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

Open Access 01-12-2017 | Research

Evidence for an early innate immune response in the motor cortex of ALS

Authors: Javier H. Jara, Barış Genç, Macdonell J. Stanford, Peter Pytel, Raymond P. Roos, Sandra Weintraub, M. Marsel Mesulam, Eileen H. Bigio, Richard J. Miller, P. Hande Özdinler

Published in: Journal of Neuroinflammation | Issue 1/2017

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Abstract

Background

Recent evidence indicates the importance of innate immunity and neuroinflammation with microgliosis in amyotrophic lateral sclerosis (ALS) pathology. The MCP1 (monocyte chemoattractant protein-1) and CCR2 (CC chemokine receptor 2) signaling system has been strongly associated with the innate immune responses observed in ALS patients, but the motor cortex has not been studied in detail.

Methods

After revealing the presence of MCP1 and CCR2 in the motor cortex of ALS patients, to elucidate, visualize, and define the timing, location and the extent of immune response in relation to upper motor neuron vulnerability and progressive degeneration in ALS, we developed MCP1-CCR2-hSOD1G93A mice, an ALS reporter line, in which cells expressing MCP1 and CCR2 are genetically labeled by monomeric red fluorescent protein-1 and enhanced green fluorescent protein, respectively.

Results

In the motor cortex of MCP1-CCR2-hSOD1G93A mice, unlike in the spinal cord, there was an early increase in the numbers of MCP1+ cells, which displayed microglial morphology and selectively expressed microglia markers. Even though fewer CCR2+ cells were present throughout the motor cortex, they were mainly infiltrating monocytes. Interestingly, MCP1+ cells were found in close proximity to the apical dendrites and cell bodies of corticospinal motor neurons (CSMN), further implicating the importance of their cellular interaction to neuronal pathology. Similar findings were observed in the motor cortex of ALS patients, where MCP1+ microglia were especially in close proximity to the degenerating apical dendrites of Betz cells.

