Unveiling the role of CXCL8/CXCR2 in intervertebral disc degeneration: A path to promising therapeutic strategies

Abstract

Background

Intervertebral disc degeneration(IVDD) is the primary etiology of low back pain and radicular pain. Recent studies have found that chemokines play a role in IVDD, but the underlying mechanism is largely unclear.

Methods

Bioinformatics analysis was employed to screen CXCL8 as the target gene. The expression levels of CXCL8 and CXCR2 were quantified using RT-qPCR, western blot(WB), immunohistochemistry(IHC), and enzyme-linked immuno-sorbent assay(ELISA). In the IVDD mouse model, X-ray images, Safranin O-fast green staining(SO-FG), IHC, and WB were conducted to assess the therapeutic effects of CXCL8 on IVDD. Reactive oxygen species (ROS) production, apoptosis of nucleus pulposus cells (NPCs), and the involvement of the NF-κB pathway were evaluated through WB, flow cytometry, immunofluorescence(IF), and Tunnel assay.

Results

In our study, we observed that CXCL8 emerged as one of the chemokines that were up-regulated in IVDD. The mitigation of extracellular matrix degradation (ECM) and the severity of IVDD were significantly achieved by neutralizing CXCL8 or its receptor CXCR2(SB225002, CXCR2 antagonist). The release of CXCL8 from infiltrated macrophages within intervertebral discs (IVDs) was predominantly observed upon stimulation. CXCL8 exerted its effects on NPCs by inducing apoptosis and ECM degradation through the activation of CXCR2. Specifically, the formation of the CXCL8/CXCR2 complex triggered the NF-κB signaling pathway, resulting in an abnormal increase in intracellular ROS levels and ultimately contributing to the development of IVDD.

Conclusion

Our findings suggest that macrophage-derived CXCL8 and subsequent CXCR2 signaling play crucial roles in mediating inflammation, oxidative stress, and apoptosis in IVDD. Targeting the CXCL8/CXCR2 axis may offer promising therapeutic strategies to ameliorate IVDD.

The translational potential of this article

This study indicates that CXCL8 can effectively exacerbate the excessive apoptosis and oxidative stress of NPCs through activating the NF-κB pathway. This study may provide new potential targets for preventing and reversing IVDD.