Abstract
It is well established that the immunization with ocular antigens causes a retinal ganglion cell (RGC) decline, which is accompanied by glia alterations. In this study, the degenerative effects of the immunization with an optic nerve homogenate (ONA) and its purified compound S100 were analyzed on retinas and optic nerves. Since a participation of glia cells in cell death mechanisms is currently discussed, rats were immunized with S100 or ONA. At 14 and 28 days, immune-histological and Western blot analyses were performed to investigate the optic nerve structure (SMI-32), retinal ganglion cells (Brn-3a), apoptosis (cleaved caspase 3, FasL), and glial profile (Iba1, ED1, GFAP, vimentin). Neurofilament dissolution in S100 animals was evident at 14 days (p = 0.047) and increased at 28 days (p = 0.01). ONA optic nerves remained intact at early stages and degenerated later on (p = 0.002). In both groups, RGC loss was detected via immune-histology and Western blot at 28 days (ONA: p = 0.02; S100: p = 0.005). Additionally, more Iba1+ retinal microglia could be detected at early stages (ONA: p = 0.006; S100: p = 0.028). A slight astrocyte response was detected on Western blots only on ONA retinas (p = 0.01). Hence, the RGC and optic nerve decline was partly antigen dependent, while neuronal loss is paralleled by an early microglial response.
Similar content being viewed by others
References
Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69
Boehm N, Wolters D, Thiel U, Lossbrand U, Wiegel N, Pfeiffer N, Grus FH (2012) New insights into autoantibody profiles from immune privileged sites in the eye: a glaucoma study. Brain Behav Immun 26:96–102
Caporale CM, Capasso M, Luciani M, Prencipe V, Creati B, Gandolfi P, De Angelis MV, Di Muzio A, Caporale V, Uncini A (2006) Experimental axonopathy induced by immunization with Campylobacter jejuni lipopolysaccharide from a patient with Guillain-Barre syndrome. J Neuroimmunol 174:12–20
Casola C, Schiwek JE, Reinehr S, Kuehn S, Grus FH, Kramer M, Dick HB, Joachim SC. 2015. S100 alone has the same destructive effect on retinal ganglion cells as in combination with HSP 27 in an autoimmune glaucoma model. J Mol Neurosci.
Choi C, Benveniste EN (2004) Fas ligand/Fas system in the brain: regulator of immune and apoptotic responses. Brain Res Brain Res Rev 44:65–81
Coleman M (2005) Axon degeneration mechanisms: commonality amid diversity. Nat Rev Neurosci 6:889–898
Ebneter A, Casson RJ, Wood JP, Chidlow G (2010) Microglial activation in the visual pathway in experimental glaucoma: spatiotemporal characterization and correlation with axonal injury. Invest Ophthalmol Vis Sci 51:6448–6460
Gao HM, Jiang J, Wilson B, Zhang W, Hong JS, Liu B (2002) Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson’s disease. J Neurochem 81:1285–1297
Graeber MB, Streit WJ, Kiefer R, Schoen SW, Kreutzberg GW (1990) New expression of myelomonocytic antigens by microglia and perivascular cells following lethal motor neuron injury. J Neuroimmunol 27:121–132
Gregory MS, Hackett CG, Abernathy EF, Lee KS, Saff RR, Hohlbaum AM, Moody KS, Hobson MW, Jones A, Kolovou P and others. 2011. Opposing roles for membrane bound and soluble Fas ligand in glaucoma-associated retinal ganglion cell death. PLoS One 6:e17659.
