Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Acta Neuropathologica Communications
Published in: Acta Neuropathologica Communications 1/2013

Open Access 01-12-2013 | Research

MCP-1/CCR2 signaling-mediated astrocytosis is accelerated in a transgenic mouse model of SOD1-mutated familial ALS

Authors: Motoko Kawaguchi-Niida, Tomoko Yamamoto, Yoichiro Kato, Yuri Inose, Noriyuki Shibata

Published in: Acta Neuropathologica Communications | Issue 1/2013

Login to get access

Abstract

Background

Emerging evidence suggests that innate immunity and increased oxidative stress contribute to pathomechanisms in amyotrophic lateral sclerosis (ALS). The aim of the present study was to verify the involvement of monocyte chemoattractant protein-1 (MCP-1) and its specific CC chemokine receptor 2 (CCR2) in the disease progression of ALS. We here demonstrate the expression state of MCP-1 and CCR2 in lumbar spinal cords of mice overexpressing a transgene for G93A mutant human superoxide dismutase 1 (SOD1) (ALS mice) as a mouse model of ALS as well as the involvement of MCP-1/CCR2-mediated signaling in behavior of cultured astrocytes derived from those mice.

Results

Quantitative polymerase chain reaction analysis revealed that MCP-1 and CCR2 mRNA levels were significantly higher in ALS mice than those in nontransgenic littermates (control mice) at the presymptomatic stage. Immunoblot analysis disclosed a significantly higher CCR2/β-actin optical density ratio in the postsymptomatic ALS mouse group than those in the age-matched control mouse group. Immunohistochemically, MCP-1 determinants were mainly localized in motor neurons, while CCR2 determinants were exclusively localized in reactive astrocytes. Primary cultures of astrocytes derived from ALS mice showed a significant increase in proliferation activity under recombinant murine MCP-1 stimuli as compared to those from control mice.

