TREM1/3 Deficiency Impairs Tissue Repair After Acute Kidney Injury and Mitochondrial Metabolic Flexibility in Tubular Epithelial Cells.

Alessandra Tammaro,Marco Colonna,Jaklien C Leemans,Nike Claessen,Sandrine Florquin,Angelique M L Scantlebery,Alessandra Soriani,Mark C Dessing,Elena Rampanelli,Loes M Butter,Cristiana Borrelli

doi:10.3389/fimmu.2019.01469

Abstract

Long-term sequelae of acute kidney injury (AKI) are associated with incomplete recovery of renal function and the development of chronic kidney disease (CKD), which can be mediated by aberrant innate immune activation, mitochondrial pathology, and accumulation of senescent tubular epithelial cells (TECs). Herein, we show that the innate immune receptor Triggering receptor expressed on myeloid cells-1 (TREM-1) links mitochondrial metabolism to tubular epithelial senescence. TREM-1 is expressed by inflammatory and epithelial cells, both players in renal repair after ischemia/reperfusion (IR)-induced AKI. Hence, we subjected WT and TREM1/3 KO mice to different models of renal IR. TREM1/3 KO mice displayed no major differences during the acute phase of injury, but increased mortality was observed in the recovery phase. This detrimental effect was associated with maladaptive repair, characterized by persistent tubular damage, inflammation, fibrosis, and TEC senescence. In vitro, we observed an altered mitochondrial homeostasis and cellular metabolism in TREM1/3 KO primary TECs. This was associated with G2/M arrest and increased ROS accumulation. Further exposure of cells to ROS-generating triggers drove the cells into a stress-induced senescent state, resulting in decreased wound healing capacity. Treatment with a mitochondria anti-oxidant partly prevented the senescent phenotype, suggesting a role for mitochondria herein. In summary, we have unraveled a novel (metabolic) mechanism by which TREM1/3 deficiency drives senescence in TECs. This involves redox imbalance, mitochondrial dysfunction and a decline in cellular metabolic activities. These finding suggest a novel role for TREM-1 in maintaining tubular homeostasis through regulation of mitochondrial metabolic flexibility.

Highlights

Acute kidney injury (AKI) remains a financial burden for society due to its high morbidity and mortality rates
Since Triggering receptor expressed on myeloid cells-1 (TREM-1) protein remains highly expressed during active repair (t = 5) and that TREM-1+ cells co-localize with Lotus tetragonolobus lectin (LTL), a proximal tubular marker (Figure 1C), we further investigated the role of TREM-1 in tissue repair
Triggering Receptor Expressed on Myeloid cells-1 (TREM1)/3 KO animals displayed increased mortality during the recovery phase compared to WT mice (Figure 1D), renal function and inflammatory parameters, such as keratinocyte chemoattractant (KC) and monocyte chemoattractant protein-1 (MCP-1) (Table 1) were unchanged in both animal strains in sham or day 1-5 post-IR

Summary

Introduction

Acute kidney injury (AKI) remains a financial burden for society due to its high morbidity and mortality rates. The proximal tubular epithelial cells (TECs), have a high metabolic rate, sensitive to ischemic injuries [2]. The renal epithelium has the ability to regenerate after injury; surviving TECs enter the cell cycle within a few hours following AKI, in order to promote tubular proliferation and return to homeostasis [3,4,5]. This is the so-called “adaptive repair” post-AKI, which results in the recovery of renal function. It is not surprising that mitochondrial dysfunction in TECs is thought to be a pathogenic mechanism underlying the AKI-CKD transition [8,9,10]

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