Cytosolic escape of mitochondrial DNA triggers cGAS-STING-NLRP3 axis-dependent nucleus pulposus cell pyroptosis

Kun Wang,Rongjin Luo,Hui Liu,Liang Ma,Wencan Ke,Zhiwei Liao,Kangcheng Zhao,Yu Song,Jie Lei,Xinghuo Wu,Yukun Zhang,Weifeng Zhang,Wenbin Hua,Xiaobo Feng,Cao Yang,Gaocai Li,Bingjin Wang

doi:10.1038/s12276-022-00729-9

Abstract

Low back pain (LBP) is a major musculoskeletal disorder and the socioeconomic problem with a high prevalence that mainly involves intervertebral disc (IVD) degeneration, characterized by progressive nucleus pulposus (NP) cell death and the development of an inflammatory microenvironment in NP tissue. Excessively accumulated cytosolic DNA acts as a damage-associated molecular pattern (DAMP) that is monitored by the cGAS-STING axis to trigger the immune response in many degenerative diseases. NLRP3 inflammasome-dependent pyroptosis is a type of inflammatory programmed death that promotes a chronic inflammatory response and tissue degeneration. However, the relationship between the cGAS-STING axis and NLRP3 inflammasome-induced pyroptosis in the pathogenesis of IVD degeneration remains unclear. Here, we used magnetic resonance imaging (MRI) and histopathology to demonstrate that cGAS, STING, and NLRP3 are associated with the degree of IVD degeneration. Oxidative stress induced cGAS-STING axis activation and NLRP3 inflammasome-mediated pyroptosis in a STING-dependent manner in human NP cells. Interestingly, the canonical morphological and functional characteristics of mitochondrial permeability transition pore (mPTP) opening with the cytosolic escape of mitochondrial DNA (mtDNA) were observed in human NP cells under oxidative stress. Furthermore, the administration of a specific pharmacological inhibitor of mPTP and self-mtDNA cytosolic leakage effectively reduced NLRP3 inflammasome-mediated pyroptotic NP cell death and microenvironmental inflammation in vitro and degenerative progression in a rat disc needle puncture model. Collectively, these data highlight the critical roles of the cGAS-STING-NLRP3 axis and pyroptosis in the progression of IVD degeneration and provide promising therapeutic approaches for discogenic LBP.

Highlights

Low back pain (LBP) is a major musculoskeletal disorder and the leading cause of disability worldwide with a high prevalence[1,2,3,4].Globally, LBP is the second most common reason for medical consultation in industrialized countries[5,6]
We showed that mitochondrial DNA (mtDNA) leaking into the cytosol via mitochondrial permeability transition pore (mPTP) acted as a damage-associated molecular pattern (DAMP) and that activation of the cyclic GMP-AMP synthase (cGAS)-STINGNLRP3 axis was responsible for nucleus pulposus (NP) cell pyroptosis induced by oxidative stress
intervertebral disc (IVD) degeneration was accompanied by the activation of the cGAS-stimulator of interferon genes (STING) axis and NLR pyrin domain containing 3 (NLRP3) inflammasome To examine the roles of the cGAS-STING axis and NLRP3 inflammasome in IVD degenerative progression, we collected tissue samples from patients who underwent open spine surgery or lumbar discectomy surgery because of idiopathic scoliosis or lumbar disc herniation

Summary

Introduction

LBP is the second most common reason for medical consultation in industrialized countries[5,6]. It is well established that LBP is mainly involved in intervertebral disc (IVD) degeneration[3,7]. IVDs are complex avascular fibrocartilaginous tissues consisting of nucleus pulposus (NP), annulus fibrosus (AF), and cartilaginous endplates, which connect adjacent vertebral bodies to absorb spine axial compressive forces and to facilitate load transmission[8,9]. As the hydrogel-like core of the IVD, healthy. NP tissue is primarily composed of NP cells and extracellular matrix (ECM), and its elastic property distributes hydraulic pressure in all directions within each IVD10. Resident NP cells are critical for NP tissue function and ECM metabolism to maintain the gelatinous properties of NP tissue[11]

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Conclusion