Journal
LIFE SCIENCES
Volume 310, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2022.121116
Keywords
Advanced glycation end products; Diabetes; STING signaling; Macrophage; Scavenger receptor class B member 3 (CD36)
Funding
- Japan Society for the Promotion of Science [21K15354, 21K06588, 20K07290, 18K06905]
- 2021 Kindai University Research Enchancement Grant [SR08, KD2102]
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Glycol-AGEs impair the innate immune response by suppressing the upstream process in TLR4 signaling, and also have a suppressive effect on STING signaling in macrophages.
Aims: We have previously reported that advanced glycation end products derived from incubation of albumin with glycolaldehyde (glycol-AGE), lead to suppression of the toll-like receptor 4 (TLR4) signaling response to lipopolysaccharide. Glycol-AGE-induced suppression of TLR4 signaling is involved in the downregulation of CD14, which is an adaptor protein necessary for transferring lipopolysaccharide to TLR4. Therefore, glycol-AGEs impair the innate immune response through suppression of the upstream process in TLR4 signaling. However, the effect of glycol-AGEs on intracellular signaling related to the innate immune response remains unclear. This study aimed to examined the effect of glycol-AGEs on stimulator of interferon gene (STING) signaling in macrophages.Main methods: In differentiated THP-1 cells, which are a human monocytic leukemia cell line, cyclic GMP-AMP (cGAMP) transfection was used to activate STING signaling. The phosphorylation levels of TANK-binding kinase 1 (TBK1)/interferon regulatory transcription factor 3 (IRF3) were evaluated by western blot analysis. Downstream cytokine levels were evaluated by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assays.Key findings: Glycol-AGEs suppressed cGAMP-induced phosphorylation of TBK1 and IRF3, as well as the production of cytokines regulated by IRF3. There was no effect of glycol-AGEs on the efficacy of cGAMP transfection. Treatment of a neutralizing antibody against CD36 prevented cGAMP-induced phosphorylation of TBK1 and IRF3, and also upregulation of interferon-beta and C-X-C motif chemokine ligand 10 in glycol-AGE-treated cells. Significance: Glycol-AGEs negatively regulate cGAMP-induced activation of STING/TBK1/IRF3 signaling via CD36. Our findings suggest that glycol-AGEs lead to impairment of the innate immune response by suppressing intracellular signaling.
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