Conclusions

Our findings reveal that the intricate cellular interplay between immune cells and upper motor neurons observed in the motor cortex of ALS mice is indeed recapitulated in ALS patients. We generated and characterized a novel model system, to study the cellular and molecular basis of this close cellular interaction and how that relates to motor neuron vulnerability and progressive degeneration in ALS.
Appendix
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Literature
1.
Ferraiuolo L, Kirby J, Grierson AJ, Sendtner M, Shaw PJ. Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nat Rev Neurol. 2011;7:616–30.CrossRefPubMed
2.
3.
Puentes F, Malaspina A, Van Noort JM, Amor S. Non-neuronal cells in ALS: role of glial, immune cells and blood-CNS Barriers. Brain Pathol. 2016;26:248–57.CrossRefPubMed
4.
Troost D, Sillevis Smitt PA, De Jong JM, Swaab DF. Neurofilament and glial alterations in the cerebral cortex in amyotrophic lateral sclerosis. Acta Neuropathol. 1992;84:664–73.CrossRefPubMed
5.
McGeer PL, McGeer EG. Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve. 2002;26:459–70.CrossRefPubMed
6.
Kawamata T, Akiyama H, Yamada T, McGeer PL. Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Pathol. 1992;140:691–707.PubMedPubMedCentral
7.
Sasaki S, Maruyama S. Immunocytochemical and ultrastructural studies of the motor cortex in amyotrophic lateral sclerosis. Acta Neuropathol. 1994;87:578–85.CrossRefPubMed
8.
Ozdinler PH, Benn S, Yamamoto TH, Guzel M, Brown Jr RH, Macklis JD. Corticospinal motor neurons and related subcerebral projection neurons undergo early and specific neurodegeneration in hSOD1G93A transgenic ALS mice. J Neurosci. 2011;31:4166–77.CrossRefPubMedPubMedCentral
9.
Yasvoina MV, Genc B, Jara JH, Sheets PL, Quinlan KA, Milosevic A, Shepherd GM, Heckman CJ, Ozdinler PH. eGFP expression under UCHL1 promoter genetically labels corticospinal motor neurons and a subpopulation of degeneration-resistant spinal motor neurons in an ALS mouse model. J Neurosci. 2013;33:7890–904.CrossRefPubMedPubMedCentral
10.
Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX, et al. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science. 1994;264:1772–5.CrossRefPubMed
11.
Hall ED, Oostveen JA, Gurney ME. Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia. 1998;23:249–56.CrossRefPubMed
12.
Levine JB, Kong J, Nadler M, Xu Z. Astrocytes interact intimately with degenerating motor neurons in mouse amyotrophic lateral sclerosis (ALS). Glia. 1999;28:215–24.CrossRefPubMed
13.
Bilsland LG, Nirmalananthan N, Yip J, Greensmith L, Duchen MR. Expression of mutant SOD1 in astrocytes induces functional deficits in motoneuron mitochondria. J Neurochem. 2008;107:1271–83.CrossRefPubMed
14.
Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, Cleveland DW. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci. 2008;11:251–3.CrossRefPubMedPubMedCentral
15.
Rodriguez MJ, Mahy N. Neuron-microglia interactions in motor neuron degeneration. The inflammatory hypothesis in amyotrophic lateral sclerosis revisited. Curr Med Chem. 2016;23:4753–72.CrossRefPubMed
16.
Philips T, Robberecht W. Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol. 2011;10:253–63.CrossRefPubMed
17.
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;25:1025–35.CrossRefPubMed
18.
Brettschneider J, Toledo JB, Van Deerlin VM, Elman L, McCluskey L, Lee VM, Trojanowski JQ. Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis. PLoS ONE. 2012;7, e39216.CrossRefPubMedPubMedCentral
19.
Turner MR, Cagnin A, Turkheimer FE, Miller CC, Shaw CE, Brooks DJ, Leigh PN, Banati RB. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C] (R)-PK11195 positron emission tomography study. Neurobiol Dis. 2004;15:601–9.CrossRefPubMed
20.
Zurcher NR, Loggia ML, Lawson R, Chonde DB, Izquierdo-Garcia D, Yasek JE, Akeju O, Catana C, Rosen BR, Cudkowicz ME, et al. Increased in vivo glial activation in patients with amyotrophic lateral sclerosis: assessed with [(11) C]-PBR28. Neuroimage Clin. 2015;7:409–14.CrossRefPubMedPubMedCentral
