Deletion of Arginase 2 Ameliorates Retinal Neurodegeneration in a Mouse Model of Multiple Sclerosis

Chithra D. Palani, Abdelrahman Y. Fouda, Fang Liu, Zhimin Xu, Eslam Mohamed, Shailedra Giri, Sylvia B. Smith, Ruth B Caldwell, S. Priya Narayanan

Research output: Contribution to journalArticle

Abstract

Optic neuritis is a major clinical feature of multiple sclerosis (MS) and can lead to temporary or permanent vision loss. Previous studies from our laboratory have demonstrated the critical involvement of arginase 2 (A2) in retinal neurodegeneration in models of ischemic retinopathy. The current study was undertaken to investigate the role of A2 in MS-mediated retinal neuronal damage and degeneration. Experimental autoimmune encephalomyelitis (EAE) was induced in wild-type (WT) and A2 knockout (A2−/−) mice. EAE-induced motor deficits, loss of retinal ganglion cells, retinal thinning, inflammatory signaling, and glial activation were studied in EAE-treated WT and A2−/− mice and their respective controls. Increased expression of A2 was observed in WT retinas in response to EAE induction. EAE-induced motor deficits were markedly reduced in A2−/− mice compared with WT controls. Retinal flat mount studies demonstrated a significant reduction in the number of RGCs in WT EAE retinas in comparison with normal control mice. A significant improvement in neuronal survival was evident in retinas of EAE-induced A2−/− mice compared with WT. RNA levels of the proinflammatory molecules CCL2, COX2, IL-1α, and IL-12α were significantly reduced in the A2−/− EAE retinas compared with WT EAE. EAE-induced activation of glia (microglia and Müller cells) was markedly reduced in A2−/− retinas compared with WT. Western blot analyses showed increased levels of phospho-ERK1/2 and reduced levels of phospho-BAD in the WT EAE retina, while these changes were prevented in A2−/− mice. In conclusion, our studies establish EAE as an excellent model to study MS-mediated retinal neuronal damage and suggest the potential value of targeting A2 as a therapy to prevent MS-mediated retinal neuronal injury.

Original languageEnglish (US)
Pages (from-to)8589-8602
Number of pages14
JournalMolecular Neurobiology
Volume56
Issue number12
DOIs
StatePublished - Dec 1 2019

Keywords

  • Arginase 2
  • EAE
  • Neurodegeneration
  • Optic neuritis
  • Retina
  • Retinal ganglion cells

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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  • Cite this

    Palani, C. D., Fouda, A. Y., Liu, F., Xu, Z., Mohamed, E., Giri, S., Smith, S. B., Caldwell, R. B., & Narayanan, S. P. (2019). Deletion of Arginase 2 Ameliorates Retinal Neurodegeneration in a Mouse Model of Multiple Sclerosis. Molecular Neurobiology, 56(12), 8589-8602. https://doi.org/10.1007/s12035-019-01691-w