Grus FH, Boehm N, Beck S, Schlich M, Lossbrandt U, Pfeiffer N (2010) Autoantibody profiles in tear fluid as a diagnostic tool in glaucoma. Invest Ophthalmol Vis Sci 51:6110
Grus FH, Joachim SC, Hoffmann EM, Pfeiffer N (2004) Complex autoantibody repertoires in patients with glaucoma. Mol Vis 10:132–137
Grus FH, Joachim SC, Wuenschig D, Rieck J, Pfeiffer N (2008) Autoimmunity and glaucoma. J Glaucoma 17:79–84
Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394
Horstmann L, Schmid H, Heinen AP, Kurschus FC, Dick B, Joachim SC (2013) Inflammatory demyelination induces glia alterations and ganglion cell loss in the retina of anexperimental autoimmune encephalomyelitis model. J Neuroinflammation 10:120
Joachim SC, Gramlich OW, Laspas P, Schmid H, Beck S, von Pein HD, Dick HB, Pfeiffer N, Grus FH (2012) Retinal ganglion cell loss is accompanied by antibody depositions and increased levels of microglia after immunization with retinal antigens. PLoS One 7:e40616
Joachim SC, Mondon C, Gramlich OW, Grus FH, Dick HB (2014) Apoptotic retinal ganglion cell death in an autoimmune glaucoma model is accompanied by antibody depositions. J Mol Neurosci 52:216–224
Joachim SC, Reinehr S, Kuehn S, Laspas P, Gramlich OW, Kuehn M, Tischoff I, von Pein HD, Dick HB, Grus FH (2013) Immune response against ocular tissues after immunization with optic nerve antigens in a model of autoimmune glaucoma. Mol Vis 19:1804–1814
Ju KR, Kim HS, Kim JH, Lee NY, Park CK (2006) Retinal glial cell responses and Fas/FasL activation in rats with chronic ocular hypertension. Brain Res 1122:209–221
Laspas P, Gramlich OW, Muller HD, Cuny CS, Gottschling PF, Pfeiffer N, Dick HB, Joachim SC, Grus FH (2011) Autoreactive antibodies and loss of retinal ganglion cells in rats induced by immunization with ocular antigens. Invest Ophthalmol Vis Sci 52:8835–8848
Lawson LJ, Frost L, Risbridger J, Fearn S, Perry VH (1994) Quantification of the mononuclear phagocyte response to Wallerian degeneration of the optic nerve. J Neurocytol 23:729–744
Massoll C, Mando W, Chintala SK (2013) Excitotoxicity upregulates SARM1 protein expression and promotes Wallerian-like degeneration of retinal ganglion cells and their axons. Invest Ophthalmol Vis Sci 54:2771–2780
McGeer PL, Itagaki S, Tago H, McGeer EG (1987) Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 79:195–200
Nadal-Nicolas FM, Jimenez-Lopez M, Sobrado-Calvo P, Nieto-Lopez L, Canovas-Martinez I, Salinas-Navarro M, Vidal-Sanz M, Agudo M (2009) Brn3a as a marker of retinal ganglion cells: qualitative and quantitative time course studies in naive and optic nerve-injured retinas. Invest Ophthalmol Vis Sci 50:3860–3868
Nakazawa T, Nakazawa C, Matsubara A, Noda K, Hisatomi T, She H, Michaud N, Hafezi-Moghadam A, Miller JW, Benowitz LI (2006) Tumor necrosis factor-alpha mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma. J Neurosci 26:12633–12641
Reichert F, Rotshenker S (1996) Deficient activation of microglia during optic nerve degeneration. J Neuroimmunol 70:153–161
Reinehr S, Becker S, Kuehn S, Casola C, Noristani R, Dick B, Joachim S (2013) Activation of the complement system in an autoimmune model of glaucoma. Invest Ophthalmol Vis Sci 54:753
Ridet JL, Malhotra SK, Privat A, Gage FH (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20:570–577
Rothermundt M, Peters M, Prehn JH, Arolt V (2003) S100B in brain damage and neurodegeneration. Microsc Res Tech 60:614–632
Salinas-Navarro M, Alarcon-Martinez L, Valiente-Soriano FJ, Jimenez-Lopez M, Mayor-Torroglosa S, Aviles-Trigueros M, Villegas-Perez MP, Vidal-Sanz M (2010) Ocular hypertension impairs optic nerve axonal transport leading to progressive retinal ganglion cell degeneration. Exp Eye Res 90:168–183
Sasaki Y, Ohsawa K, Kanazawa H, Kohsaka S, Imai Y (2001) Iba1 is an actin-cross-linking protein in macrophages/microglia. Biochem Biophys Res Commun 286:292–297
Schlamp CL, Li Y, Dietz JA, Janssen KT, Nickells RW (2006) Progressive ganglion cell loss and optic nerve degeneration in DBA/2J mice is variable and asymmetric. BMC Neurosci 7:66
Son JL, Soto I, Oglesby E, Lopez-Roca T, Pease ME, Quigley HA, Marsh-Armstrong N (2010) Glaucomatous optic nerve injury involves early astrocyte reactivity and late oligodendrocyte loss. Glia 58:780–789
Streit WJ (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40:133–139
Sucher NJ, Lipton SA, Dreyer EB (1997) Molecular basis of glutamate toxicity in retinal ganglion cells. Vis Res 37:3483–3493
Svajger U, Obermajer N, Jeras M. 2013. IFN-gamma-rich environment programs dendritic cells toward silencing of cytotoxic immune responses. J Leukoc Biol.