Conclusions

Our results provide in vivo and in vitro evidence that MCP-1 stimulates astrocytes via CCR2 to induce astrocytosis in ALS with SOD1 gene mutation. Thus, it is likely that MCP-1/CCR2-mediated sigaling is involved in the disease progression of ALS.
Appendix
Available only for authorised users
Literature
1.
Ince PG, Highley JR, Kirby J, Wharton SB, Takahashi H, Strong MJ, Shaw PJ: Molecular pathology and genetic advances in amyotrophic lateral sclerosis: an emerging molecular pathway and the significance of glial pathology. Acta Neuropathol 2011, 122: 657–671. 10.1007/s00401-011-0913-0CrossRefPubMed
2.
Rowland LP, Shneider NA: Amyotrophic lateral sclerosis. N Engl J Med 2001, 344: 1688–1700. 10.1056/NEJM200105313442207CrossRefPubMed
3.
Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon Y, Deng HX: Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 1994, 264: 1772–1775. 10.1126/science.8209258CrossRefPubMed
4.
5.
Shibata N, Kawaguchi-Niida M, Yamamoto T, Toi S, Hirano A, Kobayashi M: Effects of the PPARγ activator pioglitazone on p38 MAP kinase and IκBα in the spinal cord of a transgenic mouse model of amyotrophic lateral sclerosis. Neuropathology 2008, 28: 387–398. 10.1111/j.1440-1789.2008.00890.xCrossRefPubMed
6.
Conductier G, Blondeau N, Guyon A, Nahon JL, Rovère C: The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. J Neuroimmunol 2010, 224: 93–100. 10.1016/j.jneuroim.2010.05.010CrossRefPubMed
7.
8.
Li MQ, Li HP, Meng YH, Wang XQ, Zhu XY, Mei J, Li DJ: Chemokine CCL2 enhances survival and invasiveness of endometrial stromal cells in an autocrine manner by activating Akt and MAPK/Erk1/2 signal pathway. Fertil Steril 2012,97(4):919–929. 10.1016/j.fertnstert.2011.12.049CrossRefPubMed
9.
Loberg RD, Day LL, Harwood J, Ying C, St John LN, Giles R, Neeley CK, Pienta KJ: CCL2 is a potent regulator of prostate cancer cell migration and proliferation. Neoplasia 2006, 8: 578–586. 10.1593/neo.06280PubMedCentralCrossRefPubMed
10.
Lu Y, Cai Z, Galson DL, Xiao G, Liu Y, George DE, Melhem MF, Yao Z, Zhang J: Monocyte chemotactic protein-1 (MCP-1) acts as a paracrine and autocrine factor for prostate cancer growth and invasion. Prostate 2006, 66: 1311–1318. 10.1002/pros.20464CrossRefPubMed
11.
El Khoury J, Luster AD: Mechanisms of microglia accumulation in Alzheimer's disease: therapeutic implications. Trends Pharmacol Sci 2008, 29: 626–632. 10.1016/j.tips.2008.08.004CrossRefPubMed
12.
Huang DR, Wang J, Kivisakk P, Rollins BJ, Ransohoff RM: Absence of monocyte chemoattractant protein 1 in mice leads to decreased local macrophage recruitment and antigen-specific T helper cell type 1 immune response in experimental autoimmune encephalomyelitis. J Exp Med 2001, 193: 713–726. 10.1084/jem.193.6.713PubMedCentralCrossRefPubMed
13.
Hughes PM, Allegrini PR, Rudin M, Perry VH, Mir AK, Wiessner C: Monocyte chemoattractant protein-1 deficiency is protective in a murine stroke model. J Cereb Blood Flow Metab 2002, 22: 308–317.CrossRefPubMed
14.
Baron P, Bussini S, Cardin V, Corbo M, Conti G, Galimberti D, Scarpini E, Bresolin N, Wharton S, Shaw PJ, Silani V: Production of monocyte chemoattractant protein-1 in amyotrophic lateral sclerosis. Muscle Nerve 2005, 32: 541–544. 10.1002/mus.20376CrossRefPubMed
15.
Gupta PK, Prabhakar S, Sharma S, Anand A: A predictive model for amyotrophic lateral sclerosis (ALS) diagnosis. J Neurol Sci 2012, 312: 68–72. 10.1016/j.jns.2011.08.021CrossRefPubMed
16.
Henkel JS, Engelhardt JI, Siklós L, Simpson EP, Kim SH, Pan T, Goodman JC, Siddique T, Beers DR, Appel SH: Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol 2004, 55: 221–235. 10.1002/ana.10805CrossRefPubMed
17.
Simpson EP, Henry YK, Henkel JS, Smith RG, Appel SH: Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden. Neurology 2004, 62: 1758–1765. 10.1212/WNL.62.10.1758CrossRefPubMed