21.
Alshikho MJ, Zurcher NR, Loggia ML, Cernasov P, Chonde DB, Izquierdo Garcia D, Yasek JE, Akeju O, Catana C, Rosen BR, et al. Glial activation colocalizes with structural abnormalities in amyotrophic lateral sclerosis. Neurology. 2016.
22.
Jara JH, Villa SR, Khan NA, Bohn MC, Ozdinler PH. AAV2 mediated retrograde transduction of corticospinal motor neurons reveals initial and selective apical dendrite degeneration in ALS. Neurobiol Dis. 2012;47:174–83.CrossRefPubMedPubMedCentral
23.
Henkel JS, Engelhardt JI, Siklos 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;55:221–35.CrossRefPubMed
24.
Baron P, Bussini S, Cardin V, Corbo M, Conti G, Galimberti D, Scarpini E, Bresolin N, Wharton SB, Shaw PJ, Silani V. Production of monocyte chemoattractant protein-1 in amyotrophic lateral sclerosis. Muscle Nerve. 2005;32:541–4.CrossRefPubMed
25.
Nagata T, Nagano I, Shiote M, Narai H, Murakami T, Hayashi T, Shoji M, Abe K. Elevation of MCP-1 and MCP-1/VEGF ratio in cerebrospinal fluid of amyotrophic lateral sclerosis patients. Neurol Res. 2007;29:772–6.CrossRefPubMed
26.
Henkel JS, Beers DR, Siklos 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;31:427–37.CrossRefPubMed
27.
Butovsky O, Siddiqui S, Gabriely G, Lanser AJ, Dake B, Murugaiyan G, Doykan CE, Wu PM, Gali RR, Iyer LK, et al. Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J Clin Invest. 2012;122:3063–87.CrossRefPubMedPubMedCentral
28.
Chiu IM, Morimoto ET, Goodarzi H, Liao JT, O’Keeffe S, Phatnani HP, Muratet M, Carroll MC, Levy S, Tavazoie S, et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 2013;4:385–401.CrossRefPubMedPubMedCentral
29.
Zondler L, Muller K, Khalaji S, Bliederhauser C, Ruf WP, Grozdanov V, Thiemann M, Fundel-Clemes K, Freischmidt A, Holzmann K, et al. Peripheral monocytes are functionally altered and invade the CNS in ALS patients. Acta Neuropathol. 2016;132:391–411.CrossRefPubMed
30.
Zhao W, Beers DR, Hooten KG, Sieglaff DH, Zhang A, Kalyana-Sundaram S, Traini CM, Halsey WS, Hughes AM, Sathe GM, et al. Characterization of gene expression phenotype in amyotrophic lateral sclerosis monocytes. JAMA Neurol. 2017.
31.
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.CrossRefPubMed
32.
Mantovani S, Garbelli S, Pasini A, Alimonti D, Perotti C, Melazzini M, Bendotti C, Mora G. Immune system alterations in sporadic amyotrophic lateral sclerosis patients suggest an ongoing neuroinflammatory process. J Neuroimmunol. 2009;210:73–9.CrossRefPubMed
33.
Jung H, Bhangoo S, Banisadr G, Freitag C, Ren D, White FA, Miller RJ. Visualization of chemokine receptor activation in transgenic mice reveals peripheral activation of CCR2 receptors in states of neuropathic pain. J Neurosci. 2009;29:8051–62.CrossRefPubMedPubMedCentral
34.
Painz R, Walter I, Kolbe T, Rigler D, Vogl C, Steinborn R, Rulicke T, Helmreich M, Karaghiosoff M, Muller M. Organ-specific and differential requirement of TYK2 and IFNAR1 for LPS-induced iNOS expression in vivo. Immunobiology. 2007;212:863–75.CrossRefPubMed
35.
Paxinos G, Franklin KBJ. The mouse brain in stereotaxic coordinates. 2nd ed. San Diego: Academic; 2001.
36.
Boche D, Perry VH, Nicoll JA. Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol. 2013;39:3–18.CrossRefPubMed
37.
Udaka F, Kameyama M, Tomonaga M. Degeneration of Betz cells in motor neuron disease. A Golgi study. Acta Neuropathol. 1986;70:289–95.CrossRefPubMed
38.
Boillee S, Vande Velde C, Cleveland DW. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron. 2006;52:39–59.CrossRefPubMed
39.
40.
Jara JH, Genc B, Klessner JL, Ozdinler PH. Retrograde labeling, transduction, and genetic targeting allow cellular analysis of corticospinal motor neurons: implications in health and disease. Front Neuroanat. 2014;8:16.CrossRefPubMedPubMedCentral
41.
42.
