Background/Purpose: In healthy individuals, TREM-1 proteins are cell surface receptors expressed by hematopoietic cells of the myeloid lineage. TREM-1 is a potent amplifier of proinflammatory responses. TREM-2 acts to downregulate inflammatory cytokines and is associated with suppressive macrophages. In prior studies increased soluble TREM-1 (sTREM-1) levels in serum accurately correlated with sepsis. TREM-1 hyper-expression has been observed in auto-inflammatory responses, such as rheumatoid arthritis and inflammatory bowel disease. In both sepsis and arthritis models, TREM-1 inhibitors prevent tissue destruction caused by inflammation. We posit that TREM-1  plays a significant role in regulating SLE renal disease and that TREM-1 is involved in the amplification of the inflammatory response.

Methods: We have explored TREM-1 expression and function in a murine anti-glomerular basement membrane antibody-induced nephritis (anti-GBM) model which shares a number of relevant pathogenic features with lupus nephritis. Mice  were pre-sensitized on day -5 (5 days before induction of anti-GBM) with rabbit IgG (250 µg/mouse) in adjuvant. On day 0, the mice received anti-GBM serum; 200µg of total IgG in a 300µl volume intravenously per mouse. After induction of anti-GBM disease, urine was collected from 129/SvJ and B6 mice at different timepoints and sTREM-1 was assessed by ELISA. Renal disease was measured by proteinuria and renal pathology. The impact of a TREM-1 inhibitory peptide (LP17) was assessed.

Results: In the anti-GBM model, 129/SvJ mice developed severe GN, whereas B6 mice did not. Renal macrophages from 129/SvJ mice expressed elevated TREM-1 compared to B6 mice. Anti-GBM disease induced elevated urine sTREM-1 levels in 129/SvJ versus control B6 mice. After induction of anti-GBM disease, urine was collected from 129/SvJ and B6 mice at different timepoints and sTREM-1 was assessed by ELISA . Elevated sTREM-1  levels were detected in the urine of 129/SvJ mice from day 7 through day 21. In the anti-GBM model, TREM-1 blockade with an inhibitory peptide ameliorated renal inflammation compared to control peptide. TREM-1 blockade inhibited proteinuria, as well as renal disease as measured by GN class, severity of tubulo-interstitial disease, crescent formation, and inflammatory cell infiltrates. Elevated sTREM-1 levels were detected in serum of spontaneous murine lupus (SLN) models compared to controls and in SLN renal biopsies. Finally, elevated sTREM-1 levels were detected in serum of SLE patients with nephritis and TREM-1 was detected in renal biopsies from SLE patients but not controls.

Conclusion: These studies suggest that the TREM-1 hyper-expression in the nephritis prone 129/SvJ strain has critical pathogenic relevance, and that TREM-1 is amenable to therapeutic targeting for nephritis. These studies could have important implications in the understanding of pathogenic mechanisms driving SLE renal disease. More specific assays for nephritis, such as TREM-1 as a prognostic indicator of disease, might greatly enhance quality of therapeutic management for SLE nephritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/triggering-receptor-expressed-on-myeloid-cells-1-in-systemic-lupus-erythematosus/