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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2017

Open Access 01-12-2017 | Research

Pleiotrophin regulates microglia-mediated neuroinflammation

Authors: Rosalía Fernández-Calle, Marta Vicente-Rodríguez, Esther Gramage, Jimena Pita, Carmen Pérez-García, Marcel Ferrer-Alcón, María Uribarri, María P. Ramos, Gonzalo Herradón

Published in: Journal of Neuroinflammation | Issue 1/2017

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Abstract

Background

Pleiotrophin (PTN) is a cytokine found highly upregulated in the brain in different disorders characterized by overt neuroinflammation such as neurodegenerative diseases, drug addiction, traumatic injury, and ischemia. In the present work, we have explored whether PTN modulates neuroinflammation and if Toll-like receptor 4 (TLR4), crucial in the initiation of an immune response, is involved.

Methods

In immunohistochemistry assays, we studied lipopolysaccharide (LPS, 7.5 mg/kg i.p.)-induced changes in glial fibrillary acidic protein (GFAP, astrocyte marker) and ionized calcium-binding adaptor molecule 1 (Iba1, microglia marker) expression in the prefrontal cortex (PFC) and striatum of mice with transgenic PTN overexpression in the brain (PTN-Tg) and in wild-type (WT) mice. Cytokine protein levels were assessed in the PFC by X-MAP technology. The influence of TLR4 signaling in LPS effects in both genotypes was assessed by pretreatment with the TLR4 antagonist (TAK-242, 3.0 mg/kg i.p.). Murine BV2 microglial cells were treated with PTN (0.5 μg/ml) and LPS (1.0 μg/ml) and assessed for the release of nitric oxide (NO).

Results

We found that LPS-induced microglial activation is significantly increased in the PFC of PTN-Tg mice compared to that of WT mice. The levels of TNF-α, IL-6, and MCP-1 in response to LPS were significantly increased in the PFC of PTN-Tg mice compared to that of WT mice. Pretreatment with TAK-242 efficiently blocked increases in cytokine contents in a similar manner in both genotypes. Concomitant incubation of BV2 cells with LPS and PTN significantly potentiated the production of NO compared to cells only treated with LPS.

