June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
LXB4 regulates optic nerve microglia phenotype and function in ocular hypertension neuropathy
Shubham Maurya; SHRUTHI KARNAM; Maggie Lin; Matangi Kumar; Tanirika Singh; Elainna Ng; John G Flanagan; Karsten Gronert
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
  • Maggie Lin
    Herbert Wertheim School of Optometry, University of California Berkeley, Berkeley, California, United States
  • Matangi Kumar
    Herbert Wertheim School of Optometry, University of California Berkeley, Berkeley, California, United States
  • Tanirika Singh
    Herbert Wertheim School of Optometry, University of California Berkeley, Berkeley, California, United States
  • Elainna Ng
    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; Maggie Lin None; Matangi Kumar None; Tanirika Singh None; Elainna Ng None; John Flanagan None; Karsten Gronert None
  • Footnotes
    Support  5R01EY030218-03
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1576. doi:
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      Shubham Maurya, SHRUTHI KARNAM, Maggie Lin, Matangi Kumar, Tanirika Singh, Elainna Ng, John G Flanagan, Karsten Gronert; LXB4 regulates optic nerve microglia phenotype and function in ocular hypertension neuropathy. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1576.

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Abstract

Purpose : Lipoxin (LX) B4, a neuroprotective mediator in the retina, has anti-inflammatory actions that target leukocytes in other tissues. Lipoxins target RGCs, and the pathway in the retina is downregulated during ocular hypertension (OHT). Recent evidence indicates LXB4 regulates retinal microglial homeostatic function and phenotype. Morphological characterization of microglia and RNAseq was used to investigate the regulation of retina and optic nerve (ON) microglia during OHT and the impact of LXB4 treatment.

Methods : Silicone oil model of OHT was used to investigate the neuroprotective mechanism of LXB4 treatment. OCT imaging and RGC counts were endpoints for neurodegeneration. Morphological phenotype of microglia in retina and ON were assessed following 1wk of OHT. Functional phenotype of microglia in homeostatic and reactive states was measured by an automated MATLAB script for comprehensive Z-stack morphological analysis (17 features) of all IBA-1 stained microglia. CD68 staining was a marker for microglia reactivity. RNAseq analysis of mouse ON was used as a discovery approach to understand the mechanism of LXB4 microglia regulation during OHT. Macaque ON was analyzed by LC/MS/MS-based lipidomics and RNAseq to determine the functional expression of the LXB4 pathway.

Results : Microglia features were altered towards reactive phenotype in both retina (13 features, n= 11, p<0.05) and ON (8 features, n= 7, p<0.05). Importantly, treatment with LXB4 significantly inhibited transition of microglia to a reactive phenotype in ON (5 features restored, n=8, p<0.05), which was validated by CD68 staining (n=8, p<0.05). Differential expression analysis of ON genes from RNAseq identified 152 genes downregulated by LXB4 treatment (Log2FC < -1, p<0.05), and pathway enrichment identified selective targeting of the immune response and leukocyte migration by LXB4. RNAseq and lipidomics established expression of lipoxin pathway genes (Alox5, Alox5ap, Alox15, and Fpr2 ) and endogenous formation of LXB4 in macaque ON.

Conclusions : Microglial phenotype and functions are altered in the retina and ON as an early response to OHT. Neuroprotective LXB4 is produced in macaque ON. Inhibiting microglia reactivity in ON by LXB4 identifies a new target and bioaction. LXB4 regulation of selective immune and migration pathways discovered potential mechanisms for the neuroprotective actions of LXB4 in ON.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
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Copyright © 2025 Association for Research in Vision and Ophthalmology.
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