June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
LXB4 regulation of microglia responses in ocular hypertension induced neuropathy
Author Affiliations & Notes
  • Shubham Maurya
    Herbert Wertheim School of Optometry, University of California Berkeley, Berkeley, California, United States
  • Shruthi Karnam
    Herbert Wertheim School of Optometry, University of California Berkeley, Berkeley, California, United States
  • Lily Yang
    Herbert Wertheim School of Optometry, University of California Berkeley, Berkeley, California, United States
  • John G Flanagan
    Herbert Wertheim School of Optometry, University of California Berkeley, Berkeley, California, United States
  • Karsten Gronert
    Herbert Wertheim School of Optometry, University of California Berkeley, Berkeley, California, United States
  • Footnotes
    Commercial Relationships   Shubham Maurya None; Shruthi Karnam None; Lily Yang None; John Flanagan None; Karsten Gronert None
  • Footnotes
    Support  NIH 5R01EY030218-02
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 921 – A0390. doi:
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    • Get Citation

      Shubham Maurya, Shruthi Karnam, Lily Yang, John G Flanagan, Karsten Gronert; LXB4 regulation of microglia responses in ocular hypertension induced neuropathy. Invest. Ophthalmol. Vis. Sci. 2022;63(7):921 – A0390.

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

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Abstract

Purpose : The neuroprotective role of specialized pro-resolving mediators such as lipoxins (LXA4 and LXB4) are lost during retinal insult, including ocular hypertension (OHT). Using a silicone oil (SO) based model of OHT induced neuropathy and LXB4 treatment, we aimed to better understand the novel mechanisms involved in LXB4 mediated neuroprotection.

Methods : To discover novel targets for LXB4 homeostatic function, we performed single-cell (SC) transcriptomics of retinal cells after treating the healthy C57BL6/J mice (n=4 retina) with LXB4 by intraperitoneal (IP) injection and topical eye drops. For inducing OHT, we used the established SO model that causes stable and sustained OHT. To validate and explore novel targets of LXB4 under OHT conditions, mice (n=3) were treated with LXB4 by IP and topical eye drops every other day from day 7 to day 28. Gene expression of potential targets was analyzed by qPCR.

Results : LXB4 treatment-induced changes in transcriptomic profile in a limited number of retinal cell types in healthy mice. Unexpectedly, LXB4 treatment markedly changed gene expression for a distinct pathway in microglia. These selected genes were C5ar1, Clec4a2, Entpd1, Il6ra, and CD37, which are components of the new microglia ‘sensome’ paradigm, responsible for regulating the microglia phenotype switch in stress/immune responses. LXB4 treatment downregulated these sensome genes by ≥2-fold (p < 0.05). Further, we analyzed the expression of LXB4-regulated sensome genes under OHT conditions at 4 and 8 weeks. Notably, expression of the microglia sensome gene Clec4a2 was elevated at 4 weeks by 1.63-fold (n=4, p<0.05) and at 8 weeks by 1.84-fold (n=3, p<0.05). Consistent with scRNA results from healthy mice, LXB4 treatment in mice with the OHT reduced Clec4a2 expression compared to sham treatment.

Conclusions : Our data identify a novel cellular target and potential mechanism of action for the neuroprotective LXB4, namely by regulation of microglial sensome gene Clec4a2. The microglia sensome is an essential mechanism for directing microglia activation, an early event in glaucoma pathogenesis. LXB4 regulation of the microglia sensome is of interest given the homeostatic and protective actions of lipoxins in rat and mouse models of OHT-induced glaucomatous injury.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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