Conclusions

Our findings identify for the first time that PTN is a novel and potent regulator of neuroinflammation. Pleiotrophin potentiates LPS-stimulated microglia activation. Our results suggest that regulation of the PTN signaling pathways may constitute new therapeutic opportunities particularly in those neurological disorders characterized by increased PTN cerebral levels and neuroinflammation.
Literature
1.
Barbierato M, Facci L, Argentini C, Marinelli C, Skaper SD, Giusti P. Astrocyte-microglia cooperation in the expression of a pro-inflammatory phenotype. CNS Neurol Disord Drug Targets. 2013;12:608–18.CrossRefPubMed
2.
Hanke ML, Kielian T. Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci (Lond). 2011;121:367–87.CrossRef
3.
O'Neill LA. Therapeutic targeting of Toll-like receptors for inflammatory and infectious diseases. Curr Opin Pharmacol. 2003;3:396–403.CrossRefPubMed
4.
Akira S, Takeda K. Functions of toll-like receptors: lessons from KO mice. C R Biol. 2004;327:581–9.CrossRefPubMed
5.
Amor S, Peferoen LA, Vogel DY, Breur M, van der Valk P, Baker D, van Noort JM. Inflammation in neurodegenerative diseases—an update. Immunology. 2014;142:151–66.CrossRefPubMedPubMedCentral
6.
Herradon G, Perez-Garcia C. Targeting midkine and pleiotrophin signalling pathways in addiction and neurodegenerative disorders: recent progress and perspectives. Br J Pharmacol. 2014;171:837–48.CrossRefPubMedPubMedCentral
7.
Najjar S, Pearlman DM, Alper K, Najjar A, Devinsky O. Neuroinflammation and psychiatric illness. J Neuroinflammation. 2013;10:43.PubMedPubMedCentral
8.
Silva AP, Martins T, Baptista S, Goncalves J, Agasse F, Malva JO. Brain injury associated with widely abused amphetamines: neuroinflammation, neurogenesis and blood-brain barrier. Curr Drug Abuse Rev. 2003;3:239–54.CrossRef
9.
Clark KH, Wiley CA, Bradberry CW. Psychostimulant abuse and neuroinflammation: emerging evidence of their interconnection. Neurotox Res. 2013;23:174–88.CrossRefPubMed
10.
Moratalla R, Khairnar A, Simola N, Granado N, Garcia-Montes JR, Porceddu PF, Tizabi Y, Costa G, Morelli M. Amphetamine-related drugs neurotoxicity in humans and in experimental animals: main mechanisms. Prog Neurobiol. 2015; doi:10.​1016/​j.​pneurobio.​2015.​09.​011.
11.
Curtin K, Fleckenstein AE, Robison RJ, Crookston MJ, Smith KR, Hanson GR. Methamphetamine/amphetamine abuse and risk of Parkinson’s disease in Utah: a population-based assessment. Drug Alcohol Depend. 2015;146:30–8.CrossRefPubMed
12.
13.
Nimmo AJ, Vink R. Recent patents in CNS drug discovery: the management of inflammation in the central nervous system. Recent Pat CNS Drug Discov. 2009;4:86–95.CrossRefPubMed
14.
Le Greves P. Pleiotrophin gene transcription in the rat nucleus accumbens is stimulated by an acute dose of amphetamine. Brain Res Bull. 2005;65:529–32.CrossRefPubMed
15.
Alguacil LF, Herradon G. Midkine and pleiotrophin in the treatment of neurodegenerative diseases and drug addiction. Recent Pat CNS Drug Discov. 2015;10:28–33.CrossRefPubMed
16.
Marchionini DM, Lehrmann E, Chu Y, He B, Sortwell CE, Becker KG, Freed WJ, Kordower JH, Collier TJ. Role of heparin binding growth factors in nigrostriatal dopamine system development and Parkinson’s disease. Brain Res. 2007;1147:77–88.CrossRefPubMed
17.
Achour A, M'Bika JP, Baudouin F, Caruelle D, Courty J. Pleiotrophin induces expression of inflammatory cytokines in peripheral blood mononuclear cells. Biochimie. 2008;90:1791–5.CrossRefPubMed
18.
Silver K, Desormaux A, Freeman LC, Lillich JD. Expression of pleiotrophin, an important regulator of cell migration, is inhibited in intestinal epithelial cells by treatment with non-steroidal anti-inflammatory drugs. Growth Factors. 2012;30:258–66.CrossRefPubMed
19.
