TREM-1 in lupus nephritis

Lupus nephritis results from the rapid recruitment of leukocytes into renal tissue causing a destructive inflammatory response. Serial renal biopsies are not feasible, however, a better understanding of pathogenic mechanisms driving kidney diseases and more specific assays could greatly enhance prognosis and treatment. As a “first look” we will determine if Triggering Receptor Expressed on Myeloid (TREM) family member proteins, TREM-1 and TREM-2, are hyper-expressed in systemic lupus erythematosus (SLE) nephritis. In healthy individuals, TREM 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. TREM-1 is hyper-expressed on peripheral blood monocytes, but not neutrophils, in sepsis. Moreover, increased soluble TREM-1 (sTREM-1) levels in serum accurately correlate with sepsis. TREM-1 hyper-expression is 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 and TREM-2 play significant and opposing roles in regulating SLE renal disease with TREM-1 involved in amplification and TREM-2 in the resolution of the inflammatory response. We have explored TREM-1 expression and function in a murine anti-glomerular basement membrane antibody-induced nephritis (anti-GBM) model. In the anti-GBM model, TREM-1 blockade with inhibitory peptide ameliorated renal inflammation compared to control peptide. Elevated sTREM-1 levels were also detected in serum of SLE patients with nephritis and in serum of spontaneous murine lupus models compared to controls. TREM-1 was also detected in renal biopsies from SLE patients and murine lupus mice but not controls. The proposed studies will survey the expression of TREM-1 and TREM-2 in SLE, which has never been described, from well-characterized SLE patients and other renal diseases including autoinflammatory diseases (anti-neutrophil cytoplasmic antibody mediated disease and IgA nephropathy) and non-inflammatory kidney diseases (membranous nephropathy and focal segmental glomerulosclerosis). First, we will determine sTREM-1 and sTREM-2 levels in sera and urine of patients with SLE and other kidney diseases compared to healthy subjects. Second, TREM-1 and TREM-2 expression profiles in kidney biopsy specimens will be compared in SLE and other renal diseases. We will determine specific cell types expressing TREM-1 and TREM-2 in biopsy specimens. Third, we will ascertain if a TREM-1 inhibitory peptide can curtail nephritis in two murine lupus models. Our long term goals are to determine whether relative sTREM-1 and sTREM-2 levels might be valuable as prognostic indicators of renal inflammation and whether TREM-1 inhibitors might prevent end stage renal disease.