18.
Wilms H, Sievers J, Dengler R, Bufler J, Deuschl G, Lucius R: Intrathecal synthesis of monocyte chemoattractant protein-1 (MCP-1) in amyotrophic lateral sclerosis: further evidence for microglial activation in neurodegeneration. J Neuroimmunol 2003, 144: 139–142. 10.1016/j.jneuroim.2003.08.042CrossRefPubMed
19.
Beers DR, Zhao W, Liao B, Kano O, Wang J, Huang A, Appel SH, Henkel JS: Neuroinflammation modulates distinct regional and temporal clinical responses in ALS mice. Brain Behav Immun 2011, 25: 1025–1035. 10.1016/j.bbi.2010.12.008PubMedCentralCrossRefPubMed
20.
Henkel JS, Beers DR, Siklós L, Appel SH: The chemokine MCP-1 and the dendritic and myeloid cells it attracts are increased in the mSOD1 mouse model of ALS. Mol Cell Neurosci 2006, 31: 427–437. 10.1016/j.mcn.2005.10.016CrossRefPubMed
21.
Mantovani S, Garbelli S, Pasini A, Alimonti D, Perotti C, Melazzini M, et al.: Immune system alterations in sporadic amyotrophic lateral sclerosis patients suggest an ongoing neuroinflammatory process. J Neuroimmunol 2009, 210: 73–79. 10.1016/j.jneuroim.2009.02.012CrossRefPubMed
22.
Zhang R, Gascon R, Miller RG, Gelinas DF, Mass J, Lancero M, Narvaez A, McGrath MS: MCP-1 chemokine receptor CCR2 is decreased on circulating monocytes in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol 2006, 179: 87–93. 10.1016/j.jneuroim.2006.06.008CrossRefPubMed
23.
Dawson J, Miltz W, Mir AK, Wiessner C: Targeting monocyte chemoattractant protein-1 signalling in disease. Expert Opin Ther Targets 2003, 7: 35–48. 10.1517/14728222.7.1.35CrossRefPubMed
24.
Roebuck KA, Carpenter LR, Lakshminarayanan V, Page SM, Moy JN, Thomas LL: Stimulus-specific regulation of chemokine expression involves differential activation of the redox-responsive transcription factors AP-1 and NF-κB. J Leukoc Biol 1999, 65: 291–298.PubMed
25.
Allavena P, Bianchi G, Zhou D, van Damme J, Jílek P, Sozzani S, Mantovani A: Induction of natural killer cell migration by monocyte chemotactic protein-1, -2 and −3. Eur J Immunol 1994, 24: 3233–3236. 10.1002/eji.1830241249CrossRefPubMed
26.
Amantea D, Nappi G, Bernardi G, Bagetta G, Corasaniti MT: Post-ischemic brain damage: pathophysiology and role of inflammatory mediators. FEBS J 2009, 276: 13–26. 10.1111/j.1742-4658.2008.06766.xCrossRefPubMed
27.
Hinojosa AE, Garcia-Bueno B, Leza JC, Madrigal JL: CCL2/MCP-1 modulation of microglial activation and proliferation. J Neuroinflammation 2011, 8: 77. 10.1186/1742-2094-8-77PubMedCentralCrossRefPubMed
28.
Lee EO, Park HJ, Kang JL, Kim HS, Chong YH: Resveratrol reduces glutamate-mediated monocyte chemotactic protein-1 expression via inhibition of extracellular signal-regulated kinase 1/2 pathway in rat hippocampal slice cultures. J Neurochem 2010, 112: 1477–1487. 10.1111/j.1471-4159.2009.06564.xCrossRefPubMed
29.
Mahad D, Callahan MK, Williams KA, Ubogu EE, Kivisäkk P, Tucky B, et al.: Modulating CCR2 and CCL2 at the blood–brain barrier: relevance for multiple sclerosis pathogenesis. Brain 2006, 129: 212–223.CrossRefPubMed
30.
Semple BD, Bye N, Rancan M, Ziebell JM, Morganti-Kossmann MC: Role of CCL2 (MCP-1) in traumatic brain injury (TBI): evidence from severe TBI patients and CCL2−/− mice. J Cereb Blood Flow Metab 2010, 30: 769–782. 10.1038/jcbfm.2009.262PubMedCentralCrossRefPubMed
31.
Tanabe S, Heesen M, Berman MA, Fischer MB, Yoshizawa I, Luo Y, Dorf ME: Murine astrocytes express a functional chemokine receptor. J Neurosci 1997, 17: 6522–6528.PubMed
32.
Kuhle J, Lindberg RL, Regeniter A, Mehling M, Steck AJ, Kappos L, Czaplinski A: Increased levels of inflammatory chemokines in amyotrophic lateral sclerosis. Eur J Neurol 2009, 16: 771–774. 10.1111/j.1468-1331.2009.02560.xCrossRefPubMed
