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Recognition of DNA by the cell is an important immunological signature that marks the initiation of an innate immune response. AIM2 is a cytoplasmic sensor that recognizes dsDNA of microbial or host origin. Upon binding to DNA, AIM2 assembles a multiprotein complex called the inflammasome, which drives pyroptosis and proteolytic cleavage of the proinflammatory cytokines pro‐IL‐1β and pro‐IL‐18. Release of microbial DNA into the cytoplasm during infection by Francisella, Listeria, Mycobacterium, mouse cytomegalovirus, vaccinia virus, Aspergillus, and Plasmodium species leads to activation of the AIM2 inflammasome. In contrast, inappropriate recognition of cytoplasmic self‐DNA by AIM2 contributes to the development of psoriasis, dermatitis, arthritis, and other autoimmune and inflammatory diseases. Inflammasome‐independent functions of AIM2 have also been described, including the regulation of the …