TY - JOUR
T1 - Glycolaldehyde-derived advanced glycation end products suppress STING/TBK1/IRF3 signaling via CD36
AU - Nishinaka, Takashi
AU - Hatipoglu, Omer Faruk
AU - Wake, Hidenori
AU - Watanabe, Masahiro
AU - Toyomura, Takao
AU - Mori, Shuji
AU - Nishibori, Masahiro
AU - Takahashi, Hideo
N1 - Funding Information:
This work was supported in part by a Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research ( 21K15354 to T.N., 21K06588 to O.F.H., 20K07290 to H.W., and 18K06905 to H.T.) and by a 2021 Kindai University Research Enchancement Grant ( SR08 to T.N. and KD2102 to H.W.).
Publisher Copyright:
© 2022 The Authors
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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-β 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.
AB - 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-β 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.
KW - Advanced glycation end products
KW - Diabetes
KW - Macrophage
KW - Scavenger receptor class B member 3 (CD36)
KW - STING signaling
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U2 - 10.1016/j.lfs.2022.121116
DO - 10.1016/j.lfs.2022.121116
M3 - Article
C2 - 36302498
AN - SCOPUS:85141818523
SN - 0024-3205
VL - 310
JO - Life Sciences
JF - Life Sciences
M1 - 121116
ER -
