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Different modulation of STING/TBK1/IRF3 signaling by advanced glycation end products

Takashi Nishinaka1, Omer Faruk Hatipoglu1, Hidenori Wake1

  • 1Department of Pharmacology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.

Archives of Biochemistry and Biophysics
|November 2, 2023
PubMed

Insights

Advanced glycation end products (AGEs) affect the innate immune system by modulating STING/TBK1/IRF3 signaling. The impact of AGEs on this pathway depends on the specific carbonyl compound used in their formation, with some suppressing and one enhancing signaling.

Area of Science:

  • Immunology
  • Biochemistry
  • Molecular Biology

Background:

  • Advanced glycation end products (AGEs) are formed from non-enzymatic reactions between carbonyl compounds and proteins.
  • The stimulator of interferon gene (STING)/TANK-binding kinase 1 (TBK1)/interferon regulatory transcription factor 3 (IRF3) pathway is crucial for innate immune responses.

Purpose of the Study:

  • To investigate the differential effects of various AGEs on STING/TBK1/IRF3 signaling.
  • To determine the relationship between AGE structure and their immunomodulatory activity.

Main Methods:

  • Preparation of AGEs from different carbonyl compounds (glucose, glyceraldehyde, glycolaldehyde, methylglyoxal, glyoxal).
  • Assessment of AGEs' effects on cyclic GMP-AMP (cGAMP)-induced STING/TBK1/IRF3 activation in vitro.
  • Analysis of lysine modification in relation to signaling modulation.

Main Results:

  • AGEs derived from aldehydes and dicarbonyl compounds generally suppressed STING/TBK1/IRF3 signaling with varying efficiencies.
  • Lysine modification correlated with the suppressive capacity of AGEs.
  • A glucose-derived AGE (AGE1) uniquely enhanced STING/TBK1/IRF3 activation via toll-like receptor 4.

Conclusions:

  • The modulation of STING/TBK1/IRF3 signaling by AGEs is highly dependent on the type and concentration of the precursor carbonyl compound.
  • AGEs can either suppress or enhance innate immune signaling, suggesting a complex role in immune regulation.
  • Lysine residue modification is a key factor in AGEs' interaction with the STING/TBK1/IRF3 pathway.
Keywords:
Advanced glycation end productsMacrophageProtein modificationSTING/TBK1/IRF3 signaling

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