Vicente-Rodriguez M, Rojo-Gonzalez L, Gramage E, Fernandez-Calle R, Chen Y, Perez-Garcia C, Ferrer-Alcon M, Uribarri M, Bailey A, Herradon G. Pleiotrophin overexpression regulates amphetamine-induced reward and striatal dopaminergic denervation without changing the expression of dopamine D1 and D2 receptors: implications for neuroinflammation. Eur Neuropsychopharmacol. 2016;26:1794–805.CrossRefPubMed
20.
Gramage E, Rossi L, Granado N, Moratalla R, Herradon G. Genetic inactivation of pleiotrophin triggers amphetamine-induced cell loss in the substantia nigra and enhances amphetamine neurotoxicity in the striatum. Neuroscience. 2010;170:308–16.CrossRefPubMed
21.
Gramage E, Putelli A, Polanco MJ, Gonzalez-Martin C, Ezquerra L, Alguacil LF, Perez-Pinera P, Deuel TF, Herradon G. The neurotrophic factor pleiotrophin modulates amphetamine-seeking behaviour and amphetamine-induced neurotoxic effects: evidence from pleiotrophin knockout mice. Addict Biol. 2010;15:403–12.CrossRefPubMed
22.
Asari A, Kanemitsu T, Kurihara H. Oral administration of high molecular weight hyaluronan (900 kDa) controls immune system via Toll-like receptor 4 in the intestinal epithelium. J Biol Chem. 2010;285:24751–8.CrossRefPubMedPubMedCentral
23.
Ferrer-Alcón M, Uribarri M, Díaz A, Del Olmo N, Valdizán EM, Gramage E, Martín M, Castro E, Pérez-García C, Mengod G, Maldonado R, Herradon G, Pazos A, Palacios JM. A new non-classical transgenic animal model of Depression Program No. 776.04/FF9 Neuroscience Meeting Planner. New Orleans: Society for Neuroscience; 2012. Online.
24.
Vicente-Rodriguez M, Perez-Garcia C, Ferrer-Alcon M, Uribarri M, Sanchez-Alonso MG, Ramos MP, Herradon G. Pleiotrophin differentially regulates the rewarding and sedative effects of ethanol. J Neurochem. 2014;131:688–95.CrossRefPubMed
25.
Aigner L, Arber S, Kapfhammer JP, Laux T, Schneider C, Botteri F, Brenner HR, Caroni P. Overexpression of the neural growth-associated protein GAP-43 induces nerve sprouting in the adult nervous system of transgenic mice. Cell. 1995;83:269–78.CrossRefPubMed
26.
Caroni P. Overexpression of growth-associated proteins in the neurons of adult transgenic mice. J Neurosci Methods. 1997;71:3–9.CrossRefPubMed
27.
Vicente-Rodriguez M, Perez-Garcia C, Haro M, Ramos MP, Herradon G. Genetic inactivation of midkine modulates behavioural responses to ethanol possibly by enhancing GABA(A) receptor sensitivity to GABA(A) acting drugs. Behav Brain Res. 2014;274:258–63.CrossRefPubMed
28.
Vicente-Rodriguez M, Herradon G, Ferrer-Alcon M, Uribarri M, Perez-Garcia C. Chronic cocaine use causes changes in the striatal proteome depending on the endogenous expression of pleiotrophin. Chem Res Toxicol. 2015;28:1443–54.CrossRefPubMed
29.
Gramage E, Martin YB, Ramanah P, Perez-Garcia C, Herradon G. Midkine regulates amphetamine-induced astrocytosis in striatum but has no effects on amphetamine-induced striatal dopaminergic denervation and addictive effects: functional differences between pleiotrophin and midkine. Neuroscience. 2011;190:307–17.CrossRefPubMed
30.
Luo XL, Liu SY, Wang LJ, Zhang QY, Xu P, Pan LL, Hu JF. A tetramethoxychalcone from Chloranthus henryi suppresses lipopolysaccharide-induced inflammatory responses in BV2 microglia. Eur J Pharmacol. 2016;774:135–43.CrossRefPubMed
31.
Lastres-Becker I, Garcia-Yague AJ, Scannevin RH, Casarejos MJ, Kugler S, Rabano A, Cuadrado A. Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson’s disease. Antioxid Redox Signal. 2016;25:61–77.CrossRefPubMedPubMedCentral
32.
Torika N, Asraf K, Danon A, Apte RN, Fleisher-Berkovich S. Telmisartan modulates glial activation: in vitro and in vivo studies. PLoS One. 2016;11:e0155823.CrossRefPubMedPubMedCentral
33.
Frey D, Jung S, Brackmann F, Richter-Kraus M, Trollmann R. Hypoxia potentiates LPS-mediated cytotoxicity of BV2 microglial cells in vitro by synergistic effects on glial cytokine and nitric oxide system. Neuropediatrics. 2015;46:321–8.CrossRefPubMed
34.