33.
Philips T, Robberecht W: Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol 2011, 10: 253–263. 10.1016/S1474-4422(11)70015-1CrossRefPubMed
34.
Tateishi T, Yamasaki R, Tanaka M, Matsushita T, Kikuchi H, Isobe N, Ohyagi Y, Kira J: CSF chemokine alterations related to the clinical course of amyotrophic lateral sclerosis. J uroimmunol 2010, 222: 76–81.
35.
Coughlan CM, McManus CM, Sharron M, Gao Z, Murphy D, Jaffer S, et al.: Expression of multiple functional chemokine receptors and monocyte chemoattractant protein-1 in human neurons. Neuroscience 2000, 97: 591–600. 10.1016/S0306-4522(00)00024-5CrossRefPubMed
36.
Meng SZ, Oka A, Takashima S: Developmental expressison of monocyte chemoattractant protein-1 in the human cerebellum and brainstem. Brain Dev 1999, 21: 30–35. 10.1016/S0387-7604(98)00065-5CrossRefPubMed
37.
Butovsky O, Siddiqui S, Gabriely G, Lanser AJ, Dake B, Murugaiyanf G, et al.: Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J Clin Invest 2012, 122: 3063–3087. 10.1172/JCI62636PubMedCentralCrossRefPubMed
38.
Sargsyan SA, Blackburn DJ, Barber SC, Monk PN, Shaw PJ: Mutant SOD1 G93A microglia have an inflammatory phenotype and elevated production of MCP-1. NeuroReport 2009, 20: 1450–1455. 10.1097/WNR.0b013e328331e8faPubMedCentralCrossRefPubMed
39.
Semple BD, Kossmann T, Morganti-Kossmann MC: Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. J Cereb Blood Flow Metab 2010, 30: 459–473. 10.1038/jcbfm.2009.240PubMedCentralCrossRefPubMed
40.
Croitoru-Lamoury J, Guillemin GJ, Boussin FD, Mognetti B, Gigout LI, Chéret A, Vaslin B, Le Grand R, Brew BJ, Dormont D: Expression of chemokines and their receptors in human and simian astrocytes: evidence for a central role of TNFα and IFNγ in CXCR4 and CCR5 modulation. Glia 2003, 41: 354–370. 10.1002/glia.10181CrossRefPubMed
41.
Hickman SE, El Khoury J: Mechanisms of mononuclear phagocyte recruitment in Alzheimer's disease. CNS Neurol Disord Drug Targets 2010, 9: 168–173. 10.2174/187152710791011982PubMedCentralCrossRefPubMed
42.
Tanuma N, Sakuma H, Sasaki A, Matsumoto Y: Chemokine expression by astrocytes plays a role in microglia/macrophage activation and subsequent neurodegeneration in secondary progressive multiple sclerosis. Acta Neuropathol 2006, 112: 195–204. 10.1007/s00401-006-0083-7CrossRefPubMed
43.
Jee Y, Yoon WK, Okura Y, Tanuma N, Matsumoto Y: Upregulation of monocyte chemotactic protein-1 and CC chemokine receptor 2 in the central nervous system is closely associated with relapse of autoimmune encephalomyelitis in Lewis rats. J Neuroimmunol 2002, 128: 49–57. 10.1016/S0165-5728(02)00147-9CrossRefPubMed
44.
Quinones MP, Kalkonde Y, Estrada CA, Jimenez F, Ramirez R, Mahimainathan L, et al.: Role of astrocytes and chemokine systems in acute TNFalpha induced demyelinating syndrome: CCR2-dependent signals promote astrocyte activation and survival via NF-kappaB and Akt. Mol Cell Neurosci 2008, 37: 96–109. 10.1016/j.mcn.2007.08.017PubMedCentralCrossRefPubMed
45.
Andjelkovic AV, Song L, Dzenko KA, Cong H, Pachter JS: Functional expression of CCR2 by human fetal astrocytes. J Neurosci Res 2002, 70: 219–231. 10.1002/jnr.10372CrossRefPubMed
46.
47.
Xia MQ, Hyman BT: Chemokines/chemokine receptors in the central nervous system and Alzheimer's disease. J Neurovirol 1999, 5: 32–41. 10.3109/13550289909029743CrossRefPubMed
48.
49.
Ferraiuolo L, Higginbottom A, Heath PR, Barber S, Greenald D, Kirby J, Shaw PJ: Dysregulation of astrocyte-motoneuron cross-talk in mutant superoxide dismutase 1-related amyotrophic lateral sclerosis. Brain 2011, 134: 2627–2641. 10.1093/brain/awr193PubMedCentralCrossRefPubMed
50.
