Spatially Distinct TREM2+ Macrophages Are Associated with Compartment-Specific Protection in Diabetic Kidney Disease

BACKGROUND: Diabetic kidney disease (DKD) is driven by complex pathological mechanisms including lipid accumulation, chronic inflammation, and fibrosis, contributing to progressive kidney dysfunction. Macrophages are key contributors to DKD pathogenesis, yet their functional heterogeneity in the diabetic kidney remains poorly defined. While TREM2+ macrophages have been identified within the diabetic microenvironment, the relationship between their developmental origin, anatomical localization, and functional specialization remains unclear. METHODS: In this study, we integrated single cell-RNA sequencing, spatial transcriptomic analysis of diabetic OVE26 kidneys, and reciprocal bone marrow transplantation in a high fat diet plus streptozotocin-induced diabetic model to examine how TREM2+ macrophages are distributed across renal compartments and how TREM2 deficiency affects DKD injury. RESULTS: Global TREM2 deficiency markedly exacerbated tubulointerstitial injury and glomerular hypertrophy in DKD, establishing TREM2 as a protective factor. Single-cell RNA sequencing and spatial mapping revealed that TREM2 induction in diabetic kidneys occurs in two spatially distinct macrophage populations: Mrc1+ kidney-resident macrophages localized to the periglomerular niche, and Ccr2+ monocyte-derived macrophages infiltrating the tubulointerstitium. Transcriptomic and functional analyses were consistent with a role of TREM2 in macrophage phagocytic and lipid-handling programs. Its loss led to the downregulation of phagosome and endocytic pathways, resulting in failed clearance of apoptotic debris and lipid aggregates, which was particularly pronounced in the tubulointerstitium. Reciprocal bone marrow transplant experiments suggest that recipient-resident TREM2 was more associated with preservation of glomerular structure, whereas donor-derived hematopoietic TREM2 was more strongly associated with limiting tubular lipid accumulation, apoptotic tubular epithelial cells, and tubulointerstitial injury. CONCLUSIONS: These findings suggested that TREM2-expressing macrophages contributed to compartment-specific protective responses in diabetic kidney disease. TREM2 deficiency was associated with greater diabetic glomerular and tubular injury, with distinct phenotypes observed in donor hematopoietic and recipient compartments.