Extracellular microRNA 130b‐3p inhibits eCIRP‐induced inflammation

Abstract

Although microRNAs regulate mRNA expression intracellularly, they are often released into the circulation in inflammatory diseases. During sepsis, secreted extracellular cold-inducible RNAbinding protein (eCIRP) acts as a damage-associated molecular pattern (DAMP), inducing tissue damage by elevating inflammatory cytokines and chemokines. Here, we report that the circulating microRNA 130b-3p inhibits eCIRP-mediated sterile and cecal ligation and puncture (CLP)-induced non-sterile inflammation. We find that levels of miR-130b-3p are increased in the serum of septic mice and patients and that it strongly interacts with recombinant murine (rm) CIRP in vitro and with eCIRP in the serum of septic mice in vivo. Combining a miR-130b-3p mimic with rmCIRP significantly decreases TNF-a release by macrophages compared to only rmCIRP-treated cells. This combined treatment also dose-dependently decreases the affinity of rmCIRP with its receptor TLR4/ MD2. Finally, injection of a miR-130b-3p mimic significantly reduces rmCIRP-or CLP-induced systemic inflammation and acute lung injury in mice. These data show that extracellular miR-130b-3p functions as a novel endogenous inhibitor of eCIRP and point to an innovative therapeutic approach to treat inflammatory diseases.

Functional Analyses of Bovine Foamy Virus-Encoded miRNAs Reveal the Importance of a Defined miRNA for Virus Replication and Host–Virus Interaction

“…The high intracellular concentrations of miR-BF1-5p and miR-BF2-5p [8] may be a prerequisite (or at least an advantage) for extracellular functions (e.g., in the form of free or exosome-associated miRNAs with local or systemic effects) [61]. For instance, it has recently been shown that under conditions of bacterial sepsis, the extracellular form of the murine and human miR-130b-3p is released into the blood and interacts, thereby attenuating the pro-inflammatory function of CIRP (cold-inducible RNA binding protein), a ligand of TLR4-mediated innate inflammatory signaling [62,63].…”

Exosomes in Sepsis

“…Exosomes are abundant in microRNAs (miRNAs), small non-coding RNAs which regulate gene expression (44,47). Dysregulated miRNAs in sepsis patients include, but not limited to, miR-25, miR-130b-3p, miR-133a, miR-146, miR-150, and miR-223 (48,49). MiR-146 and miR-155 are well-characterized miRNAs induced by proinflammatory stimuli such as LPS and linked to TNF-α production (50).…”

Frontline Science: Extracellular CIRP generates a proinflammatory Ly6G+CD11bhi subset of low-density neutrophils in sepsis

“…Wild-type (WT) and CIRP −/− mice were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). 30,34,35 Mice were anesthetized with 2% isoflurane inhalation. The abdomen was shaved and made sterile with 10% povidone-iodine wash. After a 1 cm midline abdominal incision, the cecum was exposed and ligated at 1 cm from the tip with 4-0 silk suture.…”

“…However, we showed that stimulation of freshly isolated BMDNs with rmCIRP significantly increased the percentage of Ly6G + CD11b hi LDNs. In sepsis, because the eCIRP level is elevated in the circulation,27,34 the circulatory eCIRP may directly induce the generation of Ly6G + CD11b hi LDNs in the blood. In the flow cytometry gating, there might be some CD11b lo cells overlapping with the CD11b hi population.…”