Soluble Tumor Necrosis Factor Alpha Promotes Retinal Ganglion Cell Death in Glaucoma via Calcium-Permeable AMPA Receptor Activation.
Loss of vision in glaucoma results from the selective death of retinal ganglion cells (RGCs). Tumor necrosis factor α (TNFα) signaling has been linked to RGC damage, however, the mechanism by which TNFα promotes neuronal death remains poorly defined. Using an in vivo rat glaucoma model, we show that TNFα is upregulated by Müller cells and microglia/macrophages soon after induction of ocular hypertension. Administration of XPro1595, a selective inhibitor of soluble TNFα, effectively protects RGC soma and axons. Using cobalt permeability assays, we further demonstrate that endogenous soluble TNFα triggers the upregulation of Ca(2+)-permeable AMPA receptor (CP-AMPAR) expression in RGCs of glaucomatous eyes. CP-AMPAR activation is not caused by defects in GluA2 subunit mRNA editing, but rather reflects selective downregulation of GluA2 in neurons exposed to elevated eye pressure. Intraocular administration of selective CP-AMPAR blockers promotes robust RGC survival supporting a critical role for non-NMDA glutamate receptors in neuronal death. Our study identifies glia-derived soluble TNFα as a major inducer of RGC death through activation of CP-AMPARs, thereby establishing a novel link between neuroinflammation and cell loss in glaucoma.


CONCLUSIONS
Tumor necrosis factor α (TNFα) has been implicated in retinal ganglion cell (RGC) death, but how TNFα exerts this effect is poorly understood. We report that ocular hypertension, a major risk factor in glaucoma, upregulates TNFα production by Müller cells and microglia. Inhibition of soluble TNFα using a dominant-negative strategy effectively promotes RGC survival. We find that TNFα stimulates the expression of calcium-permeable AMPA receptors (CP-AMPAR) in RGCs, a response that does not depend on abnormal GluA2 mRNA editing but on selective downregulation of the GluA2 subunit by these neurons. Consistent with this, CP-AMPAR blockers promote robust RGC survival supporting a critical role for non-NMDA glutamate receptors in glaucomatous damage. This study identifies a novel mechanism by which glia-derived soluble TNFα modulates neuronal death in glaucoma.
Department of Neuroscience and University of Montreal Hospital Research Center (CRCHUM), University of Montreal, Montreal, Quebec H2X 0A9, Canada.
Jorge L
JL
Cueva Vargas
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada, and.
Ingrid K
IK
Osswald
Centre for Neuronal Survival, Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada.
Nicolas
N
Unsain
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada, and.
Mark R
MR
Aurousseau
Centre for Neuronal Survival, Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada.
Philip A
http://orcid.org/0000-0002-3444-7551
PA
Barker
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada, and.
Derek
http://orcid.org/0000-0001-9491-8768
D
Bowie
Department of Neuroscience and University of Montreal Hospital Research Center (CRCHUM), University of Montreal, Montreal, Quebec H2X 0A9, Canada, adriana.di.polo@umontreal.ca.
Adriana
A
Di Polo
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003035:Cobalt / Q000378:metabolism; D004195:Disease Models, Animal; D063928:Ependymoglial Cells / Q000187:drug effects / Q000378:metabolism; D005901:Glaucoma / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects*; D012462:Saline Solution, Hypertonic / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
D002352:Carrier Proteins; D018091:Receptors, AMPA; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D012462:Saline Solution, Hypertonic; C506237:Tnfrsf1a protein, rat; D014409:Tumor Necrosis Factor-alpha; C540591:XENP 1595; D003035:Cobalt; D002795:Choline O-Acetyltransferase; C104722:glutamate receptor ionotropic, AMPA 2; D002118:Calcium
AMPA receptor; calcium; glaucoma; neuroinflammation; retinal ganglion cell; tumor necrosis factor