Effect of TREM-1 blockade and single nucleotide variants in experimental renal injury and kidney transplantation

Abstract

Renal ischemia reperfusion (IR)-injury induces activation of innate immune response which sustains renal injury and contributes to the development of delayed graft function (DGF). Triggering receptor expressed on myeloid cells-1 (TREM-1) is a pro-inflammatory evolutionary conserved pattern recognition receptor expressed on a variety of innate immune cells. TREM-1 expression increases following acute and chronic renal injury. However, the function of TREM-1 in renal IR is still unclear. Here, we investigated expression and function of TREM-1 in a murine model of renal IR using different TREM-1 inhibitors: LP17, LR12 and TREM-1 fusion protein. In a human study, we analyzed the association of non-synonymous single nucleotide variants in the TREM1 gene in a cohort comprising 1263 matching donors and recipients with post-transplant outcomes, including DGF. Our findings demonstrated that, following murine IR, renal TREM-1 expression increased due to the influx of Trem1 mRNA expressing cells detected by in situ hybridization. However, TREM-1 interventions by means of LP17, LR12 and TREM-1 fusion protein did not ameliorate IR-induced injury. In the human renal transplant cohort, donor and recipient TREM1 gene variant p.Thr25Ser was not associated with DGF, nor with biopsy-proven rejection or death-censored graft failure. We conclude that TREM-1 does not play a major role during experimental renal IR and after kidney transplantation.

Metabolic Flexibility and Innate Immunity in Renal Ischemia Reperfusion Injury: The Fine Balance Between Adaptive Repair and Tissue Degeneration

“…Interestingly, however, TREM-1 was also shown to mediate an inhibitory effect on necroptosis and pyroptosis in neonatal lung tissue, as suggested in previous work by Syed et al (145). In our hands, in the early phase of renal IRI, TREM-1 modulation did not affect tubular damage or renal function (146). However, we did find that mice lacking TREM-1 displayed maladaptive repair characterized by persistent tubular damage, inflammation, fibrosis, and mitochondrial dysfunction-induced TEC senescence when exposed to renal IRI (52).…”

Association of the salivary triggering receptor expressed on myeloid cells/its ligand peptidoglycan recognition protein 1 axis with oral inflammation in kidney disease

“…sTREM‐1 has been studied in sepsis and in other systemic conditions. Previous studies have observed that acute and chronic kidney injury and hemodialysis activate innate immunity and thus TREM‐1 expression . According to the authors’ knowledge there are only a few studies on the usefulness of TREM‐1 as an oral inflammatory biomarker .…”

Extracellular CIRP as an endogenous TREM-1 ligand to fuel inflammation in sepsis

“…This could be artificially elevated because of conditions present in vivo that we cannot reproduce artificially, such as involvement of other biological cofactors, temperature, and molecular stability. The TREM-1 antagonists function primarily as decoy receptors and to prevent receptor dimerization (21,30). Additionally, Sigalov et al have developed a ligand-independent inhibitor of TREM-1 (31,32).…”