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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2011

Open Access 01-12-2011 | Research

Neuropeptide Y inhibits interleukin-1β-induced phagocytosis by microglial cells

Authors: Raquel Ferreira, Tiago Santos, Michelle Viegas, Luísa Cortes, Liliana Bernardino, Otília V Vieira, João O Malva

Published in: Journal of Neuroinflammation | Issue 1/2011

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Abstract

Background

Neuropeptide Y (NPY) is emerging as a modulator of communication between the brain and the immune system. However, in spite of increasing evidence that supports a role for NPY in the modulation of microglial cell responses to inflammatory conditions, there is no consistent information regarding the action of NPY on microglial phagocytic activity, a vital component of the inflammatory response in brain injury. Taking this into consideration, we sought to assess a potential new role for NPY as a modulator of phagocytosis by microglial cells.

Methods

The N9 murine microglial cell line was used to evaluate the role of NPY in phagocytosis. For that purpose, an IgG-opsonized latex bead assay was performed in the presence of lipopolysaccharide (LPS) and an interleukin-1β (IL-1β) challenge, and upon NPY treatment. A pharmacological approach using NPY receptor agonists and antagonists followed to uncover which NPY receptor was involved. Moreover, western blotting and immunocytochemical studies were performed to evaluate expression of p38 mitogen-activated protein kinase (MAPK) and heat shock protein 27 (HSP27), in an inflammatory context, upon NPY treatment.

Results

Here, we show that NPY inhibits phagocytosis of opsonized latex beads and inhibits actin cytoskeleton reorganization triggered by LPS stimulation. Co-stimulation of microglia with LPS and adenosine triphosphate also resulted in increased phagocytosis, an effect inhibited by an interleukin-1 receptor antagonist, suggesting involvement of IL-1β signaling. Furthermore, direct application of LPS or IL-1β activated downstream signaling molecules, including p38 MAPK and HSP27, and these effects were inhibited by NPY. Moreover, we also observed that the inhibitory effect of NPY on phagocytosis was mediated via Y1 receptor activation.

