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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

Early pro-inflammatory cytokine elevations in the DBA/2J mouse model of glaucoma

Authors: Gina N. Wilson, Denise M. Inman, Christine M. Dengler-Crish, Matthew A. Smith, Samuel D. Crish

Published in: Journal of Neuroinflammation | Issue 1/2015

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Abstract

Background

Neuroinflammation—astrogliosis, microglial activation, and changes in cytokine signaling—is a prominent feature of neurodegenerative disorders. Glaucoma is a group of chronic neurodegenerative conditions that make up the leading cause of irreversible blindness worldwide. Neuroinflammation has been postulated to play a significant role in the pathogenesis and progression of glaucomatous neurodegeneration. Though much is known regarding inflammation in the eye in glaucoma, little is known about cytokine activity outside of the retina where pathologies develop early.

Methods

We traced the primary visual projection from the eye to the superior colliculus (SC) in DBA/2J and DBA/2J.Gpnmb + (control) mice using the anterograde tracer cholera toxin-B (CTB) to assay axonal transport deficits. Forty-eight hours later, visual structures were microdissected from fresh tissue based on transport outcome. Using magnetic bead multiplexing assays, we measured levels of 20 cytokines in the retina, proximal and distal optic nerves, CTB-positive and negative SC subdivisions, cerebellum, and serum at different ages representing different stages of pathology.

Results

Pro- and anti-inflammatory cytokine levels in mice often changed in the same direction based on strain, age, and tissue. Significant elevations in retinal pro-inflammatory cytokines were observed in young DBA/2J mice compared to controls, followed by an age-dependent decrease in the DBA/2J mice. Proximal optic nerve of young DBA/2J mice showed a 50 % or greater decrease in levels of certain cytokines compared to older DBA/2J cohorts and controls, while both proximal and distal optic nerve of DBA/2Js showed elevations in IL-1β at all ages compared to controls. Pro-inflammatory cytokine IL-6 levels varied in accordance with transport outcome in the SC: IL-6 was elevated 44–80 % in glaucomatous DBA/2J collicular regions deficient in anterograde transport from retinal ganglion cells (RGCs) compared to areas with intact transport.

