Targeting miR-10a-5p/IL-6R axis for reducing IL-6-induced cartilage cell ferroptosis

Background: Intervertebral disc degeneration (IDD) causes lower back pain, and is often accompanied with robust inflammation. However, whether inflammation plays a role in IDD remains controversial, and the mechanism is ill-elucidated. Methods: Cartilage specimens from patients with scoliosis (control) and IDD were examined for IL-6 and its receptor expression by qPCR and western blot. Primary human articular chondrocyte was employed as a model for in vitro assessment of IL-6 effects in cell viability, cellular oxidative stress and iron homeostasis by MTT, MDA, ROS and Iron Colorimetric assays. The underlying mechanism was explored by qPCR, western blot, RIP in combination with bioinformatics analysis. Results: We found in this study that IL-6 and its receptor were aberrantly expressed in cartilage tissues of IDD patients. IL-6 down-regulated miR-10a-5p, which subsequently derepressed IL-6R expression. IL-6 exposure caused cartilage cell ferroptosis by inducing cellular oxidative stress and disturbing iron homeostasis. Overexpressing miR-10a-5p suppressed IL-6R expression, and partially abolished IL-6-induced ferroptosis. Conclusion: Results from current study suggests that inflammatory cytokine IL-6 appeared in IVD aggravates its degeneration by inducing cartilage cell ferroptosis. This is caused partially by inhibiting miR-10a-5p and subsequently derepressing IL-6R signaling pathway. Our study provides a novel mechanism explaining inflammatory cytokine-caused cartilage cell death in degenerative IVD, and makes IL-6/miR-10a-5p/IL-6R axis a potential therapeutic target for intervention of IDD.

Automated summary

This study found aberrant expression of IL-6 and its receptor in cartilage tissues of IDD patients, with IL-6 inducing cartilage cell ferroptosis by down-regulating miR-10a-5p. Overexpression of miR-10a-5p suppressed IL-6R expression and partially blocked IL-6-induced ferroptosis. The IL-6/miR-10a-5p/IL-6R axis may be a potential therapeutic target for IDD intervention.