March 2012
Volume 53, Issue 14
ARVO Annual Meeting Abstract  |   March 2012
TGFβ Potentiates Retinal Ganglion Cell Death After Optic Nerve Injury
Author Affiliations & Notes
  • James T. Walsh
    Neuroscience, University of Virginia, Charlottesville, Virginia
  • Igor Smirinov
    Neuroscience, University of Virginia, Charlottesville, Virginia
  • Jonathan Kipnis
    Neuroscience, University of Virginia, Charlottesville, Virginia
  • Footnotes
    Commercial Relationships  James T. Walsh, None; Igor Smirinov, None; Jonathan Kipnis, None
  • Footnotes
    Support  NS061973
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 4676. doi:
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      James T. Walsh, Igor Smirinov, Jonathan Kipnis; TGFβ Potentiates Retinal Ganglion Cell Death After Optic Nerve Injury. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4676.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : The response to CNS injury is multifaceted, drawing on programmed responses from glia, innate and adaptive immune cells, and the injured neurons themselves. While TGFβ is well known to be involved in differentiation of adaptive immune cells and in astrocytic fibrosis after optic nerve trauma, the direct effects of this cytokine on retinal ganglion cells (RGC) in the context of optic nerve injury is not well understood.

Methods: : Optic nerve injury was preformed as a unilateral crush of the optic nerve 7mm posterior to the eye. To determine transcript levels, RNA was extracted by trizol, and mRNA was quantitated by qRT-PCR. For neuronal survival experiments, RGCs were pre-labeled using Fluoro-gold injection into the superior colliculus before injury. TGFβ inhibition in vivo was achieved by injecting anti-TGFβ antibody intravitreally immediately after injury. TGFβ signaling was quantitated by staining for phospho-SMAD2 and analyzing by flow cytometry. Primary RGC cultures were obtained from P5 retinas and incubated with TGFβ, glutamate, or a combination of TGFβ and glutamate.

Results: : We show here that TSP1 mRNA is upregulated after optic nerve injury. This appears to be a maladaptive response, as a global knockout of TSP1 or inhibition of TSP1 upregulation results in increased neuronal survival after optic nerve trauma. Specifically inhibiting the TGFβ-converting domain of TSP1 reproduces the results seen in TSP1-/- mice, and directly neutralizing anti-TGFβ antibody in the vitreous increases RGC survival after injury. Moreover, we show that TGFβ signaling pathways are activated in RGCs after optic nerve crush injury, and that TGFβ treatment of RGC cultures potentiates excitotoxic death induced by glutamate.

Conclusions: : TGFβ plays an important role in the immune privilege of the eye and has been reported to be neuroprotective after injury. TGFβ signaling increases in the retina after injury in a thrombospondin-dependent mechanism and this response is detrimental, leading to a potentiation of secondary degeneration. This is a novel mechanism that could possibly be targeted not only in traumatic injury, but in other diseases that share similar mechanisms of RGC degeneration, such as glaucoma and other retinopathies.

Keywords: trauma • neuroprotection • cytokines/chemokines 

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