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

A Tammaro,L M Butter,J Kers,G J D Teske,J C Leemans,G Navis,M C Dessing,J Damman,I Stroo,S Florquin,M Derive,D Emal,N Claessen

doi:10.1038/srep38275

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.

Highlights

In humans, renal triggering receptors expressed on myeloid cells (TREMs)-1 expression has been observed on interstitial cells of patients with obstruction-related hydronephrosis[15]
We quantified renal Trem[1] transcription by RT-PCR (Fig. 1B) and observed an increased expression in ischemia reperfusion (IR) kidneys compared to sham tissues, which was confirmed on the protein level by western blot and ELISA (Fig. 1C,D)
These findings indicate that renal IR may modulate the inflammatory response by regulation of TREM-1 surface expression

Summary

Introduction

Renal TREM-1 expression has been observed on interstitial cells of patients with obstruction-related hydronephrosis[15]. The treatment of patients with acute kidney injury in the context of DGF is purely supportive, whereas manipulation of innate immunity during necroinflammation might further reduce alloimmune priming, leading to a reduction in rejection. In the current study we investigated whether TREM-1 could be a potential target during experimental and human renal IR-induced injury. We investigated (1) the expression and function of TREM-1 in murine renal IR and (2) determined the association between non-synonymous single nucleotide variants (SNVs) in the TREM1 gene and outcomes following renal transplantation, with a particular interest for the risk to develop DGF

Objectives

Methods

Results

Conclusion