AIM2 as a therapeutic target in autoimmunity: balancing inflammasome inhibition with immune homeostasis

Absent in melanoma 2 (AIM2) is a cytosolic pattern recognition receptor that functions as a critical sensor of double-stranded DNA (dsDNA) of microbial or host origin. Upon DNA recognition, AIM2 assembles into a multiprotein inflammasome complex that drives pyroptotic cell death and maturation of the pro-inflammatory cytokines IL-1β and IL-18. Beyond its canonical role in host defense, aberrant AIM2 activation by self-DNA has been increasingly implicated in the pathogenesis of various inflammatory autoimmune diseases. This comprehensive review synthesizes current understanding of AIM2 biology. We examine the role of AIM2 in different immune cell populations, its effects on multiple downstream signaling pathways, and its complex association with autoimmune diseases such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. Finally, we discussed therapeutic prospects and remaining challenges in targeting AIM2 for the treatment of autoimmunity.