April 2011
Volume 52, Issue 14
ARVO Annual Meeting Abstract  |   April 2011
Autoinflammation in Diabetic Retinopathy
Author Affiliations & Notes
  • Susanne Mohr
    Department of Physiology, Michigan State University, East Lansing, Michigan
  • Derrick J. Feenstra
    Department of Physiology, Michigan State University, East Lansing, Michigan
  • Katherine Trueblood
    Department of Physiology, Case Western Reserve University, Cleveland, Ohio
  • George Dubyak
    Department of Physiology, Case Western Reserve University, Cleveland, Ohio
  • E.Chepchumba Yego
    US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland
  • Footnotes
    Commercial Relationships  Susanne Mohr, None; Derrick J. Feenstra, None; Katherine Trueblood, None; George Dubyak, None; E.Chepchumba Yego, None
  • Footnotes
    Support  NIH Grant EY-017206, ADA research grant 7-06-RA-95
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 999. doi:
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    • Get Citation

      Susanne Mohr, Derrick J. Feenstra, Katherine Trueblood, George Dubyak, E.Chepchumba Yego; Autoinflammation in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):999.

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

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Purpose: : Hyperglycemia leads to sustained activation of caspase-1 in the retinas of diabetic animals and patients in vivo and in retinal cells in vitro. How caspase-1 activation is achieved and sustained is unknown. This study was focused on identifying mechanisms regulating high glucose-induced caspase-1 activity in vitro and in vivo.

Methods: : Capillary degeneration in diabetic wild type and caspase-1 knock-out mice was assessed by elastase digestion. Caspase-1 activation patterns were determined from retinas of normal and diabetic wild type (C57Bl6) and IL-1β receptor knock-out (IL1R-/-) mice using a caspase-1 specific fluorescence substrate. Retinal Müller cells were treated with 5mM, 25 mM, or 25mM glucose medium plus IL-1 receptor antagonist (IL-1ra) for up to 96 hours followed by caspase-1 activity measurements. QPCR and Western Blot analysis were used to determine NALP3 levels in retinal Müller cells and retinal tissue of non-diabetic and diabetic donors.

Results: : Caspase-1 knock-out inhibits the diabetes-induced increase in numbers of acellular capillaries/mm2 by 65±19% compared to wild type. Hyperglycemia induced a multi-phasic pattern of caspase-1 activation in retinal tissue and Müller cells compared to controls. The IL-1ra, which prevents downstream signaling of caspase-1/IL-1β, significantly decreased late phase caspase-1 activity by 30.48 ± 10.61% at 72 hours compared to high glucose alone. In vivo, knock-out of the IL-1 receptor prevented late phase activation of caspase-1 in the diabetic retina. Hyperglycemia-induced caspase-1 activation is mediated by the induction of the NALP3 inflammasome. NALP3 levels increased by 10 ± 5% in retinal tissue from diabetic donors compared to non-diabetic donors.

Conclusions: : Diabetes induces an autoinflammatory response within retinal tissue that is mediated by the continuous activation of the caspase-1/IL-1β signaling pathway via the NALP3 inflammasome. Interfering in the caspase-1/IL-1β activation feedback cycle represents a novel therapeutic strategy to prevent the progression of diabetic retinopathy.

Keywords: diabetic retinopathy • inflammation • cytokines/chemokines 

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