Papadeas ST, Kraig SE, O'Banion C, Lepore AC, Maragakis NJ: Astrocytes carrying the superoxide dismutase 1 (SOD1G93A) mutation induce wild-type motor neuron degeneration in vivo. Proc Natl Acad Sci USA 2011, 108: 17803–17808. 10.1073/pnas.1103141108PubMedCentralCrossRefPubMed
51.
van Der Voorn P, Tekstra J, Beelen RH, Tensen CP, Van Der Valk P, De Groot CJ: Expression of MCP-1 by reactive astrocytes in demyelinating multiple sclerosis lesions. Am J Pathol 1999, 154: 45–51. 10.1016/S0002-9440(10)65249-2PubMedCentralCrossRefPubMed
52.
53.
Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, Cleaveland DW: Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 2008, 11: 251–253. 10.1038/nn2047PubMedCentralCrossRefPubMed
54.
Jayapal KP, Philp RJ, Kok YJ, Yap MG, Sherman DH, Griffin TJ, Hu WS: Uncovering genes with divergent mRNA-protein dynamics in Streptomyces coelicolor. PLoS One 2008, 3: e2097. 10.1371/journal.pone.0002097PubMedCentralCrossRefPubMed
55.
Kabashi E, Durham HD: Failure of protein quality control in amyotrophic lateral sclerosis. Biochim Biophys Acta 2006, 1762: 1038–1050. 10.1016/j.bbadis.2006.06.006CrossRefPubMed
56.
Sica A, Saccani A, Borsatti A, Power CA, Wells TN, Luini W, Polentarutti N, Sozzani S, Mantovani A: Bacterial lipopolysaccharide rapidly inhibits expression of C-C chemokine receptors in human monocytes. J Exp Med 1997, 185: 969–974. 10.1084/jem.185.5.969PubMedCentralCrossRefPubMed
57.
Saccani A, Saccani S, Orlando S, Sironi M, Bernasconi S, Ghezzi P, Mantovani A, Sica A: Redox regulation of chemokine receptor expression. Proc Natl Acad Sci USA 2000, 97: 2761–2766. 10.1073/pnas.97.6.2761PubMedCentralCrossRefPubMed
58.
Limoli CL, Giedzinski E, Baure J, Rola R, Fike JR: Redox changes induced in hippocampal precursor cells by heavy ion irradiation. Radiat Environ Biophys 2007, 46: 167–172. 10.1007/s00411-006-0077-9CrossRefPubMed
59.
Díaz-Amarilla P, Olivera-Bravo S, Trias E, Cragnolini A, Martínez-Palma L, Cassina P, Beckman J, Barbeito L: Phenotypically aberrant astrocytes that promote motoneuron damage in a model of inherited amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 2011, 108: 18126–18131. 10.1073/pnas.1110689108PubMedCentralCrossRefPubMed
60.
Gurney ME: Transgenic-mouse model of amyotrophic lateral sclerosis. N Engl J Med 1994, 331: 1721–1722. 10.1056/NEJM199412223312516CrossRefPubMed
61.
Sapan CV, Lundblad RL, Price NC: Colorimetric protein assay techniques. Biotechnol Appl Biochem 1999, 29: 99–108.PubMed
62.
Kawaguchi M, Shibata N, Horiuchi S, Kobayashi M: Glyoxal inactivates glutamate transporter-1 in cultured rat astrocytes. Neuropathology 2005, 25: 27–36. 10.1111/j.1440-1789.2004.00579.xCrossRefPubMed
Metadata
Title
MCP-1/CCR2 signaling-mediated astrocytosis is accelerated in a transgenic mouse model of SOD1-mutated familial ALS
Authors
Motoko Kawaguchi-Niida
Tomoko Yamamoto
Yoichiro Kato
Yuri Inose
Noriyuki Shibata
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Acta Neuropathologica Communications / Issue 1/2013
Electronic ISSN: 2051-5960
DOI
https://doi.org/10.1186/2051-5960-1-21

Other articles of this Issue 1/2013

Acta Neuropathologica Communications 1/2013 Go to the issue

Research

Myelin alters the inflammatory phenotype of macrophages by activating PPARs

Research

Reducing TDP-43 aggregation does not prevent its cytotoxicity

Research

Identification of a neuronal transcription factor network involved in medulloblastoma development

Research

The Arctic AβPP mutation leads to Alzheimer’s disease pathology with highly variable topographic deposition of differentially truncated Aβ

Research

Deciphering the pathogenesis of sporadic Creutzfeldt-Jakob disease with codon 129 M/V and type 2 abnormal prion protein

Research

Evidence for new targets and synergistic effect of metronomic celecoxib/fluvastatin combination in pilocytic astrocytoma