CGAS-STING Signalling in Metabolic Diseases: from Signalling Networks to Targeted Intervention

Mechanism underlying STING signalling pathway activation in metabolic diseases. A) The cGAS-STING pathway in adipose tissue mediates obesity. Overnutrition leads to mitochondrial stress (MT stress) and dysfunction, resulting in the release of mtDNA in adipocytes through DsbA-L inhibition. mtDNA is recognized by cGAS and activates the STING-TBK1-IRF3 pathway to produce Type I interferon or activate TBK1-NF-κB pathway, both of which leads to proinflammatory cytokine production. Similarly, LPS activates IRF3 by binding to TLR4 receptors. Activation of TNFR1 receptors by TNF-α and TLR4 receptors by palmitate synergistically increases CCL2/MCP-1 production, leading to macrophage infiltration and inflammation in the context of obesity. IRF3 inhibition of GLUT4 expression in adipocytes leads to insulin resistance. However, STING activation of TBK1/IKKε suppresses cAMP-PKA signalling by inhibiting PDE3B/4 expression, reducing thermogenesis, and ultimately attenuating obesity. B) The cGAS-STING pathway in the liver mediates NAFLD/NASH/ALD. MCD/HFD/free fatty acids (FFAs) and LPS cause MT stress and the release of mtDNA. The activation of mtDNA in hepatocytes/hepatic stellate cells is similar to that in adipocytes; it leads to increased inflammation, lipid accumulation and liver fibrosis through the production of proinflammatory cytokines. Transport of cGAMP from hepatocytes to immune cells via CX32 causes the spread of inflammatory effects. Alcohol-induced ER stress or activation of LPS/TLR4 signalling can activate the cGAS-STING-IRF3 pathway, resulting in apoptosis. However, IRF3 represses Scd1 transcription in response to poly (I:C)/TLR3/TRIF signalling, leading to the inhibition of adipogenesis. C) The cGAS-STING pathway in islet tissue mediates glucose homeostasis. Both HFD-induced mtDNA release and palmitic or PA-induced DNA leakage can activate the cGAS-STING pathway, which induces the production of Type I interferons and proinflammatory cytokines, causing inflammation, insulin resistance and lipotoxicity in islets. Additionally, a decrease in the number of Vsig4+ macrophages lead to the increased entry of mEVs into cells, thereby inducing the release of DNA, which activates the cGAS-STING-TBK1 pathway. However, IRF3 upregulates the expression of the transcription factor Pax6 to promote the expression of the target genes Glut2 and Abcc8, resulting in GSIS and thus maintaining glucose homeostasis. D) The cGAS-STING pathway in cardiovascular tissue mediates CVD. HFD-/PA-induced increases in MT stress and reduced mitochondrial ALDH2 activity mediated by decreased melatonin levels lead to impaired mitochondrial function, causing the release of mtDNA. Activation of Caspase-11-induced GSDMD activation by LPS, leading to the release of mtDNA from damaged mitochondria. Subsequently, mtDNA activates the STING-IRF3 pathway, promoting macrophage infiltration and cardiac fibrosis. DNA fragmentation in SMCs drives DNA transfer to macrophages and promotes the expression of MMP-9, which contributes to extracellular matrix formation. Activated IRF3 enters the nucleus and induces the expression of MST1, which promotes YAP phosphorylation and suppresses the transcription of the cyclin D gene, leading to inhibition of endothelial cell angiogenesis. It also enhances the expression of ICAM-1 and VCAM-1, thereby increasing the inflammatory response and promoting SMC proliferation, thereby exerting a proatherogenic effect.

Publication

The Role of cGAS-STING Signalling in Metabolic Diseases: from Signalling Networks to Targeted Intervention. (2024) Jiahui Gong, et al. Int J Biol Sci. 2024;20(1):152-174. Figure: F2. Homo sapiens

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