Conclusions

Altogether, we have identified a novel role for NPY in the regulation of microglial phagocytic properties, in an inflammatory context.
Appendix
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Literature
1.
Garden G, Möller T: Microglia Biology in Health and Disease. J Neuroimmune Pharmacol. 2006, 1 (2): 127-137. 10.1007/s11481-006-9015-5.CrossRefPubMed
2.
Block ML, Zecca L, Hong J-S: Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurol. 2007, 8 (1): 57-69. 10.1038/nrn2038.CrossRef
3.
Walter L, Neumann H: Role of microglia in neuronal degeneration and regeneration. Seminars in Immunopathology. 2009, 31 (4): 513-525. 10.1007/s00281-009-0180-5.CrossRefPubMed
4.
5.
Rivest S: Molecular insights on the cerebral innate immune system. Brain Behav Immun. 2003, 17 (1): 13-19. 10.1016/S0889-1591(02)00055-7.CrossRefPubMed
6.
Allan SM: Pragmatic Target Discovery From Novel Gene to Functionally Defined Drug Target. Methods Mol Med. 2005, 104: 333-346.PubMed
7.
Bernardino L, Ferreira R, Cristóvão AJ, Sales F, Malva JO: Inflammation and neurogenesis in temporal lobe epilepsy. Current Drug Targets - CNS & Neurological Disorders. 2005, 4 (4): 349-360. 10.2174/1568007054546171.CrossRef
8.
Vezzani A, Granata T: Brain Inflammation in Epilepsy: Experimental and Clinical Evidence. Epilepsia. 2005, 46 (11): 1724-1743. 10.1111/j.1528-1167.2005.00298.x.CrossRefPubMed
9.
Ferreira R, Santos T, Cortes L, Cochaud S, Agasse F, Silva AP, Xapelli S, Malva JO: Neuropeptide Y inhibits interleukin-1 beta (IL-1β)-induced microglia motility. J Neurochem. 2011.
10.
Wheway J, Herzog H, Mackay F: NPY and Receptors in Immune and Inflammatory Diseases. Curr Top Med Chem. 2007, 7 (17): 1743-1752. 10.2174/156802607782341046.CrossRefPubMed
11.
Silva AP, Cavadas C, Grouzmann E: Neuropeptide Y and its receptors as potential therapeutic drug targets. Clin Chim Acta. 2002, 326 (1-2): 3-25. 10.1016/S0009-8981(02)00301-7.CrossRefPubMed
12.
Schuck S, Manninen A, Honsho M, Fullekrug J, Simons K: Generation of single and double knockdowns in polarized epithelial cells by retrovirus-mediated RNA interference. Proc Natl Acad Sci USA. 2004, 101 (14): 4912-4917. 10.1073/pnas.0401285101.PubMedCentralCrossRefPubMed
13.
Cardoso CM, Jordao L, Vieira OV: Rab10 regulates phagosome maturation and its overexpression rescues Mycobacterium-containing phagosomes maturation. Traffic. 2010, 11 (2): 221-235. 10.1111/j.1600-0854.2009.01013.x.CrossRefPubMed
14.
Pinheiro PS, Rodrigues RJ, Rebola N, Xapelli S, Oliveira CR, Malva JO: Presynaptic kainate receptors are localized close to release sites in rat hippocampal synapses. Neurochem Int. 2005, 47 (5): 309-316. 10.1016/j.neuint.2005.05.007.CrossRefPubMed
15.
16.
Ferreira R, Xapelli S, Santos T, Silva AP, Cristovao A, Cortes L, Malva JO: Neuropeptide Y Modulation of Interleukin-1 beta (IL-1β)-induced Nitric Oxide Production in Microglia. J Biol Chem. 2010, 285 (53): 41921-41934. 10.1074/jbc.M110.164020.PubMedCentralCrossRefPubMed
17.
Griffiths R, Stam E, Downs J, Otterness I: ATP induces the release of IL-1 from LPS-primed cells in vivo. J Immunol. 1995, 154 (6): 2821-2828.PubMed
18.
Grahames CBA, Michel AD, Chessell IP, Humphrey PPA: Pharmacological characterization of ATP- and LPS-induced IL-1B release in human monocytes. Br J Pharmacol. 1999, 127 (8): 1915-1921. 10.1038/sj.bjp.0702732.PubMedCentralCrossRefPubMed
19.
Ferrari D, Chiozzi P, Falzoni S, Dal Susino M, Melchiorri L, Baricordi O, Di Virgilio F: Extracellular ATP triggers IL-1 beta release by activating the purinergic P2Z receptor of human macrophages. J Immunol. 1997, 159 (3): 1451-1458.PubMed
20.
Bernardino L, Balosso S, Ravizza T, Marchi N, Ku G, Randle JC, Malva JO, Vezzani A: Inflammatory events in hippocampal slice cultures prime neuronal susceptibility to excitotoxic injury: a crucial role of P2X7 receptor-mediated IL-1β release. J Neurochem. 2008, 106 (1): 271-280. 10.1111/j.1471-4159.2008.05387.x.CrossRefPubMed
21.
Abreu MT, Arditi M: Innate immunity and toll-like receptors: clinical implications of basic science research. J Pediatr. 2004, 144 (4): 421-429. 10.1016/j.jpeds.2004.01.057.CrossRefPubMed
