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

Open Access 01-12-2017 | Research

Neuronal CCL2 expression drives inflammatory monocyte infiltration into the brain during acute virus infection

Authors: Charles L. Howe, Reghann G. LaFrance-Corey, Emma N. Goddery, Renee K. Johnson, Kanish Mirchia

Published in: Journal of Neuroinflammation | Issue 1/2017

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Abstract

Background

Viral encephalitis is a dangerous compromise between the need to robustly clear pathogen from the brain and the need to protect neurons from bystander injury. Theiler’s murine encephalomyelitis virus (TMEV) infection of C57Bl/6 mice is a model of viral encephalitis in which the compromise results in hippocampal damage and permanent neurological sequelae. We previously identified brain-infiltrating inflammatory monocytes as the primary driver of this hippocampal pathology, but the mechanisms involved in recruiting these cells to the brain were unclear.

Methods

Chemokine expression levels in the hippocampus were assessed by microarray, ELISA, RT-PCR, and immunofluorescence. Monocyte infiltration during acute TMEV infection was measured by flow cytometry. CCL2 levels were manipulated by immunodepletion and by specific removal from neurons in mice generated by crossing a line expressing the Cre recombinase behind the synapsin promoter to animals with floxed CCL2.

Results

Inoculation of the brain with TMEV induced hippocampal production of the proinflammatory chemokine CCL2 that peaked at 6 h postinfection, whereas inoculation with UV-inactivated TMEV did not elicit this response. Immunofluorescence revealed that hippocampal neurons expressed high levels of CCL2 at this timepoint. Genetic deletion of CCR2 and systemic immunodepletion of CCL2 abrogated or blunted the infiltration of inflammatory monocytes into the brain during acute infection. Specific genetic deletion of CCL2 from neurons reduced serum and hippocampal CCL2 levels and inhibited inflammatory monocyte infiltration into the brain.

