Increase of Cytosolic Double-stranded DNA in Nucleus Pulposus Cell Accelerates Intervertebral Disc Degeneration via Activation of cGAS-STING Signaling

The pathogenesis of Intervertebral Disc Degeneration (IDD) is complex and multifactorial, with cellular senescence of nucleus pulposus (NP) cells and inflammation playing major roles in the progression of IDD. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a key mediator of inflammation during infection, cellular stress, and tissue damage. Here, we present a progressive increase of cytosolic dsDNA with concomitant upregulation of STING in IDD. Increased nuclear and mitochondrial dsDNA and high expression STING from degenerative NP cells together significantly promoted IDD. The deficiency of STING or cGAS-protected intervertebral disc (IVD) in the mouse models of age-induced, lumbar instability-induced IDD by using STINGgt/gt and cGAS -/- mice. Mechanistically, the accumulation of cytoplasmic dsDNA and increased STING expression enhanced the pro-inflammatory response, apoptosis, and senescence of NP cells. Therapeutically, the blockade of STING (reduce expression or suppress activation) in vivo demonstrated a potential therapeutic modality for the treatment of IDD.