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Jennifer E Dulle, Angela Myers, Patrice E Fort; The regulatory role of α-crystallins in retinal neuroinflammation. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3625.
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Both diabetic retinopathy and optic nerve injury are characterized by retinal cell loss and neuroinflammation, though the causal relationship is still debated. Neuroinflammation is a key contributor to the pathology and progression of neurodegenerative diseases, though the paracrine signaling between neurons and the inflammatory cells are not well understood. The molecular chaperones, α-crystallins, have been implicated in both optic nerve injury and diabetic retinopathy as playing a role in neuroprotection, and have previously been shown to negatively regulate inflammation in models of stroke and multiple sclerosis. However, the function of α-crystallins in neuroinflammation in the retina and the impact on neuronal cell loss is still unclear.
The role of α-crystallins in the retinal neuroinflammatory response was investigated using two experimental models of either acute (optic nerve injury) or chronic (diabetes) inflammation in the retina. Tissue sections and flat-mounts of retinas from WT and α-crystallin-KO mice were used to evaluate the loss of ganglion cells, activation of glial cells, and the extent of cell death by immunofluorescence. The rate of retinal cell death and the neuroinflammatory response were respectively assessed by analyzing pro-apoptotic markers and pro-inflammatory cytokine levels.
In response to either optic nerve injury or diabetes, we demonstrate that α-crystallin-KO mice display both increased apoptosis in retinal cells and loss of ganglion cells compared to WT mice. Additionally, we show that loss of α-crystallins affects glial cell activation and morphology, as well as expression of pro-inflammatory cytokines. We also determine that the two isoforms of α-crystallin, αA- and αB-crystallin, have independent roles in neuroprotection and regulation of neuroinflammation as loss of the individual isoforms has differing effects on the rate of neuronal cell loss and the activation of retinal glial cells.
Our data demonstrate that in addition to the previously reported role they play in regulation of apoptosis, α-crystallins are also critical for the regulation of retinal neuroinflammation associated with neurodegeneration. This study demonstrates the therapeutic potential of α-crystallins for the regulation of retinal neuroinflammation, which may positively impact neuronal cell survival and prevent progression of retinal neurodegeneration resulting from disease or injury.
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