TREM2 in Macrophages Promotes Renal Fibrosis via Activation of β‐Catenin Signalling Pathway in Obstructive Nephropathy

Obstructive nephropathy leads to renal fibrosis, and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) drives this macrophage-mediated process, but its mechanism remains unclear. This study investigated TREM2's role in macrophage polarisation and renal fibrosis progression. In human fibrotic kidneys, TREM2 expression was significantly elevated and co-localised with macrophages. Unilateral ureteral obstruction (UUO) modelling in mice recapitulated this upregulation, accompanied by renal fibrosis, M2 macrophage polarisation and glomerular filtration rate (GFR) reduction. Trem2 deficiency (Trem2-/-) significantly attenuated these pathological changes in UUO mice, preserving GFR. Separately, TREM2 inhibitory peptide sequence IA9 administration reduced renal fibrosis and M2 polarisation in UUO mice. In bone marrow-derived macrophages (BMDMs), Trem2 deficiency suppressed IL-4/IL-13-induced M2 polarisation, migration and β-catenin expression. Critically, lithium chloride (LiCl)-mediated β-catenin stabilisation rescued these impairments in Trem2-/- BMDMs. In conclusion, TREM2 promotes renal fibrosis by activating β-catenin signalling to drive profibrotic M2 macrophage responses, establishing TREM2 blockade as a therapeutic strategy for obstructive nephropathy.