Deletion of arginase 2 attenuates neuroinflammation in an experimental model of optic neuritis

Abstract

Vision impairment due to optic neuritis (ON) is one of the major clinical presentations in Multiple Sclerosis (MS) and is characterized by inflammation and degeneration of the optic nerve and retina. Currently available treatments are only partially effective and have a limited impact on the neuroinflammatory pathology of the disease. A recent study from our laboratory highlighted the beneficial effect of arginase 2 (A2) deletion in suppressing retinal neurodegeneration and inflammation in an experimental model of MS. Utilizing the same model, the present study investigated the impact of A2 deficiency on MS-induced optic neuritis. Experimental autoimmune encephalomyelitis (EAE) was induced in wild-type (WT) and A2 knockout (A2-/-) mice. EAE-induced cellular infiltration, as well as activation of microglia and macrophages, were reduced in A2-/- optic nerves. Axonal degeneration and demyelination seen in EAE optic nerves were observed to be reduced with A2 deletion. Further, the lack of A2 significantly ameliorated astrogliosis induced by EAE. In conclusion, our findings demonstrate a critical involvement of arginase 2 in mediating neuroinflammation in optic neuritis and suggest the potential of A2 blockade as a targeted therapy for MS-induced optic neuritis.

Treatment with MDL 72527 Ameliorated Clinical Symptoms, Retinal Ganglion Cell Loss, Optic Nerve Inflammation, and Improved Visual Acuity in an Experimental Model of Multiple Sclerosis

“…The inflammation of the optic nerve is a major feature in EAE mice [ 21 , 50 ]. In the present study, we investigated the impact of MDL 72527 on EAE-induced optic nerve inflammation.…”

Neuroprotective Effects of Fingolimod in a Cellular Model of Optic Neuritis

“…It is vital to understand the underlying mechanisms of MS-induced neuronal damage and dysfunction. Even though MS research on the pathophysiology and associated molecular mechanisms have evolved over decades of research, including our laboratory [ 35 , 36 ], the field lacks reliable in vitro models to study neurodegeneration. Synthetic molecules such as trimethyltin [ 37 ], oxaliplatin [ 38 ], and cuprizone [ 39 ], although successful in creating a neurodegenerative environment, do not accurately represent the neuroinflammatory changes observed in an MS brain.…”

Pharmacological Inhibition of Spermine Oxidase Suppresses Excitotoxicity Induced Neuroinflammation in Mouse Retina

“…Immunostaining of retinal cryostat sections was performed as per the methods established in our laboratory [27,93,96]. Briefly, eyes were removed and fixed in 4% paraformaldehyde overnight at 4 • C and cryoprotected in 30% sucrose for 24 h. Cryostat sections (10 µm) obtained on glass slides were permeabilized in 0.1% Triton X-100 (30 min) followed by blocking in 10% normal donkey serum for 1 h at room temperature.…”

“…C8-B4 cells (ATCC) were kindly provided by Dr. Susan Fagan (University of Georgia), were cultured in DMEM high glucose medium (Gibco) and 10% FBS (Atlantic biologics), 100 I.U./mL penicillin, and 100 (µg/mL) streptomycin (ATCC). Cells were cultured at a density of 15,000 cells/well in a chamber slide (Thermo Fisher) with complete medium and treated with 25 µg/mL acrolein-BSA conjugate (StressMarq Biosciences) in complete medium for 6 h. Following the incubation, the culture media was removed, and cells were washed with 1× PBS and fixed with 4% paraformaldehyde for 10 min and subjected to immunocytochemistry according to the method standardized in our laboratory [35,96]. This was followed by PBS wash, and the chamber slides were stored in humidified containers at 4 • C. Permeabilization of the cells was performed using 0.1% Triton X-100 in PBS (5 min), followed by PBS wash, and blocking was achieved using 10% donkey serum at room temperature for 1 h. Cells were washed and incubated with respective primary antibodies (Table 1) overnight.…”