in monocytes, macrophages, and HEK-293 cells.
    Am J Physiol Cell Physiol. 2003 Aug;285(2):C286-99 PMID: 12660148
  23. Kinetics and mechanism of ATP-dependent IL-1 beta release from microglial cells.
    J Immunol. 2000 May 1;164(9):4893-8 PMID: 10779799
  24. Acid sphingomyelinase deficiency increases susceptibility to fatal alphavirus encephalomyelitis.
    J Virol. 2006 Nov;80(22):10989-99 PMID: 16943298
  25. Experimental autoimmune encephalomyelitis-associated behavioral syndrome as a model of 'depression due to multiple sclerosis'.
    Brain Behav Immun. 2002 Oct;16(5):533-43 PMID: 12401467
  26. ATP-induced apoptosis of thymocytes is mediated by activation of P2 X 7 receptor and involves de novo ceramide synthesis and mitochondria.
    Biochim Biophys Acta. 2006 Jan;1761(1):73-82 PMID: 16325464
  27. P2X7 and phospholipid signalling: the search of the "missing link" in epithelial cells.
    Cell Signal. 2006 Dec;18(12):2098-104 PMID: 16815675
  28. Effects of sphingomyelin degradation on cell cholesterol oxidizability and steady-state distribution between the cell surface and the cell interior.
    Biochim Biophys Acta. 1989 Oct 2;985(1):90-6 PMID: 2790049
  29. New roles for astrocytes: redefining the functional architecture of the brain.
    Trends Neurosci. 2003 Oct;26(10):523-30 PMID: 14522144
  30. Physiology of apoptosis.
    Am J Physiol Renal Physiol. 2000 Oct;279(4):F605-15 PMID: 10997910
  31. Release of extracellular membrane particles carrying the stem cell marker prominin-1 (CD133) from neural progenitors and other epithelial cells.
    J Cell Sci. 2005 Jul 1;118(Pt 13):2849-58 PMID: 15976444
  32. Regulation of death receptor signaling and apoptosis by ceramide.
    Pharmacol Res. 2003 May;47(5):393-9 PMID: 12676513
  33. Nonclassical IL-1 beta secretion stimulated by P2X7 receptors is dependent on inflammasome activation and correlated with exosome release in murine macrophages.
    J Immunol. 2007 Aug 1;179(3):1913-25 PMID: 17641058
  34. Contribution of platelet microparticle formation and granule secretion to the transmembrane migration of phosphatidylserine.
    J Biol Chem. 1993 Apr 5;268(10):7171-8 PMID: 8463253
  35. Acid and neutral sphingomyelinases: roles and mechanisms of regulation.
    Biochem Cell Biol. 2004 Feb;82(1):27-44 PMID: 15052326
  36. Pannexin1 is part of the pore forming unit of the P2X(7) receptor death complex.
    FEBS Lett. 2007 Feb 6;581(3):483-8 PMID: 17240370
  37. Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor.
    EMBO J. 2006 Nov 1;25(21):5071-82 PMID: 17036048
  38. ATP binding cassette transporter ABC1 is required for the release of interleukin-1beta by P2X7-stimulated and lipopolysaccharide-primed mouse Schwann cells.
    Glia. 2005 Mar;49(4):511-9 PMID: 15578659
  39. Acid sphingomyelinase-deficient macrophages have defective cholesterol trafficking and efflux.
    J Biol Chem. 2001 Nov 30;276(48):44976-83 PMID: 11579092
  40. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules.
    Blood. 1999 Dec 1;94(11):3791-9 PMID: 10572093
  41. Proteomic analysis of microglia-derived exosomes: metabolic role of the aminopeptidase CD13 in neuropeptide catabolism.
    J Immunol. 2005 Aug 15;175(4):2237-43 PMID: 16081791
  42. P2X7 receptor-dependent blebbing and the activation of Rho-effector kinases, caspases, and IL-1 beta release.
    J Immunol. 2003 Jun 1;170(11):5728-38 PMID: 12759456
  43. Astrocyte-derived ATP induces vesicle shedding and IL-1 beta release from microglia.
    J Immunol. 2005 Jun 1;174(11):7268-77 PMID: 15905573
  44. Observation of topical catalysis by sphingomyelinase coupled to microspheres.
    J Am Chem Soc. 2002 Oct 16;124(41):12129-34 PMID: 12371852
  45. The secretory route of the leaderless protein interleukin 1beta involves exocytosis of endolysosome-related vesicles.
