Biomaterial Database

Cytosolic escape of mitochondrial DNA triggers cGAS-STING-NLRP3 axis-dependent nucleus pulposus cell pyroptosis. 2022

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

Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

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.

UI	MeSH Term	Description	Entries
D007249	Inflammation	A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function.	Innate Inflammatory Response,Inflammations,Inflammatory Response, Innate,Innate Inflammatory Responses
D009713	Nucleotidyltransferases	A class of enzymes that transfers nucleotidyl residues. EC 2.7.7.	Nucleotidyltransferase
D004272	DNA, Mitochondrial	Double-stranded DNA of MITOCHONDRIA. In eukaryotes, the mitochondrial GENOME is circular and codes for ribosomal RNAs, transfer RNAs, and about 10 proteins.	Mitochondrial DNA,mtDNA
D000069292	Pyroptosis	Type of programmed cell death associated with infection by intracellular pathogens. It is characterized by INFLAMMASOME formation; activation of CASPASE 1; and CYTOKINES mediated inflammation.	Caspase-1 Dependent Cell Death,Inflammatory Apoptosis,Pyroptotic Cell Death,Apoptoses, Inflammatory,Apoptosis, Inflammatory,Caspase 1 Dependent Cell Death,Cell Death, Pyroptotic,Cell Deaths, Pyroptotic,Death, Pyroptotic Cell,Deaths, Pyroptotic Cell,Inflammatory Apoptoses,Pyroptoses,Pyroptotic Cell Deaths
D000070614	Nucleus Pulposus	Fibrocartilage inner core of the intervertebral disc. Prolapsed or bulged nucleus pulposus leads to INTERVERTEBRAL DISC DISPLACEMENT while proliferation of cells in the nucleus pulposus is associated with INTERVERTEBRAL DISC DEGENERATION.
D000071199	NLR Family, Pyrin Domain-Containing 3 Protein	An NLR protein that contains an N-terminal PYRIN DOMAIN and ATP-binding site and 9 C-terminal LEUCINE-rich repeats; it is expressed primarily by MACROPHAGES. It is a core component of the INFLAMMASOME and directs its assembly in response to pathogen infection and damage-associated stimuli. Mutations in the NLRP3 gene are associated with FAMILIAL COLD AUTOINFLAMMATORY SYNDROME.	Cold Autoinflammatory Syndrome 1 Protein,NACHT, LRR and PYD Domains-Containing Protein 3,NLRP3 Protein,NACHT, LRR and PYD Domains Containing Protein 3,NLR Family, Pyrin Domain Containing 3 Protein
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D051381	Rats	The common name for the genus Rattus.	Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus
D055959	Intervertebral Disc Degeneration	Degenerative changes in the INTERVERTEBRAL DISC due to aging or structural damage, especially to the vertebral end-plates.	Degenerative Disc Disease,Degenerative Intervertebral Discs,Degenerative Intervertebral Disks,Intervertebral Disk Degeneration,Disc Degeneration,Disc Degradation,Disk Degeneration,Disk Degradation,Degeneration, Disc,Degeneration, Disk,Degeneration, Intervertebral Disc,Degeneration, Intervertebral Disk,Degenerative Disc Diseases,Degenerative Intervertebral Disc,Degenerative Intervertebral Disk,Degradation, Disc,Degradation, Disk,Disc Degeneration, Intervertebral,Disc Degenerations,Disc Degradations,Disc Disease, Degenerative,Disc, Degenerative Intervertebral,Disk Degeneration, Intervertebral,Disk Degenerations,Disk Degradations,Disk, Degenerative Intervertebral,Intervertebral Disc Degenerations,Intervertebral Disc, Degenerative,Intervertebral Disk Degenerations,Intervertebral Disk, Degenerative
D058847	Inflammasomes	Multiprotein complexes that mediate the activation of CASPASE-1. Dysregulation of inflammasomes has also been linked to a number of autoinflammatory and autoimmune disorders.	Inflammasome,Pyroptosome,Pyroptosomes