22.
Ferrari D, Chiozzi P, Falzoni S, Dal Susino M, Collo G, Buell G, Di Virgilio F: ATP-mediated cytotoxicity in microglial cells. Neuropharmacology. 1997, 36 (9): 1295-1301. 10.1016/S0028-3908(97)00137-8.CrossRefPubMed
23.
Vetvicka V, Hanikyrova M, Vetvickova J, Ross GD: Regulation of CR3 (CD11b/CD18)-dependent natural killer (NK) cell cytotoxicity by tumour target cell MHC class I molecules. Clin Exp Immunol. 1999, 115 (2): 229-235. 10.1046/j.1365-2249.1999.00800.x.PubMedCentralCrossRefPubMed
24.
Shi Y, Gaestel M: In the cellular garden of forking paths: how p38 MAPKs signal for downstream assistance. Biol Chem. 2002, 383 (10): 1519-1536. 10.1515/BC.2002.173.CrossRefPubMed
25.
Indik Z, Park J, Hunter S, Schreiber A: The molecular dissection of Fc gamma receptor mediated phagocytosis. Blood. 1995, 86 (12): 4389-4399.PubMed
26.
Arend WP, Welgus HG, Thompson RC, Eisenberg SP: Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. J Clin Invest. 1990, 85 (5): 1694-1697. 10.1172/JCI114622.PubMedCentralCrossRefPubMed
27.
Turrin N, Rivest S: Molecular and cellular immune mediators of neuroprotection. Mol Neurobiol. 2006, 34 (3): 221-242. 10.1385/MN:34:3:221.CrossRefPubMed
28.
Bedoui S, Miyake S, Straub RH, von Hörsten S, Yamamura T: More sympathy for autoimmunity with neuropeptide Y?. Trends Immunol. 2004, 25 (10): 508-512. 10.1016/j.it.2004.08.005.CrossRefPubMed
29.
Nave H, Bedoui S, Moenter F, Steffens J, Felies M, Gebhardt T, Straub RH, Pabst R, Dimitrijevic M, Stanojevic S, von Hörsten S: Reduced tissue immigration of monocytes by neuropeptide Y during endotoxemia is associated with Y2 receptor activation. J Neuroimmunol. 2004, 155 (1-2): 1-12. 10.1016/j.jneuroim.2004.05.009.CrossRefPubMed
30.
Bedoui S, Kawamura N, Straub RH, Pabst R, Yamamura T, von Hörsten S: Relevance of Neuropeptide Y for the neuroimmune crosstalk. J Neuroimmunol. 2003, 134 (1-2): 1-11. 10.1016/S0165-5728(02)00424-1.CrossRefPubMed
31.
Bedoui S, von Hörsten S, Gebhardt T: A role for neuropeptide Y (NPY) in phagocytosis: Implications for innate and adaptive immunity. Peptides. 2007, 28 (2): 373-376. 10.1016/j.peptides.2006.07.029.CrossRefPubMed
32.
De la Fuente M, Del Río M, Medina S: Changes with aging in the modulation by neuropeptide Y of murine peritoneal macrophage functions. J Neuroimmunol. 2001, 116 (2): 156-167. 10.1016/S0165-5728(01)00297-1.CrossRefPubMed
33.
Kawai T, Akira S: The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010, 11 (5): 373-384. 10.1038/ni.1863.CrossRefPubMed
34.
Wu TT, Chen TL, Chen RM: Lipopolysaccharide triggers macrophage activation of inflammatory cytokine expression, chemotaxis, phagocytosis, and oxidative ability via a toll-like receptor 4-dependent pathway: validated by RNA interference. Toxicol Lett. 2009, 191 (2-3): 195-202. 10.1016/j.toxlet.2009.08.025.CrossRefPubMed
35.
Weinrauch Y, Zychlinsky A: The induction of apoptosis by bacterial pathogens. Annu Rev Microbiol. 1999, 53: 155-187. 10.1146/annurev.micro.53.1.155.CrossRefPubMed
36.
Sansonetti PJ, Phalipon A, Arondel J, Thirumalai K, Banerjee S, Akira S, Takeda K, Zychlinsky A: Caspase-1 activation of IL-1beta and IL-18 are essential for Shigella flexneri-induced inflammation. Immunity. 2000, 12 (5): 581-590. 10.1016/S1074-7613(00)80209-5.CrossRefPubMed
37.
Hersh D, Monack DM, Smith MR, Ghori N, Falkow S, Zychlinsky A: The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1. Proc Natl Acad Sci USA. 1999, 96 (5): 2396-2401. 10.1073/pnas.96.5.2396.PubMedCentralCrossRefPubMed
38.
Monack DM, Hersh D, Ghori N, Bouley D, Zychlinsky A, Falkow S: Salmonella exploits caspase-1 to colonize Peyer's patches in a murine typhoid model. J Exp Med. 2000, 192 (2): 249-258. 10.1084/jem.192.2.249.PubMedCentralCrossRefPubMed
39.
Craciun LI, DiGiambattista M, Schandené L, Laub R, Goldman M, Dupont E: Anti-inflammatory effects of UV-irradiated lymphocytes: induction of IL-1Ra upon phagocytosis by monocyte/macrophages. Clin Immunol. 2005, 114 (3): 320-326. 10.1016/j.clim.2004.11.006.CrossRefPubMed
40.
