Linking AIM2 Inflammasome Activation, Mitochondrial Dysfunction and Chronic Inflammation in Ankylosing Spondylitis.

The absent in melanoma 2 (AIM2) inflammasome is a cytosolic DNA sensor that links genomic instability, mitochondrial dysfunction, and chronic inflammation. Unlike the nucleotide-binding domain, leucine-rich repeat (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome, AIM2 is activated directly by double-stranded Deoxyribonucleic Acid (dsDNA), including mitochondrial DNA (mtDNA) released under stress conditions. This positions AIM2 at the intersection of oxidative stress, impaired mitophagy, and innate immune dysregulation. Current therapies for ankylosis spondylitis (AS), such as anti-tumor necrosis factor (TNF), anti-interleukin 17 (IL-17), and Janus kinase (JAK) inhibitors, improve clinical outcomes; however, they do not address upstream mitochondrial dysfunction or DNA-driven inflammasome activation. By contrast, other inflammasomes, such as AIM2, remain comparatively less studied. Since autoimmune diseases, including AS, are frequently accompanied by uncontrolled innate immune responses to self-DNA, these findings provide a framework for comprehending the mechanisms of AIM2 activation and its interaction with inflammation, mitophagy, and oxidative stress. Here, we review the current evidence on AIM2 inflammasome involvement in AS pathogenesis and its potential as a therapeutic target. This approach offers new insight into disease control through re-establishing the balance between mitochondrial dysfunction and autoimmunity.