Conclusion

Dysregulation of cytokine signaling in the RGC projection of DBA/2J mice was evident early in distal retinal targets, well before intraocular pressure elevation or axonal degeneration begins.
Literature
1.
Adalbert R, Nogradi A, Babetto E, Janeckova L, Walker SA, Kerschensteiner M, et al. Severely dystrophic axons at amyloid plaques remain continuous and connected to viable cell bodies. Brain. 2009;132(Pt2):402–16.PubMed
2.
3.
Anderson DR, Hendrickson A. Effect of intraocular pressure on rapid axoplasmic transport in monkey optic nerve. Invest Ophthalmol Vis Sci. 1974;13(10):771–83.
4.
Crish SD, Sappington RM, Inman DM, Horner PJ, Calkins DJ. Distal axonopathy with structural persistence in glaucomatous neurodegeneration. Proc Natl Acad Sci U S A. 2010;107(11):5196–201.PubMedCentralCrossRefPubMed
5.
Minckler DS, Tso MO, Zimmerman LE. A light microscopic, autoradiographic study of axoplasmic transport in the optic nerve head during ocular hypotony, increased intraocular pressure, and papilledema. Am J Ophthalmol. 1976;82(5):741–57.CrossRefPubMed
6.
Minckler DS, Bunt AH, Johanson GW. Orthograde and retrograde axoplasmic transport during acute ocular hypertension in the monkey. Invest Ophthalmol Vis Sci. 1977;16:426–41.PubMed
7.
Dengler-Crish CM, Smith MA, Inman DM, Wilson GN, Young JW, Crish SD. Anterograde transport blockade precedes deficits in retrograde transport in the visual projection of the DBA/2J mouse model of glaucoma. Front Neurosci. 2014;8:1–12.CrossRef
8.
Crish SD, Dapper JD, Macnamee SE, Balaram P, Sidorova TN, Lambert WS, et al. Failure of axonal transport induces a spatially coincident increase in astrocyte BDNF prior to synapse loss in a central target. Neuroscience. 2013;229:55–70.PubMedCentralCrossRefPubMed
9.
Schlamp CL, Li Y, Dietz JA, Janssen KT, Nickells RW. Progressive ganglion cell loss and optic nerve degeneration in DBA/2J mice is variable and asymmetric. BMC Neruosci. 2006. doi:10.​1186/​1471-2202-7-66.
10.
Nickells RW. From ocular hypertension to ganglion cell death: a theoretical sequence of events leading to glaucoma. Can J Ophthalmol. 2007;42(2):278–87.CrossRefPubMed
11.
12.
13.
Almasieh M, Wilson AM, Morquette B, Vargas JLC, Di Polo A. The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res. 2012;31(2):152–81.CrossRefPubMed
14.
Wax MB, Tezel G, Yang J, Peng G, Patil RV, Agarwal N, et al. Induced autoimmunity to heat shock proteins elicits glaucomatous loss of retinal ganglion cell neurons via activated T-cell-derived Fas-ligand. Neurobiol Dis. 2008;28(46):12085–96.
15.
Tezel G, Thornton IL, Tong MG, Luo C, Yang X, Cai J, et al. Immunoproteomic analysis of potential serum biomarker candidates in human glaucoma. Invest Ophthalmol Vis Sci. 2012;53(13):8222–31.PubMedCentralCrossRefPubMed
16.
17.
Bosco A, Inman DM, Steele MR, Wu G, Soto I, Marsh-Amstrong N, et al. Reduced retina microglial activation and improved optic nerve integrity with minocycline treatment in the DBA/2J mouse model of glaucoma. Invest Ophthalmol Vis Sci. 2008;49(4):1437–46.CrossRefPubMed
18.
19.
MacNair CE, Fernandes KA, Schlamp CL, Libby RT, Nickells RW. Tumor necrosis factor alpha has an early protective effect on retinal ganglion cells after optic nerve crush. J Neuroinflammation. 2014;11:194.CrossRef
20.
Morzaev D, Nicholson JD, Caspi T, Weiss S, Hochhauser E, Goldenberg-Cohen N. Toll-like receptor-4 knockout mice are more resistant to optic nerve crush damage than wild-type mice. Clin Exp Ophthalmol. 2015. doi:10.​1111/​ceo.​12521.
21.
Zhou X, Li F, Kong L, Tomita H, Li C, Cao W. Involvement of inflammation, degradation and apoptosis in a mouse model of glaucoma. J Biol Chem. 2005;280:31240–8.CrossRefPubMed
22.
Kuchtey J, Rezaei KA, Jaru-Ampornpan P, Sternberg Jr P, Kuchtey RW. Multiplex cytokine analysis reveals elevated concentration of interleukin-8 in glaucomatous aqueous humor. Invest Ophthalmol Vis Sci. 2010;15(12):6441–7.CrossRef
23.
Johnson EC, Doser TA, Cepurna WO, Dyck JA, Jia L, Guo Y, et al. Cell proliferation and interleukin-6-type cytokine signaling are implicated by gene expression responses in early optic nerve head injury in rat glaucoma. Invest Ophthalmol Vis Sci. 2011;52(1):504–18.PubMedCentralCrossRefPubMed
24.
