miR-146a targeted to splenic macrophages prevents sepsis-induced multiple organ injury

Abstract

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.

Long noncoding RNA colorectal neoplasia differentially expressed alleviates sepsis‐induced liver injury via regulating miR‐126‐5p

“…miRNAs also wield diverse functions in sepsis. For example, miR‐146a in spleen macrophages can reduce organ injury caused by inflammation and sepsis; honokiol alleviates sepsis‐induced acute renal injury via miR‐218‐5p/HO‐1 signaling pathway . In this study, the expression of miR‐126‐5p was observed to be markedly upregulated in injured liver tissues and hepatic cells, and overexpressed miR‐126‐5p could notably induced apoptosis.…”

Mathematical modeling of septic shock: an innovative tool for assessing therapeutic hypotheses

“…The pro-inflammatory response then indirectly stimulates the production rate of the energetic (E) response (K inE ) and the production rate of the anti-inflammatory (A) response (K inA ). The energetic response stimulates both pro-inflammation and antiinflammation, while anti-inflammation serves as the immuno-regulatory component of the system by restoring intracellular homeostasis post-transcriptional regulatory mechanism for gene expression in many cellular processes, including the immune response, as well as playing a crucial role in the endotoxin tolerance system [34][35][36][37][38][48][49][50]. For example, when miR146, miR155 and miR125b are stimulated by LPS in human monocytic cells [51][52][53], they can inhibit TLR4/IL-1R signaling via the post-transcriptional regulation of signaling proteins such as IL-1 receptor-associated kinase 1 (IRAK-1) and TNF receptor-associated factor 6 (TRAF6) [49,53].…”

“…In order to consider the increasing importance of epigenetic regulation (including microRNA; miRNA) in sepsis [34][35][36][37][38], the objective of the present study was to improve the model proposed by Calvano et al [28] by adding epigenetic regulatory loops. Moreover, we aimed to obtain further insights into the therapeutic options for modifying the pro-/anti-inflammatory balance by including a pharmacology modeling stratum.…”

The Protective Effects of Melatonin Against LPS-Induced Septic Myocardial Injury: A Potential Role of AMPK-Mediated Autophagy

“…Interestingly, decreased autophagy was reported to contribute to the pathogenesis and severity of sepsis, especially septic myocardial injury (11)(12)(13). The mechanisms involved can be attributed to the increased secretion of pro-inflammatory cytokines (14)(15)(16). These imply the potential role of autophagy in decreasing pro-inflammatory cytokines and protecting against septic injury.…”