Obesity-induced NLRP3 inflammasome activation in nucleus pulposus cells accelerates intervertebral disk degeneration

Intervertebral disc degeneration (IVDD) is a common imaging change, and it is characterized by increased production of inflammatory cytokines such as IL-1β and elevated degradation of extracellular matrix (ECM). IVDD has been indicated as the most important reason of low back pain and the leading cause of disability. IVDD is a common concomitant disease in patients with obesity; and obesity is a metabolic syndrome pathological condition that results in the concentrations of circulating fatty acid increasing and metabolic stress. Increasing circulating fatty acid could evoke a widespread inflammation response, leading to ECM degradation. Yet, how IVDD is induced by obesity, and how circulating fatty acid affects nucleus pulposus cells inflammatory response is unclear. Here we present evidence that a high fat diet (HFD) leads to IVDD and saturated fatty acid induces the activation of NLRP3 inflammasome, causing caspase-1, IL-1β production and HMGB1 release in NP cells. This involves mitochondria dsRNA (mt-dsRNA) release and double-stranded RNA-dependent protein kinase (PKR) activation. PKR deficiency inhibited NLRP3 inflammasome activation and catabolic degeneration in NP cells and rescued the phenotypes of IVDD in vivo and in vitro. Moreover, metformin prevents PKR activation and protects NP cells by attenuating mitochondria damage to NP cells. This research presents a comprehensive understanding of NLRP3 inflammasome activation mediated by mt-dsRNA-PKR axis in NP cells that underlies the development of IVDD and recommends metformin as a therapeutic drug for treating IVDD.