TAFA4 Mitigates Intervertebral Disc Degeneration by Modulating Macrophage Polarization and Inhibiting ROS-NLRP3...

Intervertebral disc degeneration (IVDD) is a complex pathological process involving inflammation, oxidative stress, and immune dysregulation. Emerging evidence suggests that neuroimmune interactions contribute to IVDD progression, but the role of neuropeptide-like factors remains poorly understood.

We investigated whether Gαi-interacting protein (GINIP+) sensory neurons infiltrate degenerative discs and secrete TAFA chemokine like family member 4 (TAFA4), a neuron-derived cytokine known to influence macrophage activity. In vivo and in vitro models were used to assess TAFA4 expression, its regulatory effects on macrophage polarization, reactive oxygen species (ROS) production, inflammasome activation, and disc cell phenotype. Knockdown of TAFA4 was achieved via lentiviral transduction in rabbit discs and cell coculture models.

TAFA4 was upregulated in IVDD tissues and colocalized with GINIP+ neurons. Knockdown of TAFA4 in vivo exacerbated disc degeneration, increased M1 macrophage presence, elevated ROS levels, and activated the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. In vitro, GINIP+ neurons promoted macrophage M2 polarization and interleukin (IL)-10 production while suppressing tumor necrosis factor-α and IL-1β. These effects were reversed by TAFA4 knockdown. Moreover, TAFA4 attenuated ROS-dependent NLRP3 activation and preserved anabolic marker expression (ACAN [aggrecan], COL II [type II collagen], SOX9 [SRY-box transcription factor 9]), while reducing catabolic and hypertrophic-related markers (MMP13 [matrix metalloproteinase 13], ADAMTS5 [a disintegrin and metalloproteinase with thrombospondin motifs 5], COL X [collagen type X alpha 1 chain], RUNX2 [Runt-related transcription factor 2]) in nucleus pulposus cells.

TAFA4 acts as a neuron-derived mediator of neuroimmune crosstalk in IVDD that modulates macrophage polarization and oxidative stress, thereby delaying disc degeneration. This neuron-immune axis represents a potential therapeutic target.