June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
PPARα regulates monocyte activation through interaction with the cGAS-STING pathway
Author Affiliations & Notes
  • Jian-Xing (Jay) Ma
    Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
  • lijie Dong
    Tianjin Medical University, Tianjin, China
  • Xiang Ma
    The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Wentao Liang
    Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
    The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Yusuke Takahashi
    Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
  • Xiao-min Zhang
    Tianjin Medical University, Tianjin, China
  • Xiaorong Li
    Tianjin Medical University, Tianjin, China
  • Rui Cheng
    Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
  • Footnotes
    Commercial Relationships   Jian-Xing (Jay) Ma None; lijie Dong None; Xiang Ma None; Wentao Liang None; Yusuke Takahashi None; Xiao-min Zhang None; Xiaorong Li None; Rui Cheng None
  • Footnotes
    Support  NIH grants (EY019309, EY033330, EY030472, EY012231, EY028949, EY032930, EY032931)
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1008. doi:
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      Jian-Xing (Jay) Ma, lijie Dong, Xiang Ma, Wentao Liang, Yusuke Takahashi, Xiao-min Zhang, Xiaorong Li, Rui Cheng; PPARα regulates monocyte activation through interaction with the cGAS-STING pathway. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1008.

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

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Abstract

Purpose : Monocyte activation and adhesion to the retinal vasculature play a pathogenic role in diabetic retinopathy (DR). Two independent and prospective clinical studies reported that fenofibrate, an agonist of peroxisome proliferator-activated receptor alpha (PPARα), has robust therapeutic effects on DR in type 2 diabetic patients. The purpose of this study was to explore the role of PPARα in monocyte activation.

Methods : Flow cytometry was performed to measure PPARα levels in CD11b positive monocytes from diabetic human subjects, and type 1 and type 2 diabetic animal models. Monocyte adhesion, phagocytosis and migration were studied using endothelial cell-monocyte adhesion assay, phagocytosis assay and Transwell migration assay. The metabolic profile in monocytes was analyzed using a Seahorse Analyzer.

Results : PPARα levels were down-regulated in monocytes from diabetic patients and animal models, correlating with monocyte activation, including increased adhesion, migration, and phagocytosis. Activation of PPARα by fenofibrate attenuated monocyte activation induced by diabetes or by oxidative stress in vitro. PPARα knockout alone induced monocyte activation. Furthermore, monocyte-specific PPARα overexpression ameliorated, while monocyte-specific PPARα knockout aggravated, monocyte activation in diabetic conditions. PPARα knockout impaired mitochondrial function and increased cytosolic mitochondrial DNA release, leading to activation of the cyclic GMP–AMP (cGAS) and cyclic GMP–AMP receptor stimulator of interferon genes (STING) pathway in monocytes. STING knockout or inhibitor attenuated monocyte activation induced by diabetes or by PPARα knockout.

Conclusions : PPARα regulates the activation of monocytes through metabolic reprogramming and interacts with the cGAS-STING pathway in monocytes, suggesting that PPARα in monocytes is a potential therapeutic target for DR.

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

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