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Regulation of Monocyte Activation by PPARα Through Interaction With the cGAS-STING Pathway

Lijie Dong1, Rui Cheng2,3, Xiang Ma2,3

  • 1Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China.

Diabetes
|April 14, 2023
PubMed

Insights

Peroxisome proliferator-activated receptor-α (PPARα) deficiency activates monocytes in diabetes, contributing to diabetic complications. Restoring PPARα function may offer a therapeutic strategy for diabetic retinopathy.

Area of Science:

  • Immunology
  • Metabolic Disorders
  • Ophthalmology

Background:

  • Monocyte activation is implicated in diabetic complications like diabetic retinopathy (DR).
  • The regulatory mechanisms of monocyte activation in diabetes are not fully understood.
  • Fenofibrate, a peroxisome proliferator-activated receptor-α (PPARα) agonist, shows therapeutic potential for DR.

Purpose of the Study:

  • To investigate the role of PPARα in regulating monocyte activation in diabetes.
  • To elucidate the molecular pathways linking PPARα to monocyte activation under diabetic conditions.

Main Methods:

  • Assessed PPARα levels in monocytes from diabetic patients and animal models.
  • Utilized PPARα knockout and overexpression models in monocytes.
  • Analyzed mitochondrial function and glycolysis.
  • Investigated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway.

Main Results:

  • PPARα levels were downregulated in diabetic monocytes, correlating with activation.
  • PPARα deficiency exacerbated monocyte activation, impaired mitochondrial function, and increased glycolysis.
  • PPARα deficiency led to cytosolic mitochondrial DNA release and cGAS-STING pathway activation.
  • Targeting the STING pathway attenuated diabetes-induced monocyte activation.

Conclusions:

  • PPARα acts as a negative regulator of monocyte activation in diabetes.
  • PPARα influences monocyte activation via metabolic reprogramming (mitochondria and glycolysis).
  • The cGAS-STING pathway is a key mediator in PPARα-regulated monocyte activation during diabetes.

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