Sappington RM, Chan M, Calkins DJ. Interleukin-6 protects retinal ganglion cells from pressure-induced death. Invest Ophthalmol Vis Sci. 2006;47(7):2932–42.CrossRefPubMed
25.
Howell GR, Macalinao DG, Sousa GL, Walden M, Soto I, Kneeland SC, et al. Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. J Clin Invest. 2011;121(4):1429–44.PubMedCentralCrossRefPubMed
26.
John SWM, Smith RS, Savinova OV, Hawes NL, Chang B, Turnbull D, et al. Essential iris atrophy, pigment dispersion, and glaucoma in DBA/2J mice. Invest Ophthalmol Vis Sci. 1998;39(6):951–62.PubMed
27.
Howell GR, Libby RT, Marchant JK, Wilson LA, Cosma IM, Smith RS, et al. Absence of glaucoma in DBA/2J mice homozygous for wild-type versions of Gpnmb and Tyrp1. BMC Gen. 2007. doi:10.​1186/​1471-2156-8-45.
28.
Buckingham BP, Inman DM, Lambert W, Oglesby E, Calkins DJ, Steele MR, et al. Progressive ganglion cell degeneration precedes neuronal loss in a mouse model of glaucoma. J Neurosci. 2008;28(11):2735–44.CrossRefPubMed
29.
Lanchin JM, McGee PL, Greenbaum CJ, Palmer J, Pescovitz MD, Gottlieb P, et al. Sample size requirements for studies of treatment effects on beta-cell function in newly diagnosed type 1 diabetes. PLoS ONE. 2011;6(11):e26471.CrossRef
30.
Hageman GS, Kirchoff-Rempe MA, Lews GP, Fisher SK, Anderson DH. Sequestration of basic fibroblast growth factor in the primate retinal interphotoreceptor matrix. Proc Natl Acad Sci U S A. 1991;88:6706–10.PubMedCentralCrossRefPubMed
31.
Wen R, Song Y, Cheng T, Matthes MT, Yasumura D, LaVail MM, et al. Injury-induced upregulation of bFGF and CNTF mRNAs in the rat retina. J Neurosci. 1995;15(11):7377–85.PubMed
32.
Puro DG, Mano T. Modulation of calcium channels in human retinal glial cells by basic fibroblast growth factor: a possible role in retinal pathobiology. J Neurosci. 1991;11(6):1873–80.PubMed
33.
Neufeld AH. Microglia in the optic nerve head and the region of parapapillary chorioretinal atrophy in glaucoma. Arch Ophthalmol. 1999;117(8):1050–6.CrossRefPubMed
34.
Cuchillo-Ibanez I, Seereeram A, Byers HL, Leung KY, Ward MA, Anderton BH, et al. Phosphorylation of tau regulates its axonal transport by controlling its binding to kinesin. FASEB J. 2008;22(9):3186–95.CrossRefPubMed
35.
Huang P, Zhang S-M, Zhang C. The two sides of cytokine signaling and glaucomatous optic neuropathy. J Ocul Biol Dis Inform. 2009;2:98–103.CrossRef
36.
37.
Yan X, Tezel G, Wax MB, Edward DP. Matrix metalloproteinases and tumor necrosis factor alpha in glaucomatous optic nerve head. Arch Ophthalmol. 2000;118:666–73.CrossRefPubMed
38.
Tezel G, Li LY, Patil RV, Wax MB. Tumor necrosis factor-alpha and its receptor-1 in the retina of normal and glaucomatous eyes. Invest Ophthalmol Vis Sci. 2001;42(8):1787–94.PubMed
39.
Noda M, Takii K, Parajuli B, Kawanokuchi J, Sonobe Y, Takeuchi H, et al. FGF-2 released from degenerating neurons exerts microglial-induced neuroprotection via FGFR3-ERK signaling pathway. J Neuroinflammation. 2014. doi:10.​1186/​1742-2094-11-76.
40.
41.
42.
Falzone TL, Stokin GB, Lillo C, Rodrigues EM, Westerman EL, Williams DS, et al. Axonal stress kinase activation and tau misbehavior induced by kinesin-1 transport defects. J Neurosci. 2009;29(18):5758–67.PubMedCentralCrossRefPubMed
43.
Echevarria FD, Walker CC, Abella SK, Won M, Sappington RM. Stressor-dependent alterations in glycoprotein 130: implications for glial cell reactivity, cytokine signaling and ganglion cell health in glaucoma. J Clin Exp Ophthalmol. 2013;4(3):1–28.
44.
Chidlow G, Wood JPM, Ebneter A, Casson RJ. Interleukin-6 is an efficacious marker of axonal transport disruption during experimental glaucoma and stimulates neuritogenesis in cultured retinal ganglion cells. Neurobiol Dis. 2012;48(3):568–81.CrossRefPubMed
45.
Luterman JD, Haroutunian V, Yemul S, Ho L, Purohit D, Aisen PS, et al. Cytokine gene expression as a function of the clinical progression of Alzheimer disease dementia. Arch Neurol. 2000;57(8):1153–60.CrossRefPubMed
Metadata
Title
Early pro-inflammatory cytokine elevations in the DBA/2J mouse model of glaucoma
Authors
Gina N. Wilson
Denise M. Inman
Christine M. Dengler-Crish
Matthew A. Smith
Samuel D. Crish
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-015-0399-0

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