Medina S, Del Río M, Hernanz A, De la Fuente M: The NPY effects on murine leukocyte adherence and chemotaxis change with age: Adherent cell implication. Regulatory Peptides. 2000, 95 (1-3): 35-45. 10.1016/S0167-0115(00)00134-8.CrossRefPubMed
41.
Mathern GW, Cifuentes F, Leite JP, Pretorius JK, Babb TL: Hippocampal EEG excitability and chronic spontaneous seizures are associated with aberrant synaptic reorganization in the rat intrahippocampal kainate model. Electroencephalogr Clin Neurophysiol. 1993, 87 (5): 326-339. 10.1016/0013-4694(93)90186-Y.CrossRefPubMed
42.
Dureus P, Louis D, Grant AV, Bilfinger TV, Stefano GB: Neuropeptide Y inhibits human and invertebrate immunocyte chemotaxis, chemokinesis, and spontaneous activation. Cell Mol Neurobiol. 1993, 13 (5): 541-546. 10.1007/BF00711462.CrossRefPubMed
43.
Ahmed AA, Wahbi AH, Nordlin K: Neuropeptides modulate a murine monocyte/macrophage cell line capacity for phagocytosis and killing of Leishmania major parasites. Immunopharmacol Immunotoxicol. 2001, 23 (3): 397-409. 10.1081/IPH-100107339.CrossRefPubMed
44.
Gregory DJ, Olivier M: Subversion of host cell signalling by the protozoan parasite Leishmania. Parasitology. 2005, 130 (Suppl): S27-35.CrossRefPubMed
45.
Wheway J, Mackay CR, Newton RA, Sainsbury A, Boey D, Herzog H, Mackay F: A fundamental bimodal role for neuropeptide Y1 receptor in the immune system. The Journal of Experimental Medicine. 2005, 202 (11): 1527-1538. 10.1084/jem.20051971.PubMedCentralCrossRefPubMed
46.
Bedoui S, Kromer A, Gebhardt T, Jacobs R, Raber K, Dimitrijevic M, Heine J, von Hörsten S: Neuropeptide Y receptor-specifically modulates human neutrophil function. J Neuroimmunol. 2008, 195 (1-2): 88-95. 10.1016/j.jneuroim.2008.01.012.CrossRefPubMed
47.
Tricker E, Cheng G: With a little help from my friends: modulation of phagocytosis through TLR activation. Cell Res. 2008, 18 (7): 711-712. 10.1038/cr.2008.78.CrossRefPubMed
48.
Cui J, Zhu N, Wang Q, Yu M, Feng J, Li Y, Zhang J, Shen B: p38 MAPK contributes to CD54 expression and the enhancement of phagocytic activity during macrophage development. Cell Immunol. 2009, 256 (1-2): 6-11. 10.1016/j.cellimm.2008.12.003.CrossRefPubMed
49.
Shinzawa N, Nelson B, Aonuma H, Okado K, Fukumoto S, Miura M, Kanuka H: p38 MAPK-dependent phagocytic encapsulation confers infection tolerance in Drosophila. Cell Host Microbe. 2009, 6 (3): 244-252. 10.1016/j.chom.2009.07.010.CrossRefPubMed
50.
Shiratsuchi H, Basson MD: Activation of p38 MAPKalpha by extracellular pressure mediates the stimulation of macrophage phagocytosis by pressure. American Journal of Physiology - Cell Physiology. 2005, 288 (5): C1083-1093. 10.1152/ajpcell.00543.2004.CrossRefPubMed
51.
Blander JM, Medzhitov R: Regulation of Phagosome Maturation by Signals from Toll-Like Receptors. Science. 2004, 304 (5673): 1014-1018. 10.1126/science.1096158.CrossRefPubMed
52.
Ben-Levy R, Leighton IA, Doza YN, Attwood P, Morrice N, Marshall CJ, Cohen P: Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2. EMBO J. 1995, 14 (23): 5920-5930.PubMedCentralPubMed
53.
Kotlyarov A, Yannoni Y, Fritz S, Laass K, Telliez J-B, Pitman D, Lin L-L, Gaestel M: Distinct Cellular Functions of MK2. Mol Cell Biol. 2002, 22 (13): 4827-4835. 10.1128/MCB.22.13.4827-4835.2002.PubMedCentralCrossRefPubMed
54.
Benndorf R, Hayess K, Ryazantsev S, Wieske M, Behlke J, Lutsch G: Phosphorylation and supramolecular organization of murine small heat shock protein HSP25 abolish its actin polymerization-inhibiting activity. J Biol Chem. 1994, 269 (32): 20780-20784.PubMed
55.
Napoli I, Neumann H: Microglial clearance function in health and disease. Neuroscience. 2009, 158 (3): 1030-1038. 10.1016/j.neuroscience.2008.06.046.CrossRefPubMed
Metadata
Title
Neuropeptide Y inhibits interleukin-1β-induced phagocytosis by microglial cells
Authors
Raquel Ferreira
Tiago Santos
Michelle Viegas
Luísa Cortes
Liliana Bernardino
Otília V Vieira
João O Malva
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2011
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-8-169

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