Modulation of Post-Traumatic Immune Response Using the IL-1 Receptor Antagonist Anakinra for Improved Visual Outcomes
Open Access
- 15 June 2020
- journal article
- research article
- Published by Mary Ann Liebert Inc in Journal of Neurotrauma
- Vol. 37 (12), 1463-1480
- https://doi.org/10.1089/neu.2019.6725
Abstract
The purpose of this study was to characterize acute changes in inflammatory pathways in the mouse eye after blast-mediated traumatic brain injury (bTBI) and to determine whether modulation of these pathways could protect the structure and function of retinal ganglion cells (RGC). The bTBI was induced in C57BL/6J male mice by exposure to three 20 psi blast waves directed toward the head with the body shielded, with an inter-blast interval of one hour. Acute cytokine expression in retinal tissue was measured through reverse transcription-quantitative polymerase chain reaction (RT-qPCR) four hours post-blast. Increased retinal expression of interleukin (lL)-1β, IL-1α, IL-6, and tumor necrosis factor (TNF)α was observed in bTBI mice exposed to blast when compared with shams, which was associated with activation of microglia and macroglia reactivity, assessed via immunohistochemistry with ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein, respectively, one week post-blast. Blockade of the IL-1 pathway was accomplished using anakinra, an IL-1RI antagonist, administered intra-peritoneally for one week before injury and continuing for three weeks post-injury. Retinal function and RGC layer thickness were evaluated four weeks post-injury using pattern electroretinogram (PERG) and optical coherence tomography (OCT), respectively. After bTBI, anakinra treatment resulted in a preservation of RGC function and RGC structure when compared with saline treated bTBI mice. Optic nerve integrity analysis demonstrated a trend of decreased damage suggesting that IL-1 blockade also prevents axonal damage after blast. Blast exposure results in increased retinal inflammation including upregulation of pro-inflammatory cytokines and activation of resident microglia and macroglia. This may explain partially the RGC loss we observed in this model, as blockade of the acute inflammatory response after injury with the IL-1R1 antagonist anakinra resulted in preservation of RGC function and RGC layer thickness.Keywords
This publication has 63 references indexed in Scilit:
- Characterization of structure and function of the mouse retina using pattern electroretinography, pupil light reflex, and optical coherence tomographyVeterinary Ophthalmology, 2012
- Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucomaJCI Insight, 2011
- Anterior Segment Dysgenesis and Early-Onset Glaucoma inneeMice with Mutation ofSh3pxd2bInvestigative Ophthalmology & Visual Science, 2011
- Cerebrocerebellar hypometabolism associated with repetitive blast exposure mild traumatic brain injury in 12 Iraq war Veterans with persistent post-concussive symptomsNeuroImage, 2011
- Intravenous Anakinra can Achieve Experimentally Effective Concentrations in the Central Nervous System within a Therapeutic Time Window: Results of a Dose-Ranging StudyJournal of Cerebral Blood Flow & Metabolism, 2010
- The importance of systemic response in the pathobiology of blast-induced neurotraumaFrontiers in Neurology, 2010
- Systemic inflammation exacerbates behavioral and histopathological consequences of isolated traumatic brain injury in ratsExperimental Neurology, 2008
- Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucomaThe Journal of cell biology, 2007
- Interleukin-1 and neuronal injuryNature Reviews Immunology, 2005
- The interleukin 1 receptor familyDevelopmental & Comparative Immunology, 2003