Background/Purpose: ANCA-associated vasculitis (AAV) is a small-vessel vasculitis that can lead to life-threatening renal injury. Neutrophils, monocytes and macrophages play a pivotal role not only in sustaining inflammation and promoting fibrosis, but also in mediating tissue repair. In this study, we investigated the role of TREM-1 and TREM-2, two key receptors expressed on myeloid cells, in regulating myeloid cells activation and their contribution to AAV-induced kidney injury.

Methods: We analyzed blood and renal biopsy samples from patients with AAV and controls, as well as publicly available transcriptomic datasets. Surface expression of TREM-1 and TREM-2 on circulating leukocytes was assessed by flow cytometry, while serum concentrations of soluble TREM-1 (sTREM-1) and sTREM-2 were measured by ELISA. To investigate the role of TREM-1 and TREM-2 in vivo, we used a murine model of MPO-ANCA-induced glomerulonephritis. Disease was induced in wild-type, Trem1-/- or Trem2-/- mice, via passive transfer of anti-MPO antibodies. Renal inflammation and tissue injury were assessed by histological scoring.

Results: Publicly available transcriptomic datasets from microdissected renal biopsies of AAV patients revealed significant upregulation of TREM1 and TREM2 in glomerular compartments, whereas only TREM2 was upregulated in the tubulointerstitial region. Single-cell RNA sequencing of renal CD45⁺ immune cells showed a strong enrichment of TREM1⁺ neutrophils in AAV samples, while TREM2 was restricted to two macrophage subsets distinguished by FOLR2 expression.In peripheral blood, surface expression of TREM-1 and TREM-2 on circulating neutrophils and monocytes was similar between AAV patients and controls, except for higher mean TREM-1 fluorescence intensity on neutrophils in AAV. Serum levels of sTREM-1 and sTREM-2 were significantly elevated in AAV patients (both GPA and MPA) compared to controls (sTREM-1: 608.9 ± 386.2 vs. 209.2 ± 87.2 pg/mL, p< 0.0001; sTREM-2: 996.7 ± 788.7 vs. 253.8 ± 105.0 pg/mL, p< 0.0001), and both were significantly higher in AAV patients with renal involvement compared to those without. Furthermore, sTREM-1 positively correlated with CRP (r=0.30, p=0.045), serum creatinine (r=0.61, p< 0.0001) and BVAS (r=0.48, p< 0.001), and sTREM-2 correlated with serum creatinine (r=0.61, p=0.009) and BVAS (r=0.39, p=0.01).To investigate the role of TREM-1 and TREM-2 in vivo, we induced MPO-ANCA glomerulonephritis in wild-type, Trem1-/-, and Trem2-/- mice. Trem1-/- mice showed milder kidney injury, with fewer crescentic and necrotic glomeruli and increased normal glomeruli. Neutrophil infiltration was significantly reduced in the kidneys of Trem1-/- mice. In contrast, Trem2-/- mice developed more severe disease and showed reduced survival compared to wild-type mice.

Conclusion: TREM-1 and TREM-2 are differentially involved in AAV-associated glomerulonephritis. Their circulating levels correlate with disease activity, and mouse models show opposing roles in renal injury: TREM-1 promotes inflammation, whereas TREM-2 is protective. These findings identify TREM pathways as promising therapeutic targets in AAV.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/trem-1-and-trem-2-define-inflammatory-and-protective-axes-in-anca-associated-glomerulonephritis/