CytoDNA triggered NP cell inflammatory senescence via cGAS-STING axis sensing but not AIM2 inflammasome activation
Given the leading cause of disability worldwide, low back pain (LBP) is recognized as a pivotal socio-economic challenge to the aging population, which is importantly attributed to intervertebral disc degeneration (IVDD), a highly prevalent affliction of aging. Elastic nucleus pulposus (NP) tissue is essential for maintenance of IVD structural and functional integrity. Native NP cells exhibit crucial functions for regulating extracellular matrix homeostasis, constructing an accommodating biomechanical environment and maintaining the gelatinous property of NP tissue. The accumulation of senescent NP cells with inflammatory hypersecretory phenotype due to aging and other damaged factors is a distinctive hallmark of IVDD initiation and progression. In this study, we revealed a mechanism of IVDD progression in which aberrant genomic DNA damage promoted NP cell inflammatory senescence via activation of cGAS-STING axis. cGAS-STING axis activation drove inflammatory phenotype acquisition and inflammatory hypersensitivity to damaged signals of senescent NP cells via NF-ÎºB pathway-mediated transcriptional modulation. And the administration of H-151 revealed that STING pharmacological inhibitor notably suppressed the inflammatory response formation and senescence associated screctory phenotype (SASP) acquisition of senescent cells. Furthermore, blocking STING activation could suppress NF-ÎºB pathway-mediated transcriptional remodeling and inflammatory phenotype acquisition in senescent NP cells. Overall design: The transcriptional profiles of nucleus pulposus (NP) cells from three degenerated and three no-degenerated human NP tissues. The transcriptional profiles of NP cells at passage 2 (P2) generation and passage (P8) generation via serial passage.  The transcriptional profiles of P8 senescent NP cells treated with H-151 or DMSO.