    Mol Biol Cell. 1999 May;10(5):1463-75 PMID: 10233156
  46. Nitric oxide boosts chemoimmunotherapy via inhibition of acid sphingomyelinase in a mouse model of melanoma.
    Cancer Res. 2007 Aug 15;67(16):7559-64 PMID: 17699758
  47. Sphingomyelin hydrolysis to ceramide during the execution phase of apoptosis results from phospholipid scrambling and alters cell-surface morphology.
    J Cell Biol. 2000 Jul 10;150(1):155-64 PMID: 10893264
  48. Activation of ERK1/2 by extracellular nucleotides in macrophages is mediated by multiple P2 receptors independently of P2X7-associated pore or channel formation.
    Br J Pharmacol. 2006 Feb;147(3):324-34 PMID: 16341234
  49. Comparative lipid analysis of purified plasma membranes and shed extracellular membrane vesicles from normal murine thymocytes and leukemic GRSL cells.
    Biochim Biophys Acta. 1982 Jun 14;688(2):495-504 PMID: 7104337
  50. A regulated secretory pathway in cultured hippocampal astrocytes.
    J Biol Chem. 1999 Aug 6;274(32):22539-47 PMID: 10428831
  51. Regulation of heat shock protein 70 release in astrocytes: role of signaling kinases.
    Dev Neurobiol. 2007 Nov;67(13):1815-29 PMID: 17701989
  52. Ca2+ stores and Ca2+ entry differentially contribute to the release of IL-1 beta and IL-1 alpha from murine macrophages.
    J Immunol. 2003 Mar 15;170(6):3029-36 PMID: 12626557
  53. Extracellular ATP causes ROCK I-dependent bleb formation in P2X7-transfected HEK293 cells.
    Mol Biol Cell. 2003 Jul;14(7):2655-64 PMID: 12857854
  54. Cutting edge: the nucleotide receptor P2X7 contains multiple protein- and lipid-interaction motifs including a potential binding site for bacterial lipopolysaccharide.
    J Immunol. 2001 Aug 15;167(4):1871-6 PMID: 11489964
  55. Host defense against Pseudomonas aeruginosa requires ceramide-rich membrane rafts.
    Nat Med. 2003 Mar;9(3):322-30 PMID: 12563314
  56. Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles.
    J Immunol. 2001 Jun 15;166(12):7309-18 PMID: 11390481
  57. Intracellular trafficking of cholesterol monitored with a cyclodextrin.
    J Biol Chem. 1996 Aug 30;271(35):21604-13 PMID: 8702948
  58. Proteomic profiling of exosomes: current perspectives.
    Proteomics. 2008 Oct;8(19):4083-99 PMID: 18780348
  59. Mitogen-activated protein kinase and caspase signaling pathways are required for P2X7 receptor (P2X7R)-induced pore formation in human THP-1 cells.
    J Pharmacol Exp Ther. 2004 Mar;308(3):1053-61 PMID: 14634045
  60. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication.
    Leukemia. 2006 Sep;20(9):1487-95 PMID: 16791265
  61. Functional rafts in cell membranes.
    Nature. 1997 Jun 5;387(6633):569-72 PMID: 9177342
  62. Rapid secretion of interleukin-1beta by microvesicle shedding.
    Immunity. 2001 Nov;15(5):825-35 PMID: 11728343
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2009.45
Published
2009-04-22
Epub
2009-00-19
Pages
1043-54
Language
English
Region
England
NLM ID
8208664
PMCID
PMC2664656
Subset
IM
Grants
NICHD NIH HHS · R01 HD028607 · United States
NICHD NIH HHS · R01HD28607 · United States
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1038/emboj.2009.45 PMC Full Text View journal details
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