June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
The Neuroprotective Action of p58IPK is Independent of Macrophage Regulation in Retinal Disease Models
Author Affiliations & Notes
  • Todd McLaughlin
    Ophthalmology and Ross Eye Institute, University at Buffalo, Buffalo, New York, United States
    SUNY Eye Institute, State University of New York, University at Buffalo, Buffalo, New York, United States
  • Jinli Wang
    Ophthalmology and Ross Eye Institute, University at Buffalo, Buffalo, New York, United States
  • Joshua J. Wang
    Ophthalmology and Ross Eye Institute, University at Buffalo, Buffalo, New York, United States
    SUNY Eye Institute, State University of New York, University at Buffalo, Buffalo, New York, United States
  • Sarah Xin Zhang
    Ophthalmology and Ross Eye Institute, University at Buffalo, Buffalo, New York, United States
    SUNY Eye Institute, State University of New York, University at Buffalo, Buffalo, New York, United States
  • Footnotes
    Commercial Relationships   Todd McLaughlin, None; Jinli Wang, None; Joshua Wang, None; Sarah Zhang, None
  • Footnotes
    Support  NIH/NEI grants EY019949 and EY025061, and an Unrestricted Grant to the Department of Ophthalmology, SUNY-Buffalo, from Research to Prevent Blindness
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 3127. doi:
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    • Get Citation

      Todd McLaughlin, Jinli Wang, Joshua J. Wang, Sarah Xin Zhang; The Neuroprotective Action of p58IPK is Independent of Macrophage Regulation in Retinal Disease Models. Invest. Ophthalmol. Vis. Sci. 2021;62(8):3127.

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

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Abstract

Purpose : p58IPK is a multifunctional ER chaperone and a regulator of cell stress response in a variety of cell types and tissues including the retina, pancreas, and immune cells. The goal of the present study is to evaluate the neuroprotective effect of p58IPK overexpression in mouse retina and elucidate the mechanism by which p58IPK acts as a neuroprotectant involving regulation of macrophage activation.

Methods : Conditional knockout (cKO) of p58IPK in macrophages was achieved by crossing p58IPK floxed mice with a myeloid-specific Cre line (LysM-Cre). We determined knockout efficiency by qPCR in cultured bone marrow derived macrophages (BMDMs). Overexpression of p58IPK in wild type (WT) retina was accomplished by intravitreal injection of adeno-associated virus (AAV). Neurodegeneration was assessed at 14 days post-induction in two disease models, a microbead induced increase in intraocular pressure (IOP) and an ischemia-reperfusion (IR) model. The loss of RGCs was examined by immunohistochemistry (IHC) for Brn3a. The structure and function of the cKO eyes were assessed by IHC for multiple retinal markers, morphological measurements, and electroretinogram (ERG).

Results : We find that BMDMs from p58IPK fl/fl; LysM-Cre (p58IPK cKO) mice have a 97% knockdown of p58IPK mRNA compared to BMDMs from p58IPK fl/fl (WT) mice, validating the loss of p58IPK from macrophages. p58IPK cKO retina has no substantial differences from WT retina in retinal structure or cellular composition, including the number of Brn3a+ RGCs. p58IPK cKO mice have a trend for reduced b wave amplitudes in both light- and dark-adapted ERGs compared to WT mice. Injection of AAV-p58IPK in WT mice with increased IOP results in greater Brn3a+ RGC survival compared to AAV-GFP overexpression. However, in p58IPK cKO mice, in which p58IPK is lost only in macrophages, we find no difference in Brn3+ RGC survival compared to WT using the same IOP model. Similarly, p58IPK cKO mice suffer identical loss of Brn3a+ RGCs in the IR model, compared to WT.

Conclusions : Though broad p58IPK overexpression in retina reduces RGC loss in disease models, the loss of p58IPK specifically in macrophages does not substantially ameliorate RGC loss in the same model or in a second disease model. These results suggest that the neuroprotective effect of p58IPK does not likely involve a regulation of macrophage activation.

This is a 2021 ARVO Annual Meeting abstract.

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