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Published on: September 11, 2020
Kidney mitochondrial DNA contributes to systemic IL-6 release in sepsis-associated acute kidney injury
Avnee J Kumar1,2, Katharine Epler1,2, Jing Wang3
1VA San Diego Healthcare System, San Diego, California, USA.
Abstract:
Mitochondrial dysfunction is a major mechanism of acute kidney injury (AKI), and increased circulating interleukin 6 (IL-6) is associated with systemic inflammation and death due to sepsis. We tested whether kidney mitochondrial DNA (mtDNA) contributes to IL-6 release in sepsis-associated AKI via Toll-like receptor 9 (TLR9). In a murine model of sepsis via cecal ligation and puncture (CLP), we used next-generation sequencing of plasma mtDNA to inform the design of optimal target sequences for quantification by droplet digital PCR, and to identify single-nucleotide polymorphisms (SNPs) to infer tissue origin. We found significantly higher concentrations of plasma mtDNA after CLP versus shams and that plasma mtDNA SNPs matched kidney SNPs more than other organs. Kidney mtDNA contributed directly to IL-6 and mtDNA release from dendritic cells in vitro and kidney mitochondria solution led to higher IL-6 concentrations in vivo. IL-6 release was mitigated by a TLR9 inhibitor. Finally, plasma mtDNA was significantly higher in septic patients with AKI compared with those without AKI and correlated significantly with plasma IL-6. We conclude that AKI contributes to increased circulating IL-6 in sepsis via mtDNA release. Targeting kidney mitochondria and mtDNA release are potential translational avenues to decrease mortality from sepsis-associated AKI.
Insights
Kidney mitochondrial DNA (mtDNA) released during sepsis-associated acute kidney injury (AKI) promotes interleukin-6 (IL-6) release via Toll-like receptor 9 (TLR9). Targeting kidney mtDNA may reduce sepsis mortality.
Area of Science:
- Immunology
- Nephrology
- Mitochondrial Biology
Background:
- Mitochondrial dysfunction is a key mechanism in acute kidney injury (AKI).
- Elevated circulating interleukin-6 (IL-6) correlates with sepsis mortality and systemic inflammation.
- The role of kidney mitochondrial DNA (mtDNA) in sepsis-associated AKI and IL-6 release remains unclear.
Purpose of the Study:
- To investigate if kidney mtDNA contributes to IL-6 release in sepsis-associated AKI.
- To determine the involvement of Toll-like receptor 9 (TLR9) in this process.
- To explore potential therapeutic targets for sepsis-associated AKI.
Main Methods:
- A murine model of sepsis induced by cecal ligation and puncture (CLP).
- Next-generation sequencing and droplet digital PCR for plasma mtDNA quantification and SNP analysis.
- In vitro studies with dendritic cells and in vivo experiments with kidney mitochondria solution.
- Administration of a TLR9 inhibitor and analysis of plasma mtDNA and IL-6 in septic patients with and without AKI.
Main Results:
- Plasma mtDNA concentrations were significantly elevated after CLP in mice.
- mtDNA single-nucleotide polymorphisms (SNPs) indicated kidney origin.
- Kidney mtDNA stimulated IL-6 release from dendritic cells in vitro and increased IL-6 in vivo.
- TLR9 inhibition mitigated IL-6 release.
- Septic patients with AKI exhibited higher plasma mtDNA and IL-6 levels compared to those without AKI.
Conclusions:
- AKI contributes to elevated circulating IL-6 in sepsis through mtDNA release.
- Kidney mtDNA activates IL-6 release via TLR9.
- Targeting kidney mitochondria and mtDNA release presents a potential therapeutic strategy to reduce mortality in sepsis-associated AKI.
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