M1-like macrophages accelerate cartilage endplate remodelling and low back pain partially through TRADD-mediated necroptosis.

OBJECTIVE: This study aimed to investigate the role of M1-polarized macrophages in cartilage endplate (CEP) remodelling and low back pain (LBP). DESIGN: Human intervertebral disc samples were collected from patients with (n = 52) and without LBP (n = 5). Macrophage mTORC1 activation and M1-like polarization were analysed. Mice with myeloid lineage-specific TSC1 deletion (Tsc1cKO mice), which exhibit enhanced M1 macrophage polarization, were generated and subjected to surgery to induce LBP. CEP cells (CEPCs) were co-cultured with conditioned medium derived from macrophages of Tsc1cKO mice. CEP damage and LBP were assessed using histological scoring, immunostaining, spinal hypersensitivity, and radiographic analyses. Mice and CEPCs were treated with the TRADD inhibitor apostatin-1 to investigate the role of TRADD in CEP remodelling and LBP. RESULTS: Macrophage mTORC1 activation was increased in M1-polarized macrophages in CEPs during LBP. Tsc1cKO mice displayed a higher proportion of M1-like macrophages in the CEP (mean difference 9.9% [7.24%-12.56%], P < 0.001), with severe CEP remodelling and LBP. Rapamycin inhibited M1-polarized macrophage accumulation in the CEP (mean difference -14.7% [-18.92- -10.48%], P < 0.001) and ameliorated CEP remodelling and LBP. Using bioinformatics analyses, we found that TRADD-mediated CEPC necroptosis was a potential mediator of M1-polarized macrophages in LBP. Finally, apostatin-1 treatment attenujated CEP remodelling and LBP in mouse LBP and cell co-culture models. CONCLUSIONS: These findings highlight the role of mTORC1-dependent M1-polarized macrophages and TRADD-mediated necroptosis in CEP remodelling and LBP. Targeting these pathways may offer therapeutic strategies for the treatment of LBP.