Hida H, Jung CG, Wu CZ, Kim HJ, Kodama Y, Masuda T, Nishino H. Pleiotrophin exhibits a trophic effect on survival of dopaminergic neurons in vitro. Eur J Neurosci. 2003;17:2127–34.CrossRefPubMed
35.
Himburg HA, Muramoto GG, Daher P, Meadows SK, Russell JL, Doan P, Chi JT, Salter AB, Lento WE, Reya T, Chao NJ, Chute JP. Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells. Nat Med. 2010;16:475–82.CrossRefPubMedPubMedCentral
36.
Maragakis NJ, Rothstein JD. Mechanisms of disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol. 2006;2:679–89.CrossRefPubMed
37.
Qin L, Liu Y, Wang T, Wei SJ, Block ML, Wilson B, Liu B, Hong JS. NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem. 2004;279:1415–21.CrossRefPubMed
38.
Ezquerra L, Alguacil LF, Nguyen T, Deuel TF, Silos-Santiago I, Herradon G. Different pattern of pleiotrophin and midkine expression in neuropathic pain: correlation between changes in pleiotrophin gene expression and rat strain differences in neuropathic pain. Growth Factors. 2008;26:44–8.CrossRefPubMed
39.
Gramage E, Herradon G. Connecting Parkinson’s disease and drug addiction: common players reveal unexpected disease connections and novel therapeutic approaches. Curr Pharm Des. 2011;17:449–61.CrossRefPubMed
40.
Wisniewski T, Lalowski M, Baumann M, Rauvala H, Raulo E, Nolo R, Frangione B. HB-GAM is a cytokine present in Alzheimer’s and Down’s syndrome lesions. Neuroreport. 1996;7:667–71.CrossRefPubMed
41.
Mailleux P, Preud'homme X, Albala N, Vanderwinden JM, Vanderhaeghen JJ. delta-9-Tetrahydrocannabinol regulates gene expression of the growth factor pleiotrophin in the forebrain. Neurosci Lett. 1994;175:25–7.CrossRefPubMed
42.
Herradon G, Ezquerra L, Gramage E, Alguacil LF. Targeting the pleiotrophin/receptor protein tyrosine phosphatase beta/zeta signaling pathway to limit neurotoxicity induced by drug abuse. Mini Rev Med Chem. 2009;9:440–7.CrossRefPubMed
43.
Peria FM, Neder L, Marie SK, Rosemberg S, Oba-Shinjo SM, Colli BO, Gabbai AA, Malheiros SM, Zago MA, Panepucci RA, Moreira-Filho CA, Okamoto OK, Carlotti Jr CG. Pleiotrophin expression in astrocytic and oligodendroglial tumors and it’s correlation with histological diagnosis, microvascular density, cellular proliferation and overall survival. J Neurooncol. 2007;84:255–61.CrossRefPubMed
44.
Miao J, Ding M, Zhang A, Xiao Z, Qi W, Luo N, Di W, Tao Y, Fang Y. Pleiotrophin promotes microglia proliferation and secretion of neurotrophic factors by activating extracellular signal-regulated kinase 1/2 pathway. Neurosci Res. 2012;74:269–76.CrossRefPubMed
45.
46.
47.
Meng K, Rodriguez-Pena A, Dimitrov T, Chen W, Yamin M, Noda M, Deuel TF. Pleiotrophin signals increased tyrosine phosphorylation of beta beta-catenin through inactivation of the intrinsic catalytic activity of the receptor-type protein tyrosine phosphatase beta/zeta. Proc Natl Acad Sci U S A. 2000;97:2603–8.CrossRefPubMedPubMedCentral
48.
Panicker N, Saminathan H, Jin H, Neal M, Harischandra DS, Gordon R, Kanthasamy K, Lawana V, Sarkar S, Luo J, Anantharam V, Kanthasamy AG, Kanthasamy A. Fyn kinase regulates microglial neuroinflammatory responses in cell culture and animal models of Parkinson’s disease. J Neurosci. 2015;35:10058–77.CrossRefPubMedPubMedCentral
49.
Pariser H, Ezquerra L, Herradon G, Perez-Pinera P, Deuel TF. Fyn is a downstream target of the pleiotrophin/receptor protein tyrosine phosphatase beta/zeta-signaling pathway: regulation of tyrosine phosphorylation of Fyn by pleiotrophin. Biochem Biophys Res Commun. 2005;332:664–9.CrossRefPubMed
Metadata
Title
Pleiotrophin regulates microglia-mediated neuroinflammation
Authors
Rosalía Fernández-Calle
Marta Vicente-Rodríguez
Esther Gramage
Jimena Pita
Carmen Pérez-García
Marcel Ferrer-Alcón
María Uribarri
María P. Ramos
Gonzalo Herradón
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-0823-8

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