Journal
CELL PROLIFERATION
Volume 54, Issue 1, Pages -Publisher
WILEY
DOI: 10.1111/cpr.12941
Keywords
acid‐ sensitive ion channel; intervertebral disc degeneration; NLRP3 inflammasome; pyroptosis
Categories
Funding
- National Key R&D Program of China [2018YFB1105700]
- National Natural Science Foundation of China [81772401, U1603121, 81901977]
- Natural Science Foundation of Hubei Province [WJ2017Z016]
- Application Foundation and Advanced Program of Wuhan Science and Technology Bureau [2019020701011457]
- Fundamental Research Funds for the Central Universities [2019kfyXMBZ063]
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Extracellular lactate regulates intercellular reactive oxygen species (ROS) levels through ASIC1 and ASIC3, activating the NF-kappa B signaling pathway to promote NLRP3 inflammasome activation and IL-1 beta release, ultimately contributing to NP degeneration.
Objective Lactate accumulation is an important factor in the intervertebral disc degeneration (IVDD). Currently, the effect and underlying mechanism of action of lactate on nucleus pulposus (NP) cell inflammation during IVDD are unclear. Previous studies have found that the NLRP3 inflammasome plays an important role in the regulation of NP inflammation. This study focused on the regulation of acid-sensitive ion channels (ASICs) in relation to inflammation and the effect of NLRP3 on pyroptosis levels in NP cells under acidic conditions. Design For the in vitro experiments, human NP cells were exposed to 6 mM lactate solution; different groups were either treated with NLRP3 inhibitor or transfected with siRNA against NLRP3, siRNA against ASC or a mix of these, and mRNA and protein expression levels were then assessed. For the in vivo experiment, varying concentrations of lactate were injected into rat intervertebral discs and examined via magnetic resonance imaging (MRI) and histological staining. Results Extracellular lactate promoted NLRP3 inflammasome activation and degeneration of the NP extracellular matrix; furthermore, it increased the levels of inflammation and pyroptosis in the NP. Lactate-induced NLRP3 inflammasome activation was blocked by ASIC inhibitors and NLRP3 siRNA. Conclusions Extracellular lactate regulates levels of intercellular reactive oxygen species (ROS) through ASIC1 and ASIC3. ROS activate the NF-kappa B signalling pathway, thus promoting NLRP3 inflammasome activation and IL-1 beta release, both of which promote NP degeneration.
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