Conclusions

We conclude that intracranial inoculation with infectious TMEV rapidly induces the expression of CCL2 in neurons, and this cellular source is necessary for CCR2-dependent infiltration of inflammatory monocytes into the brain during the most acute stage of encephalitis. These findings highlight a unique role for neuronal production of chemokines in the initiation of leukocytic infiltration into the infected central nervous system.
Literature
1.
Shives KD, Tyler KL, Beckham JD. Molecular mechanisms of neuroinflammation and injury during acute viral encephalitis. J Neuroimmunol. 2017;308:102–11.CrossRefPubMed
2.
Buenz EJ, Rodriguez M, Howe CL. Disrupted spatial memory is a consequence of picornavirus infection. Neurobiol Dis. 2006;24:266–73.CrossRefPubMed
3.
DePaula-Silva AB, Hanak TJ, Libbey JE, Fujinami RS. Theiler’s murine encephalomyelitis virus infection of SJL/J and C57BL/6J mice: models for multiple sclerosis and epilepsy. J Neuroimmunol. 2017;308:30–42.CrossRefPubMed
4.
Howe CL, Lafrance-Corey RG, Sundsbak RS, Lafrance SJ. Inflammatory monocytes damage the hippocampus during acute picornavirus infection of the brain. J Neuroinflammation. 2012;9:50.CrossRefPubMedPubMedCentral
5.
Umpierre AD, Remigio GJ, Dahle EJ, Bradford K, Alex AB, Smith MD, West PJ, White HS, Wilcox KS. Impaired cognitive ability and anxiety-like behavior following acute seizures in the Theiler’s virus model of temporal lobe epilepsy. Neurobiol Dis. 2014;64:98–106.CrossRefPubMedPubMedCentral
6.
Broer S, Hage E, Kaufer C, Gerhauser I, Anjum M, Li L, Baumgartner W, Schulz TF, Loscher W. Viral mouse models of multiple sclerosis and epilepsy: marked differences in neuropathogenesis following infection with two naturally occurring variants of Theiler’s virus BeAn strain. Neurobiol Dis. 2016;99:121–32.CrossRefPubMed
7.
Howe CL, LaFrance-Corey RG, Mirchia K, Sauer BM, McGovern RM, Reid JM, Buenz EJ. Neuroprotection mediated by inhibition of calpain during acute viral encephalitis. Sci Rep. 2016;6:28699.CrossRefPubMedPubMedCentral
8.
Howe CL, Lafrance-Corey RG, Sundsbak RS, Sauer BM, Lafrance SJ, Buenz EJ, Schmalstieg WF. Hippocampal protection in mice with an attenuated inflammatory monocyte response to acute CNS picornavirus infection. Sci Rep. 2012;2:545.CrossRefPubMedPubMedCentral
9.
Cusick MF, Libbey JE, Doty DJ, DePaula-Silva AB, Fujinami RS. The role of peripheral interleukin-6 in the development of acute seizures following virus encephalitis. J Neurovirol. 2017;23:696-703.
10.
Cusick MF, Libbey JE, Patel DC, Doty DJ, Fujinami RS. Infiltrating macrophages are key to the development of seizures following virus infection. J Virol. 2013;87:1849–60.CrossRefPubMedPubMedCentral
11.
Patel DC, Wallis G, Dahle EJ, McElroy PB, Thomson KE, Tesi RJ, Szymkowski DE, West PJ, Smeal RM, Patel M, et al. Hippocampal TNFalpha signaling contributes to seizure generation in an infection-induced mouse model of limbic epilepsy. eNeuro. 2017;4. doi:10.​1523/​ENEURO.​0105-17.​2017.
12.
Cerri C, Caleo M, Bozzi Y. Chemokines as new inflammatory players in the pathogenesis of epilepsy. Epilepsy Res. 2017;136:77–83.CrossRefPubMed
13.
Chu HX, Arumugam TV, Gelderblom M, Magnus T, Drummond GR, Sobey CG. Role of CCR2 in inflammatory conditions of the central nervous system. J Cereb Blood Flow Metab. 2014;34:1425-9.
14.
Lim JK, Obara CJ, Rivollier A, Pletnev AG, Kelsall BL, Murphy PM. Chemokine receptor Ccr2 is critical for monocyte accumulation and survival in West Nile virus encephalitis. J Immunol. 2011;186:471–8.CrossRefPubMed
15.
Bardina SV, Michlmayr D, Hoffman KW, Obara CJ, Sum J, Charo IF, Lu W, Pletnev AG, Lim JK. Differential roles of chemokines CCL2 and CCL7 in monocytosis and leukocyte migration during West Nile virus infection. J Immunol. 2015;195:4306–18.CrossRefPubMedPubMedCentral
16.
Kim JH, Patil AM, Choi JY, Kim SB, Uyangaa E, Hossain FM, Park SY, Lee JH, Kim K, Eo SK. CCL2, but not its receptor, is essential to restrict immune privileged CNS-invasion of Japanese encephalitis virus via regulating accumulation of CD11b Ly-6C monocytes. Immunology. 2016;
17.
Chen BP, Kuziel WA, Lane TE. Lack of CCR2 results in increased mortality and impaired leukocyte activation and trafficking following infection of the central nervous system with a neurotropic coronavirus. J Immunol. 2001;167:4585–92.CrossRefPubMed
18.
Held KS, Chen BP, Kuziel WA, Rollins BJ, Lane TE. Differential roles of CCL2 and CCR2 in host defense to coronavirus infection. Virology. 2004;329:251–60.CrossRefPubMed
19.
Menasria R, Canivet C, Piret J, Gosselin J, Boivin G. Both cerebral and hematopoietic deficiencies in CCR2 result in uncontrolled herpes simplex virus infection of the central nervous system in mice. PLoS One. 2016;11:e0168034.CrossRefPubMedPubMedCentral
20.
Lafrance-Corey RG, Howe CL. Isolation of brain-infiltrating leukocytes. J Vis Exp. 2011;52:2747.
21.
Conductier G, Blondeau N, Guyon A, Nahon JL, Rovere C. The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. J Neuroimmunol. 2010;224:93–100.CrossRefPubMed
22.
