POSTN drives STAT3/NF-κB-mediated CXCL5 feedback to promote macrophage polarization in IDD

Intervertebral disc degeneration (IDD) is a leading cause of low back pain. Although POSTN is implicated in tissue remodeling and chronic inflammation, its role in NP-immune crosstalk remains unclear.

To determine whether POSTN drives CXCL5-dependent recruitment and M1 polarization of macrophages via STAT3/NF-κB signaling, and to assess whether blockade of this axis mitigates IDD.

Human IVDs were stratified by Pfirrmann grade; a puncture-induced rat model was established. POSTN was overexpressed or silenced in NPCs. Chemotaxis and co-culture assays assessed macrophage recruitment and polarization. RNA-seq with GO/KEGG enrichment, qPCR, Western blotting, ELISA, and IF/IHC profiled signaling and effector molecules. IDD severity was evaluated by MRI and histology.

POSTN was upregulated in severe IDD and spatially co-localized with CD68+/CD86+ macrophages. In NPCs, POSTN activated IL-6/JAK2/STAT3 and p-P65 (NF-κB), increased CXCL5 transcription/secretion, and enhanced macrophage chemotaxis and M1 polarization (elevated CD86 and iNOS). Genetic POSTN knockdown, STAT3 or NF-κB inhibition, and CXCR2 blockade all diminished these effects. CXCL5 amplified a bidirectional loop by elevating macrophage CXCL5 and feeding back to NPCs to upregulate POSTN/IL-6, activate caspase-dependent apoptosis, and accelerate ECM catabolism (MMP13/MMP9 expression increased;Collagen II /Aggrecan expression decreased). In vivo, Postn deficiency reduced disc CXCL5 and M1 infiltration, preserved ECM, and improved MRI and histological scores.

POSTN coordinates a POSTN-STAT3/NF-κB-CXCL5 positive-feedback circuit that recruits and polarizes macrophages, exacerbating IDD. Multi-node blockade of the POSTN/STAT3-NF-κB/CXCL5-CXCR2 axis alleviates disc degeneration and has translational potential.