TREM2 induces ligamentum flavum fibrosis by promoting TGF-β1 secretion from M2 macrophages

Lumbar spinal stenosis (LSS) is commonly caused by ligamentum flavum hypertrophy (LFH), yet the underlying mechanisms remain unclear. This study investigates the role of TREM2 in macrophages during LFH pathogenesis. Immune infiltration and single-cell analyses revealed increased M2 macrophage infiltration in LFH tissues, a finding validated in a bipedal standing mouse model where macrophage depletion attenuated fibrosis. In vitro, M2 macrophages promoted fibrosis in human ligamentum flavum cells in a TREM2-dependent manner. Mechanistically, TREM2 suppressed the transcription factor ETV7, which binds the TGF-β1 promoter to inhibit its transcription, while simultaneously activating the PI3K/Akt/HIF-2α axis to enhance TGF-β1 expression. TGF-β1 then activated Smad2/3 signalling via ALK5, driving fibrotic gene expression. Additionally, Galectin-3, which was markedly upregulated in LFH tissues, facilitated the activation of TREM2. TREM2 knockout mice exhibited reduced LFH, confirming in vivo relevance. Collectively, these findings demonstrate that TREM2 in M2 macrophages promotes LFH by relieving ETV7-mediated repression and activating the PI3K/Akt/HIF-2α/TGF-β1 cascade, positioning TREM2 as a potential therapeutic target for LSS.