Buenz EJ, Sauer BM, Lafrance-Corey RG, Deb C, Denic A, German CL, Howe CL. Apoptosis of hippocampal pyramidal neurons is virus independent in a mouse model of acute neurovirulent picornavirus infection. Am J Pathol. 2009;175:668–84.CrossRefPubMedPubMedCentral
23.
Proudfoot AE. Chemokine receptors: multifaceted therapeutic targets. Nat Rev Immunol. 2002;2:106–15.CrossRefPubMed
24.
Shi C, Jia T, Mendez-Ferrer S, Hohl TM, Serbina NV, Lipuma L, Leiner I, Li MO, Frenette PS, Pamer EG. Bone marrow mesenchymal stem and progenitor cells induce monocyte emigration in response to circulating toll-like receptor ligands. Immunity. 2011;34:590–601.CrossRefPubMedPubMedCentral
25.
Zhu Y, Romero MI, Ghosh P, Ye Z, Charnay P, Rushing EJ, Marth JD, Parada LF. Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes Dev. 2001;15:859–76.CrossRefPubMedPubMedCentral
26.
Zhang J, Lipton HL, Perelson AS, Dahari H. Modeling the acute and chronic phases of Theiler murine encephalomyelitis virus infection. J Virol. 2013;87:4052–9.CrossRefPubMedPubMedCentral
27.
Harris KG, Coyne CB. Enter at your own risk: how enteroviruses navigate the dangerous world of pattern recognition receptor signaling. Cytokine. 2013;63:230–6.CrossRefPubMedPubMedCentral
28.
Christensen JE, Simonsen S, Fenger C, Sorensen MR, Moos T, Christensen JP, Finsen B, Thomsen AR. Fulminant lymphocytic choriomeningitis virus-induced inflammation of the CNS involves a cytokine-chemokine-cytokine-chemokine cascade. J Immunol. 2009;182:1079–87.CrossRefPubMed
29.
Michlmayr D, McKimmie CS, Pingen M, Haxton B, Mansfield K, Johnson N, Fooks AR, Graham GJ. Defining the chemokine basis for leukocyte recruitment during viral encephalitis. J Virol. 2014;88:9553–67.CrossRefPubMedPubMedCentral
30.
Zhou Y, Tang H, Xiong H. Chemokine CCL2 enhances NMDA receptor-mediated excitatory postsynaptic current in rat hippocampal slices-a potential mechanism for HIV-1-associated neuropathy? J NeuroImmune Pharmacol. 2016;11:306–15.CrossRefPubMedPubMedCentral
31.
Libbey JE, Hanak TJ, Doty DJ, Wilcox KS, Fujinami RS. NBQX, a highly selective competitive antagonist of AMPA and KA ionotropic glutamate receptors, increases seizures and mortality following picornavirus infection. Exp Neurol. 2016;280:89–96.CrossRefPubMedPubMedCentral
32.
Smeal RM, Stewart KA, Iacob E, Fujinami RS, White HS, Wilcox KS. The activity within the CA3 excitatory network during Theiler’s virus encephalitis is distinct from that observed during chronic epilepsy. J Neuro-Oncol. 2012;18:30–44.
33.
Moser EI, Kropff E, Moser MB. Place cells, grid cells, and the brain’s spatial representation system. Annu Rev Neurosci. 2008;31:69–89.CrossRefPubMed
34.
Capogna M. Neurogliaform cells and other interneurons of stratum lacunosum-moleculare gate entorhinal-hippocampal dialogue. J Physiol. 2011;589:1875–83.CrossRefPubMed
35.
Price CJ, Cauli B, Kovacs ER, Kulik A, Lambolez B, Shigemoto R, Capogna M. Neurogliaform neurons form a novel inhibitory network in the hippocampal CA1 area. J Neurosci. 2005;25:6775–86.CrossRefPubMed
36.
Fuentealba P, Klausberger T, Karayannis T, Suen WY, Huck J, Tomioka R, Rockland K, Capogna M, Studer M, Morales M, Somogyi P. Expression of COUP-TFII nuclear receptor in restricted GABAergic neuronal populations in the adult rat hippocampus. J Neurosci. 2010;30:1595–609.CrossRefPubMedPubMedCentral
37.
Jarsky T, Roxin A, Kath WL, Spruston N. Conditional dendritic spike propagation following distal synaptic activation of hippocampal CA1 pyramidal neurons. Nat Neurosci. 2005;8:1667–76.CrossRefPubMed
38.
39.
Tian DS, Peng J, Murugan M, Feng LJ, Liu JL, Eyo UB, Zhou LJ, Mogilevsky R, Wang W, Wu LJ. Chemokine CCL2-CCR2 signaling induces neuronal cell death via STAT3 activation and IL-1beta production after status epilepticus. J Neurosci. 2017;37:7878–92.CrossRefPubMed
40.
Foresti ML, Arisi GM, Katki K, Montanez A, Sanchez RM, Shapiro LA. Chemokine CCL2 and its receptor CCR2 are increased in the hippocampus following pilocarpine-induced status epilepticus. J Neuroinflammation. 2009;6:40.CrossRefPubMedPubMedCentral
41.
Wang C, Yang L, Zhang J, Lin Z, Qi J, Duan S. Higher expression of monocyte chemoattractant protein 1 and its receptor in brain tissue of intractable epilepsy patients. J Clin Neurosci. 2016;28:134–40.CrossRefPubMed
42.
Choi J, Nordli DR Jr, Alden TD, DiPatri A Jr, Laux L, Kelley K, Rosenow J, Schuele SU, Rajaram V, Koh S. Cellular injury and neuroinflammation in children with chronic intractable epilepsy. J Neuroinflammation. 2009;6:38.CrossRefPubMedPubMedCentral
43.
Cerri C, Genovesi S, Allegra M, Pistillo F, Puntener U, Guglielmotti A, Perry VH, Bozzi Y, Caleo M. The chemokine CCL2 mediates the seizure-enhancing effects of systemic inflammation. J Neurosci. 2016;36:3777–88.CrossRefPubMed
Metadata
Title
Neuronal CCL2 expression drives inflammatory monocyte infiltration into the brain during acute virus infection
Authors
Charles L. Howe
Reghann G. LaFrance-Corey
Emma N. Goddery
Renee K. Johnson
Kanish Mirchia
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/s12974-017-1015-2

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