September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Increased inflammasome priming and microglial activation in a mouse model of chloroquine retinopathy
Author Affiliations & Notes
  • Wennan Lu
    Anatomy and Cell Biology, Univ of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Nestor Mas Gomez
    Anatomy and Cell Biology, Univ of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Alan M Laties
    Ophthalmology, Univ of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Claire H Mitchell
    Anatomy and Cell Biology, Univ of Pennsylvania, Philadelphia, Pennsylvania, United States
    Physiology, Univ of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Wennan Lu, None; Nestor Mas Gomez, None; Alan Laties, None; Claire Mitchell, None
  • Footnotes
    Support  NH Grant EY013434, EY015537, the Jody Sack Fund.
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 2237. doi:
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    • Get Citation

      Wennan Lu, Nestor Mas Gomez, Alan M Laties, Claire H Mitchell; Increased inflammasome priming and microglial activation in a mouse model of chloroquine retinopathy. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2237.

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

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Abstract

Purpose : The chronic use of chloroquine is associated with bull’s eye retinopathy, resulting in loss of central photoreceptors and impaired vision. The drug accumulates in the RPE, and is well known to elevate lysosomal pH. While the disease has been recognized for many years, the mechanistic steps linking elevated lysosomal pH in RPE cells to photoreceptor loss are not well understood. We have developed a mouse model of chloroquine retinopathy to identify key steps in disease progression. The model demonstrates an increase in markers of oxidative stress and a rise in the lipids surrounding Bruch’s membrane. This study represents an initial examination of inflammatory markers in the retina of mice treated with chloroquine.

Methods : The mouse chloroquine retinopathy was induced by injecting chloroquine (50mg/kg) intraperitoneally into 3-6 month old C57BL/6J mice 3x/week for 6 weeks. mRNA expression was examined in retinal tissues using qPCR. IBA-1 staining in retinal sections was detected immunohistochemically.

Results : Mice treated with chloroquine showed an increase in mRNA for inflammasome components IL-1β mRNA and caspase1 in the retina compared to untreated mice, consistent with a priming of the inflammasome. NTPDase1 was also increased, indicating a rise in extracellular ATP in the retina. Staining for microglia with IBA-1 was increase in the inner retina in chloroquine treated mice. IBA-1 positive processes were also observed extending into the outer nuclear layer in chloroquine treated mice.

Conclusions : These data provide preliminary evidence for increased inflammation in the retina of mice treated with chloroquine chronically. The rise in mRNA for caspase 1 and IL-1 β are consistent with the priming of inflammasome involvement. The increased expression of NTPDase1 suggests a rise in extracellular ATP; as ATP can activate the inflammasome through the P2X7 receptor this suggests a possible link to pathological changes observed in the mouse model. The increased staining for IBA-1 implied a rise in microglial activation in treated mice. While these observations suggest inflammatory involvement, future experiments will indicate whether this is linked to photoreceptor death.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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