Francisella tularensisis a highly virulent Gram-negative bacterium that causes the fatal zoonotic disease tularemia. The mechanisms and signaling pathways leading to the absent in melanoma 2 (Aim2) inflammasome activation have been elegantly elucidated usingFrancisella novicidaas a model. Although not pathogenic for humans,F.novicidacan cause tularemia in mice, and the inflammatory response it triggers is the polar opposite to that observed in mice infected withF.tularensisstrains. This study aimed to understand the mechanisms of Aim2 inflammasome activation inF.tularensis-infected macrophages. The results reveal that macrophages infected with theF.tularensislive vaccine strain (LVS) induce lower levels of Aim2-dependent IL-1β than those infected withF.novicida. The suppression/weak activation of Aim2 inF.tularensisLVS-infected macrophages is due to the suppression of the cGAS-STING DNA-sensing pathway. Furthermore, the introduction of exogenousF.tularensisLVS DNA into the cytosol of theF.tularensisLVS-infected macrophages, alone or in conjunction with a priming signal, failed to restore IL-1β levels similar to those observed forF.novicida-infected macrophages. These results indicated that, in addition to the bacterial DNA, DNA from some other sources, specifically from the damaged mitochondria, might contribute to the robust Aim2-dependent IL-1β levels observed inF.novicida-infected macrophages. The results indicate thatF.tularensisLVS induces mitophagy that may potentially prevent the leakage of mitochondrial DNA and the subsequent activation of the Aim2 inflammasome. Collectively, this study demonstrates that the mechanisms of Aim2 inflammasome activation established forF.novicidaare not operative inF.tularensis.