TREM2+ Macrophages Orchestrate Ontogeny-Specific Protective Functions in Diabetic Kidney Disease

Background: Macrophages are early responders in diabetic kidney disease (DKD), but their roles remain debated. While some subsets drive inflammation, others promote repair. A key gap is how macrophage origin influences these effects. TREM2, a lipid-sensing receptor involved in metabolic remodeling, is expressed in both tissue-resident and monocyte-derived macrophages. We hypothesized that TREM2 mediates compartment-specific protection in DKD through ontogeny-dependent programs. Methods: We used global TREM2 knockout mice, CX3CR1GFP/+/CCR2RFP/ dual-reporter bone marrow chimeras, and reciprocal bone marrow transplantation (BMT) under HFD-STZ-induced DKD. We combined scRNAseq of kidney immune cells, macrophage functional assays, and histopathology to assess how TREM2 loss in different macrophage compartments affects renal injury. Results: Global TREM2 deletion led to tubular injury, lipid accumulation, and fibrosis, with macrophage dysfunction, which was characterized by reduced lipid uptake, impaired efferocytosis, and increased tubular apoptosis and senescence. To understand how these impairments map to macrophage subtypes, we performed scRNA-seq, which showed TREM2 expression in both resident and infiltrating macrophages, but with divergent transcriptional states: resident macrophages were enriched for metabolic clearance, and infiltrating cells were enriched in pro-inflammatory pathways. In BMT studies, transplantation of TREM2-deficient marrow into WT recipients was sufficient to drive tubular injury and lipid accumulation, implicating infiltrating TREM2+ macrophages' role in tubulointerstitial protection. Conversely, TREM2 KO recipients developed consistent glomerular enlargement regardless of donor marrow (WT or KO), while tubular injury and lipid accumulation were not further exacerbated beyond those observed in WT recipients with KO bone marrow. These findings suggest that resident TREM2+ macrophages are required for maintaining glomerular integrity. Conclusion: TREM2+ macrophages have origin-specific protective roles in DKD: infiltrating cells mitigate tubular injury, while resident macrophages preserve glomerular integrity. These findings underscore ontogeny-specific immunometabolism as a critical framework for understanding immune regulation in DKD and may help inform future macrophage-targeted therapies. Funding: NIDDK Support