Mitochondrial DNA enables AIM2 inflammasome activation and hepatocyte pyroptosis in nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is typified by accumulating excess liver triacylglycerol, inflammation, and liver dysfunction. This study was aimed to investigate the role of mitochondrial DNA synthesis-induced activation of Absent in melanoma 2 (AIM2) inflammasome and pyroptosis in NAFLD. Mice were raised on a high-fat diet for 24 weeks to establish NAFLD models. F4/80 immunofluorescence was performed to reflect the inflammatory response in the liver of mice. Western blot, ELISA, and immunofluorescence were adopted to determine the expression of AIM2 inflammasome-related proteins and factors. EdU immunofluorescence was applied for the examination of mitochondrial DNA expression and flow cytometry for cell pyroptosis. Agarose gel electrophoresis was used to detect the integrity of extracted mouse mitochondrial DNA (mtDNA). The levels of AIM2 inflammasome-related proteins in the liver and the levels of IL-1β and IL-18 in serum were elevated in high-fat diet-induced NAFLD mice. AIM2 inflammasome activation and pyroptosis were triggered, and suppressed activation of AIM2 inflammasome alleviated the inflammation and pyroptosis in the liver of NAFLD mice. Mitochondria were severely damaged and mtDNA was synthesized after NAFLD modeling. Further, mtDNA treatment could promote palmitate (PA)-induced activation of AIM2 inflammasome and pyroptosis. Moreover, inhibition of IRF1 gene alleviated PA-induced AIM2 inflammasome activation and pyroptosis. In conclusion, mitochondrial DNA synthesis could enable AIM2 inflammasome activation and induce the hepatocyte pyroptosis, thereby exacerbating NAFLD.

Overexpression of NAG-1/GDF15 prevents hepatic steatosis through inhibiting oxidative stress-mediated dsDNA release and AIM2 inflammasome activation

“…At present, several laboratory studies have examined the implication of AIM2 in the development of steatosis and NASH in mice, while human studies are still lacking [ 122 ]. AIM2 inflammasome has been found to be overexpressed and activated in the liver of the HFD-induced NAFLD mouse model [ 43 , 44 ]. Overexpress of the AIM2 gene in mice aggravated HFD-induced NAFLD and stimulated inflammatory cell infiltration and increased expression of inflammation-related genes (IL-1β and IL-18) [ 44 ].…”

“…However, the role of the AIM2 inflammasome and its physiological relevance to NAFLD are poorly understood. At present, several studies have reported that AIM2 inflammasome activation may contribute to the progression of steatosis to NASH [ [42] , [43] , [44] ]. However, the specific role of AIM2 inflammasome in steatosis and whether it can be regulated by NAG-1/GDF15 has never been reported.…”

Role of the inflammasome, gasdermin D, and pyroptosis in non‐alcoholic fatty liver disease

“…39 Mitochondrial damage and mtDNA release modulate the activation of absent in melanoma 2 and NLRP3 inflammasomes, leading to the maturation and secretion of IL-1β and IL-18, which trigger pyroptosis that exacerbates liver inflammation and NAFLD progression. 40 The activity of many inflammasomes involved in NAFLD-NASH progression has been described, and the main difference lies in the ligand recognition sites and the adapter molecules. 41 Pyroptosis-inducing activity is carried out through GSDMD, and its overexpression is related to the spontaneous induction of liver damage without a secondary factor, which indicates that it is a crucial mechanism involved in NAFLD pathogenesis.…”

Through DNA sensors and hidden mitochondrial effects of SARS-CoV-2

“…It was observed that this extracellular mtDNA is the driver for the activation of macrophages, and the subsequent induction of the cytokine IL-1β, contributing to the establishment of chronic inflammation [ 97 ]. AIM2 has also been observed to sense mtDNA from events of mitochondrial stress, such as increased cell levels of cholesterol, which lead to the extravasation of mtDNA [ 98 ], and in non-alcoholic fatty liver disease, driving inflammation and hepatocyte pyroptosis [ 99 ].…”