Lewis KE, Rasmussen AL, Bennett W, King A, West AK, Chung RS, Chuah MI. Microglia and motor neurons during disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis: changes in arginase1 and inducible nitric oxide synthase. J Neuroinflammation. 2014;11:55.CrossRefPubMedPubMedCentral
43.
Genc B, Jara JH, Lagrimas AKB, Pytel P, Roos RP, Mesulam MM, Geula C, Bigio EH, Ozdinler PH. Apical dendrite degeneration, a novel cellular pathology for Betz cells in ALS Scientific Reports. 2017;7:41765.
44.
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 Neuroimmunol. 2010;222:76–81.CrossRefPubMed
45.
Gupta PK, Prabhakar S, Sharma S, Anand A. Vascular endothelial growth factor-A (VEGF-A) and chemokine ligand-2 (CCL2) in amyotrophic lateral sclerosis (ALS) patients. J Neuroinflammation. 2011;8:47.CrossRefPubMedPubMedCentral
46.
Butovsky O, Jedrychowski MP, Cialic R, Krasemann S, Murugaiyan G, Fanek Z, Greco DJ, Wu PM, Doykan CE, Kiner O, et al. Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann Neurol. 2015;77:75–99.CrossRefPubMed
47.
Gupta PK, Prabhakar S, Sharma NK, Anand A. Possible association between expression of chemokine receptor-2 (CCR2) and amyotrophic lateral sclerosis (ALS) patients of North India. PLoS ONE. 2012;7:e38382.CrossRefPubMedPubMedCentral
48.
Mitchell RM, Simmons Z, Beard JL, Stephens HE, Connor JR. Plasma biomarkers associated with ALS and their relationship to iron homeostasis. Muscle Nerve. 2010;42:95–103.CrossRefPubMed
49.
Kunis G, Baruch K, Miller O, Schwartz M. Immunization with a myelin-derived antigen activates the brain’s choroid plexus for recruitment of immunoregulatory cells to the CNS and attenuates disease progression in a mouse model of ALS. J Neurosci. 2015;35:6381–93.CrossRefPubMed
50.
Sierra A, Abiega O, Shahraz A, Neumann H. Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis. Front Cell Neurosci. 2013;7:6.CrossRefPubMedPubMedCentral
51.
Pasetto L, Pozzi S, Castelnovo M, Basso M, Estevez AG, Fumagalli S, De Simoni MG, Castellaneta V, Bigini P, Restelli E, et al. Targeting extracellular cyclophilin a reduces neuroinflammation and extends survival in a mouse model of amyotrophic lateral sclerosis. J Neurosci. 2017;37:1413–27.CrossRefPubMed
52.
Kawaguchi-Niida M, Yamamoto T, Kato Y, Inose Y, Shibata N. MCP-1/CCR2 signaling-mediated astrocytosis is accelerated in a transgenic mouse model of SOD1-mutated familial ALS. Acta Neuropathol Commun. 2013;1:21.CrossRefPubMedPubMedCentral
53.
Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, Hilton JF, Spitalny GM, MacArthur RB, Mitsumoto H, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol. 2007;6:1045–53.CrossRefPubMed
54.
Stommel EW, Cohen JA, Fadul CE, Cogbill CH, Graber DJ, Kingman L, Mackenzie T, Channon Smith JY, Harris BT. Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: a phase II open label clinical trial. Amyotroph Lateral Scler. 2009;10:393–404.CrossRefPubMed
55.
Cudkowicz ME, Shefner JM, Schoenfeld DA, Zhang H, Andreasson KI, Rothstein JD, Drachman DB. Trial of celecoxib in amyotrophic lateral sclerosis. Ann Neurol. 2006;60:22–31.CrossRefPubMed
56.
Miller RG, Block G, Katz JS, Barohn RJ, Gopalakrishnan V, Cudkowicz M, Zhang JR, McGrath MS, Ludington E, Appel SH, et al. Randomized phase 2 trial of NP001-a novel immune regulator: safety and early efficacy in ALS. Neurol Neuroimmunol Neuroinflamm. 2015;2, e100.CrossRefPubMedPubMedCentral
57.
Lunetta C, Lizio A, Maestri E, Sansone VA, Mora G, Miller RG, Appel SH, Chio A. Serum C-reactive protein as a prognostic biomarker in amyotrophic lateral sclerosis. JAMA Neurol. 2017.
Metadata
Title
Evidence for an early innate immune response in the motor cortex of ALS
Authors
Javier H. Jara
Barış Genç
Macdonell J. Stanford
Peter Pytel
Raymond P. Roos
Sandra Weintraub
M. Marsel Mesulam
Eileen H. Bigio
Richard J. Miller
P. Hande Özdinler
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/s12974-017-0896-4

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