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)
JournalMolecular Neurobiology
DOIs
StatePublished - Jan 1 2019

Fingerprint

Arginase
Autoimmune Experimental Encephalomyelitis
Multiple Sclerosis
Retina
Neuroglia
Optic Neuritis
Retinal Ganglion Cells
Microglia
Interleukin-12
Interleukin-1

Keywords

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

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Deletion of Arginase 2 Ameliorates Retinal Neurodegeneration in a Mouse Model of Multiple Sclerosis. / Palani, Chithra D.; Fouda, Abdelrahman Y.; Liu, Fang; Xu, Zhimin; Mohamed, Eslam; Giri, Shailedra; Smith, Sylvia B.; Caldwell, Ruth B; Narayanan, S. Priya.

In: Molecular Neurobiology, 01.01.2019.

Research output: Contribution to journalArticle

Palani, Chithra D. ; Fouda, Abdelrahman Y. ; Liu, Fang ; Xu, Zhimin ; Mohamed, Eslam ; Giri, Shailedra ; Smith, Sylvia B. ; Caldwell, Ruth B ; Narayanan, S. Priya. / Deletion of Arginase 2 Ameliorates Retinal Neurodegeneration in a Mouse Model of Multiple Sclerosis. In: Molecular Neurobiology. 2019.
@article{78cb0892d91040d5b28e0d5e84756c15,
title = "Deletion of Arginase 2 Ameliorates Retinal Neurodegeneration in a Mouse Model of Multiple Sclerosis",
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 M{\"u}ller 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.",
keywords = "Arginase 2, EAE, Neurodegeneration, Optic neuritis, Retina, Retinal ganglion cells",
author = "Palani, {Chithra D.} and Fouda, {Abdelrahman Y.} and Fang Liu and Zhimin Xu and Eslam Mohamed and Shailedra Giri and Smith, {Sylvia B.} and Caldwell, {Ruth B} and Narayanan, {S. Priya}",
year = "2019",
month = "1",
day = "1",
doi = "10.1007/s12035-019-01691-w",
language = "English (US)",
journal = "Molecular Neurobiology",
issn = "0893-7648",
publisher = "Humana Press",

}

TY - JOUR

T1 - Deletion of Arginase 2 Ameliorates Retinal Neurodegeneration in a Mouse Model of Multiple Sclerosis

AU - Palani, Chithra D.

AU - Fouda, Abdelrahman Y.

AU - Liu, Fang

AU - Xu, Zhimin

AU - Mohamed, Eslam

AU - Giri, Shailedra

AU - Smith, Sylvia B.

AU - Caldwell, Ruth B

AU - Narayanan, S. Priya

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Arginase 2

KW - EAE

KW - Neurodegeneration

KW - Optic neuritis

KW - Retina

KW - Retinal ganglion cells

UR - http://www.scopus.com/inward/record.url?scp=85068817345&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068817345&partnerID=8YFLogxK

U2 - 10.1007/s12035-019-01691-w

DO - 10.1007/s12035-019-01691-w

M3 - Article

JO - Molecular Neurobiology

JF - Molecular Neurobiology

SN - 0893-7648

ER -