Targeting CSF1 /CSF1R axis alleviates intervertebral disc degeneration and associated neuropathic pain

Chronic low back pain (LBP), predominantly driven by intervertebral disc degeneration (IVDD) is a major public health burden, yet the molecular mechanisms linking disc pathology to inflammation and pain remain poorly understood. Here, we identify a fibrotic, late-stage population of nucleus pulposus (NP) cells in degenerating intervertebral discs that aberrantly upregulate Colony Stimulating Factor 1 (CSF1). NP-derived CSF1 activates the CSF1 Receptor (CSF1R) on infiltrating macrophages, triggering a sustained pro-inflammatory cascade within the microenvironment. Using a murine model of disc injury, we demonstrate that either genetic ablation of Csf1r or pharmacologic inhibition with the selective CSF1R antagonist GW2580 markedly attenuates disc degeneration, confirmed by longitudinal MRI and histopathology, and significantly reduces associated neuropathic pain behaviors. These findings establish the CSF1–CSF1R axis as a central mechanistic link between fibrotic NP cell remodeling and macrophage-driven inflammation, highlighting it as a promising therapeutic target for mitigating disc degeneration and alleviating chronic LBP. One Sentence Summary: Blocking CSF1 signaling alleviates intervertebral disc degeneration and neuropathic pain