July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Loss of functional βA3/A1-crystallin upregulates the expression of colony stimulating factor 1 receptor (CSF-1R) and activates inflammation in Nuc1 rat retina
Author Affiliations & Notes
  • Stacey L Hose
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Sayan Ghosh
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Meysam Yazdankhah
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Imran Ahmed Bhutto
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • J. Samuel Zigler, Jr.
    Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Debasish Sinha
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
    Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Footnotes
    Commercial Relationships   Stacey Hose, None; Sayan Ghosh, None; Meysam Yazdankhah, None; Imran Bhutto, None; J. Samuel Zigler, Jr., None; Debasish Sinha, None
  • Footnotes
    Support  This work was supported by Research to Prevent Blindness (unrestricted grants to the Wilmer Eye Institute and University of Pittsburgh). This work is also supported by start-up funds to DS from Ophthalmology, University of Pittsburgh.
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 4594. doi:
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    • Get Citation

      Stacey L Hose, Sayan Ghosh, Meysam Yazdankhah, Imran Ahmed Bhutto, J. Samuel Zigler, Jr., Debasish Sinha; Loss of functional βA3/A1-crystallin upregulates the expression of colony stimulating factor 1 receptor (CSF-1R) and activates inflammation in Nuc1 rat retina
      . Invest. Ophthalmol. Vis. Sci. 2018;59(9):4594.

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

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Abstract

Purpose : We have previously shown that in the Nuc1 (a spontaneous mutation in the Cryba1 gene that encodes for βA3/A1-crystallin) rat retina there is a significant increase in the number of macrophages. By 18 months of age the Nuc1 retina is detached with clear evidence of subretinal fluid, epiretinal fibrosis and preretinal vasculature, not observed in the retina of wild type (WT) rats. This study was undertaken to identify factors and pathways contributing to the survival of the increased number of macrophages in Nuc1 retina.

Methods : Extracts prepared from retinas of WT and Nuc1 rats at 8 days, 21 days, 9 weeks and 9 months of age were used for microarray analysis. Quantitative real time-PCR was used to confirm target gene expression. Infiltrating macrophage and macrophage-like cells were identified by immunohistochemistry using antibodies to ED1, ED2 and CD11b/18 (OX-42). To determine the signaling pathway involved in the increased survival of macrophages, western blotting was performed with antibodies to IGF-II (cloneS1F2), p44/42 MAPK (Erk1/2) and phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204).

Results : Microarray analysis showed an age-dependent increase in the expression of properdin, secreted Phosphoprotein 1 and CSF-1R in retinas from Nuc1 rats relative to WT. QPCR results indicated that while expression of properdin increased most significantly at 9 months, the level of CSF-1R increased significantly as early as 21 days and increased exponentially with age. The spike in expression of CSF-1R was associated with increased macrophage population in the Nuc1 retina. Moreover, our western data suggested that the survival of the macrophages is regulated by the pro-IGF-II/MAPK/ERK1/2 pathway.

Conclusions : CSF-1 is the most pleiotropic macrophage growth factor and binding to the receptor triggers key signaling pathways, such as MAPK pathway. The MAP kinases ERK1/2 are key elements for signal integration downstream of CSF-1R, and their sustained activation leads to macrophage differentiation and survival. Therefore, inhibitors of CSF-1R may offer an attractive strategy for reducing macrophage numbers in inflammatory diseases of the retina.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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