The Role of the AIM2 Gene in Obesity-Related Glucose and Lipid Metabolic Disorders: A Recent Update

Figures

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  Figure 1. Structural basis of AIM2 inflammasome. (A) Cartoon representation of the human AIM2 hIN domain showing the tandem oligonucleotide/oligosaccharide-binding (OB) fold domain (https://doi.org/10.2210/pdb3RLN/pdb); (B) Cartoon representation of the human AIM2 PYD domain (https://doi.org/10.2210/pdb4O7Q/pdb).

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  Figure 2. The canonical AIM2 activation pathway. In the case of infection with a DNA virus or transfection with a DNA analog, dsDNA released into the cytoplasm is directly recognized by AIM2. The HIN domain of AIM2 binds to dsDNA, and PYD binds to the junction protein ASC, which then recruits Pro-Caspase-1 to form an inflammatory complex. Activated Caspase-1 cleaves pro-IL-1β and pro-IL-18, leading to the maturation and secretion of the inflammatory factors IL-1β and IL18. Moreover, activated caspase-1 can cleave Gasdermin D, leading to the release of its N-terminal fragment and destruction of the integrity of the cell membrane, which ultimately leads to cell death.

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  Figure 3. The noncanonical AIM2 activation pathway. IFN I production is first induced by cGAS at low concentrations in bacteria. dsDNA-activated cGAS produces a cGAMP, which serves as a high-affinity ligand for STING. cGAMP induces conformational changes, oligomerization, and translocation of STING and interacts with downstream TBK1 and IRF3, which phosphorylate IRF3 to produce IFN1. Moreover, IFN-β activates STAT1/STAT2 by binding to interferon receptors, which leads to the activation of the downstream transcription factors IRF9 and IRF1 after STAT1/STAT2 phosphorylation, which in turn drives ISG transcription and promotes cell lysis, resulting in the release of large amounts of bacterial DNA into the cytoplasm and thus sufficient concentrations of dsDNA for detection by AIM2 before entering the classical pathway.

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  Figure 4. The relationship between AIM2, obesity, and diabetes. Exogenous entry of intracellular dsDNA or intracellular elevation of mtDNA binding to AIM2 can activate AIM2 inflammatory vesicles and promote the development of insulin resistance and T2D. AIM2 inhibits the upregulation of P202 and IFl202b to suppress the increase in adipose tissue mass.

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  Figure 5. The role of AIM2 in fatty liver disease. A high-fat diet promotes the development of NAFLD, and AIM2 activation promotes the progression of NAFLD to NASH. FXR can inhibit the activation of AIM2. In addition, NAG-1 and GDF15 can play therapeutic roles in NAFLD by decreasing mitochondrial damage, reducing the release of dsDNA, and inhibiting the activation of AIM2.

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  Figure 6. The role of AIM2 in atherosclerosis. When low-density lipoprotein (LDL) enters endothelial cells and becomes oxidized, it damages vascular endothelial cells, and macrophages are activated to phagocytose oxidized LDL and form foam cells. Oxidized LDL increases the expression of the Aim2 gene in VSMCs, activates MMP-2, SMAD-2 and SMAD-3, and increases smooth muscle cell proliferation. The dsDNA released from necrotic cells during advanced atherosclerosis activates AIM2 inflammatory vesicles in macrophages and releases IL-1β and IL-18, which are cytokines that promote atherosclerotic plaque formation. In addition, JAK2-V617F drives macrophage proliferation, leading to the accumulation of mitochondrial oxidized DNA, which promotes DNA damage and dsDNA breaks, thereby activating AIM2.