Development of a novel agent against life-threatening
sepsis requires the in-depth understanding of the relevant pathophysiology and therapeutic targets. Given the function of
microRNAs (
miRNAs) as potent
oligonucleotide therapeutics, here we investigated the pathophysiological role of exogenously applied
miRNA in
sepsis-induced multiple organ injury. In vitro, miR-16, miR-126, miR-146a, and miR-200b suppressed the production of pro-inflammatory
cytokines in RAW264.7 macrophage cells after
lipopolysaccharide (LPS) stimulation. Of these, miR-146a displayed the most highly suppressive effect, wherein the transcriptional activity of
nuclear factor kappa B (NF-κB) was decreased via targeting of
interleukin 1 receptor-associated kinase 1 and
tumor necrosis receptor-associated factor 6.
Sepsis was induced in mice via cecal
ligation and
puncture (CLP) and an
intravenous injection of a complex of miR-146a-expressing plasmid and
polyethyleneimine. Treatment with this complex significantly decreased the level of serum inflammatory
cytokines, attenuated organ injury including kidney injury, and led to increased survival from polymicrobial
sepsis induced by CLP. miR-146a-expressing plasmid was abundantly distributed in splenic macrophages, but not in renal parenchymal cells. CLP mice treated with miR-146a displayed significantly decreased NF-κB activation and splenocyte apoptosis.
Splenectomy diminished the anti-inflammatory effects of miR-146a. The collective results support the conclusion that the induction of miR-146a expression in splenic macrophages prevents excessive
inflammation and
sepsis-induced multiple organ injury. This study establishes a novel and critical pathophysiological role for splenic macrophage interference in
sepsis-related organ injury.