Takeuchi H, Wang J, Kawanokuchi J, Mitsuma N, Mizuno T, Suzumura A (2006) Interferon-gamma induces microglial-activation-induced cell death: a hypothetical mechanism of relapse and remission in multiple sclerosis. Neurobiol Dis 22:33–39
Tezel G (2008) TNF-alpha signaling in glaucomatous neurodegeneration. Prog Brain Res 173:409–421
Tezel G (2011) The immune response in glaucoma: a perspective on the roles of oxidative stress. Exp Eye Res 93:178–186
Vidal-Sanz M, Salinas-Navarro M, Nadal-Nicolas FM, Alarcon-Martinez L, Valiente-Soriano FJ, de Imperial JM, Aviles-Trigueros M, Agudo-Barriuso M, Villegas-Perez MP (2012) Understanding glaucomatous damage: anatomical and functional data from ocular hypertensive rodent retinas. Prog Retin Eye Res 31:1–27
Wang J, Hamm RJ, Povlishock JT (2011) Traumatic axonal injury in the optic nerve: evidence for axonal swelling, disconnection, dieback, and reorganization. J Neurotrauma 28:1185–1198
Wang X, Ng YK, Tay SS (2005) Factors contributing to neuronal degeneration in retinas of experimental glaucomatous rats. J Neurosci Res 82:674–689
Wang X, Tay SS, Ng YK (2000) An immunohistochemical study of neuronal and glial cell reactions in retinae of rats with experimental glaucoma. Exp Brain Res 132:476–484
Wax MB, Tezel G (2009) Immunoregulation of retinal ganglion cell fate in glaucoma. Exp Eye Res 88:825–830
Wax MB, Tezel G, Kawase K, Kitazawa Y (2001) Serum autoantibodies to heat shock proteins in glaucoma patients from Japan and the United States. Ophthalmology 108:296–302
Wu KH, Madigan MC, Billson FA, Penfold PL (2003) Differential expression of GFAP in early v late AMD: a quantitative analysis. Br J Ophthalmol 87:1159–1166
Xu H, Forrester JV, Liversidge J, Crane IJ (2003) Leukocyte trafficking in experimental autoimmune uveitis: breakdown of blood-retinal barrier and upregulation of cellular adhesion molecules. Invest Ophthalmol Vis Sci 44:226–234
Xu H, Manivannan A, Goatman KA, Jiang HR, Liversidge J, Sharp PF, Forrester JV, Crane IJ (2004) Reduction in shear stress, activation of the endothelium, and leukocyte priming are all required for leukocyte passage across the blood–retina barrier. J Leukoc Biol 75:224–232
Acknowledgments
This work was supported by the German Research Foundation (DFG, grant JO-886/1-1 and 1-3).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The experiments were carried out in conformity with the ARVO statement for the use of animals in ophthalmic and vision research. The study was approved by the animal care committee of North Rhine-Westphalia (Germany; file reference AZ 87-51.04.2010.A382).
Conflict of Interest
The authors declare that they have no competing interests.
Additional information
Rozina Noristani and Sandra Kuehn contributed equally to this work.
Rights and permissions
About this article
Cite this article
Noristani, R., Kuehn, S., Stute, G. et al. Retinal and Optic Nerve Damage is Associated with Early Glial Responses in an Experimental Autoimmune Glaucoma Model. J Mol Neurosci 58, 470–482 (2016). https://doi.org/10.1007/s12031-015-0707-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-015-0707-2