title: Early pro-inflammatory cytokine elevations in the DBA/2J mouse model of glaucoma.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmaceutical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA. gwilso12@kent.edu.|Biomedical Sciences Graduate Program, Kent State University, 800 E. Summit Street, Kent, OH, 44240, USA. gwilso12@kent.edu.
authors.forename: Gina N
authors.initials: GN
authors.lastname: Wilson
authors.affiliation: Department of Pharmaceutical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA. dinman@neomed.edu.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Inman
authors.affiliation: Department of Pharmaceutical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA. ccrish@neomed.edu.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Dengler Crish
authors.forename: Christine M
authors.initials: CM
authors.lastname: Denger-Crish
authors.affiliation: Department of Pharmaceutical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA. msmith13@neomed.edu.|Integrated Pharmaceutical Medicine Graduate Program, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA. msmith13@neomed.edu.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Department of Pharmaceutical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA. scrish@neomed.edu.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Crish
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D002772:Cholera Toxin / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005901:Glaucoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D042282:Microdissection; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D014795:Visual Pathways / Q000378:metabolism* / Q000473:pathology
chemical_list: D016207:Cytokines; D005136:Eye Proteins; C445671:Gpnmb protein, mouse; D008562:Membrane Glycoproteins; D016222:Fibroblast Growth Factor 2; D002772:Cholera Toxin