September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Inflammation is the Sine qua non for progression of age-related macular degeneration.
Author Affiliations & Notes
  • Sayan Ghosh
    Opthalmolgy, Johns Hopkins University, Baltimore, Maryland, United States
    Physiology, University of Calcutta, Kolkata, India
  • Peng Shang
    Opthalmolgy, Johns Hopkins University, Baltimore, Maryland, United States
    Opthalmology, Tongji University, Shanghai, Shanghai, China
  • Stacey L Hose
    Opthalmolgy, Johns Hopkins University, Baltimore, Maryland, United States
  • Jiang Qian
    Opthalmolgy, Johns Hopkins University, Baltimore, Maryland, United States
  • J Samuel Zigler
    Opthalmolgy, Johns Hopkins University, Baltimore, Maryland, United States
  • Debasish Sinha
    Opthalmolgy, Johns Hopkins University, Baltimore, Maryland, United States
  • Footnotes
    Commercial Relationships   Sayan Ghosh, None; Peng Shang, None; Stacey Hose, None; Jiang Qian, None; J Zigler, None; Debasish Sinha, None
  • Footnotes
    Support  SG is supported by the Fulbright-Nehru Doctoral Research Fellowship. This work was supported by a grant from BrightFocus Foundation (to DS) and Research to Prevent Blindness (an unrestricted grant to the Wilmer Eye Institute).
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 483. doi:
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    • Get Citation

      Sayan Ghosh, Peng Shang, Stacey L Hose, Jiang Qian, J Samuel Zigler, Debasish Sinha; Inflammation is the Sine qua non for progression of age-related macular degeneration.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):483.

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

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Abstract

Purpose : Sustained low-grade inflammation or chronic inflammation has been associated with many multifactorial diseases, including age-related macular degeneration (AMD). The role of βA3/A1-crystallin in inflammation and progression of AMD-like phenotype has recently been documented. To further elaborate on the specific link between microglia polarization and the onset of AMD, lipopolysaccharide (LPS) was used to stimulate the intracellular inflammatory pathways and to establish the probable relation of para to chronic inflammation in our mouse model.

Methods : In this study Cryba1fl/fl (WT) and Cryba1-/- (KO) mice at two different ages were used. The mice were divided into four groups: WT, KO, WT+LPS, KO+LPS (N=9/group). LPS was injected intraperitoneally at a dose of 100µg/kg body weight, twice weekly for three consecutive weeks. Control animals which did not receive the LPS injections, were injected with vehicle (1X sterile PBS). After the treatment, the retina was isolated from each mouse and RNA array was performed for different cytokine, chemokines and immune molecules. Western blot analysis was performed to evaluate intracellular protein expression levels. Signaling pathways were studied by proteomics and immunohistochemistry.

Results : The bias towards a pro-inflammatory M1 phenotype was observed in the retinas of KO+LPS animals as compared to the other three groups, as evidenced by increased RNA expression of different pro-inflammatory chemokines, cytokines and transcription factors along with increase in the protein expression of IL-12 and iNOS and decreased expression of Arginase-1 and IL-10. There was noticeable increase in the expression of TLR4 pathway proteins like ERK1/2 and pSTAT3. Furthermore, there was increased nuclear localization of NFκB-p65/p50 subunits. M1 status was accompanied by increased phosphorylation of AKT2 concomitant with decreased phosphorylation of AKT1 in the retinas of the LPS stimulated KO mice. In silico binding studies suggested a role of βA3/A1-crystallin in regulating AKT2 phosphorylation, thereby contributing towards the onset of a pro-inflammatory condition.

Conclusions : Our studies provide novel evidence that the activation of the AKT2/NFκB signaling axis could contribute to the transactivation of pro-inflammatory genes and could switch the para-inflammatory response to a chronic inflammatory immune response in our genetically engineered mouse model of AMD.

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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