TY - JOUR
T1 - Diabetic Müller-Glial-Cell-Specific Il6ra Knockout Mice Exhibit Accelerated Retinal Functional Decline and Thinning of the Inner Nuclear Layer
AU - Glass, Joshua
AU - Robinson, Rebekah L.
AU - Greenway, Grace
AU - Jones, Garrett
AU - Sharma, Shruti
N1 - Publisher Copyright:
Copyright 2023 The Authors.
PY - 2023/12
Y1 - 2023/12
N2 - PURPOSE. Interleukin-6 (IL-6) is implicated in the pathology of diabetic retinopathy (DR). IL-6 trans-signaling via soluble IL-6 receptor (IL-6R) is primarily responsible for its pro-inflammatory functions, whereas cis-signaling via membrane-bound IL-6R is anti-inflammatory. Using a Müller-glial-cell-specific Il6ra−/− mouse, we examined how loss of IL-6 cis-signaling in Müller glial cells (MGCs) affected retinal thinning and electroretinography (ERG) response over 9 months of diabetes. METHODS. Diabetes was induced in wildtype and knockout mice with streptozotocin (40 mg/kg, daily for 5 days). Spectral domain optical coherence tomography (SD-OCT), ERG, and fundoscopy/fluorescein angiography (FA) were assessed at 2, 6, and 9 months of diabetes. MGCs and bipolar neurons were examined in retinal tissue sections by immunofluorescence. RESULTS. Diabetic MGC Il6ra−/− mice had significantly thinner retinas than diabetic wildtype mice at 2 (−7.6 μm), 6 (−12.0 μm), and 9 months (−5.0 μm) of diabetes, as well as significant thinning of the inner nuclear layer (INL). Diabetic MGC Il6ra−/− mice also showed a reduction in scotopic B-wave amplitude and B-wave/A-wave ratio earlier than wildtype diabetic mice. In retinal sections, we found a decrease in bipolar neuronal marker PKCα only in diabetic MGC Il6ra−/− mice, which was significantly lower than both controls and diabetic wildtype mice. Glutamine synthetase, a Müller cell marker, was reduced in both wildtype and MGC Il6ra−/− diabetic mice compared to their respective controls. CONCLUSIONS. IL-6 cis-signaling in MGCs contributes to maintenance of the INL in diabetes, and loss of the IL-6 receptor reduces MGC-mediated neuroprotection of bipolar neurons in the diabetic retina.
AB - PURPOSE. Interleukin-6 (IL-6) is implicated in the pathology of diabetic retinopathy (DR). IL-6 trans-signaling via soluble IL-6 receptor (IL-6R) is primarily responsible for its pro-inflammatory functions, whereas cis-signaling via membrane-bound IL-6R is anti-inflammatory. Using a Müller-glial-cell-specific Il6ra−/− mouse, we examined how loss of IL-6 cis-signaling in Müller glial cells (MGCs) affected retinal thinning and electroretinography (ERG) response over 9 months of diabetes. METHODS. Diabetes was induced in wildtype and knockout mice with streptozotocin (40 mg/kg, daily for 5 days). Spectral domain optical coherence tomography (SD-OCT), ERG, and fundoscopy/fluorescein angiography (FA) were assessed at 2, 6, and 9 months of diabetes. MGCs and bipolar neurons were examined in retinal tissue sections by immunofluorescence. RESULTS. Diabetic MGC Il6ra−/− mice had significantly thinner retinas than diabetic wildtype mice at 2 (−7.6 μm), 6 (−12.0 μm), and 9 months (−5.0 μm) of diabetes, as well as significant thinning of the inner nuclear layer (INL). Diabetic MGC Il6ra−/− mice also showed a reduction in scotopic B-wave amplitude and B-wave/A-wave ratio earlier than wildtype diabetic mice. In retinal sections, we found a decrease in bipolar neuronal marker PKCα only in diabetic MGC Il6ra−/− mice, which was significantly lower than both controls and diabetic wildtype mice. Glutamine synthetase, a Müller cell marker, was reduced in both wildtype and MGC Il6ra−/− diabetic mice compared to their respective controls. CONCLUSIONS. IL-6 cis-signaling in MGCs contributes to maintenance of the INL in diabetes, and loss of the IL-6 receptor reduces MGC-mediated neuroprotection of bipolar neurons in the diabetic retina.
KW - IL-6 trans-signaling
KW - Müller glia
KW - diabetic retinopathy (DR)
KW - inner nuclear layer (INL)
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U2 - 10.1167/iovs.64.15.1
DO - 10.1167/iovs.64.15.1
M3 - Article
C2 - 38038619
AN - SCOPUS:85178515533
SN - 0146-0404
VL - 64
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 15
M1 - 1
ER -