Peripheral Circulating Exosome-Mediated Delivery of miR-155 as a Novel Mechanism for Acute Lung Inflammation

Abstract

Emerging evidence has revealed that excessive activation of macrophages may result in an adverse lung inflammation involved in sepsis-related acute lung injury (ALI). However, it has never been clearly identified whether peripheral circulating serum exosomes participate in the pathogenesis of sepsis-related ALI. Therefore, the purposes of our study were to investigate the effect of serum exosomes on macrophage activation and elucidate a novel mechanism underlying sepsisrelated ALI. Here we found that exosomes were abundant in the peripheral blood from ALI mice and selectively loaded microRNAs (miRNAs), such as miR-155. In vivo experiments revealed that intravenous injection of serum exosomes harvested from ALI mice, but not control mice, increased the number of M1 macrophages in the lung, and it caused lung inflammation in naive mice. In vitro, we demonstrated that serum exosomes from ALI mice delivered miR-155 to macrophages, stimulated nuclear factor kB (NF-kB) activation, and induced the production of tumor necrosis factor alpha (TNF-a) and interleukin (IL)-6. Furthermore, we also showed that serum exosome-derived miR-155 promoted macrophage proliferation and inflammation by targeting SHIP1 and SOCS1, respectively. Collectively, our data suggest the important role of circulating exosomes secreted into peripheral blood as a key mediator of septic lung injury via exosome-shuttling miR-155.

miR‐148a suppresses inflammation in lipopolysaccharide‐induced endometritis

“…Mature miRNAs bind to the 3′‐untranslated regions (UTRs) or coding sequences of specific target mRNAs, thereby resulting in their translational repression or degradation . In recent decades, some miRNAs, which are primarily highly conservative, have rawn more and more attention due to their vital function in a wide range of basic biological processes . Although miRNAs are closely correlated with tumorigenesis and progression in various cancers, they also occupy an essential place in the progress of innate immune response .…”

“…20 In recent decades, some miRNAs, which are primarily highly conservative, have rawn more and more attention due to their vital function in a wide range of basic biological processes. 21,22 Although miRNAs are closely correlated with tumorigenesis and progression in various cancers, they also occupy an essential place in the progress of innate immune response. 23 For example, miR-146 is strongly induced in LPS-challenged THP-1 cells and negatively regulates the inflammatory response by inhibiting TNFR-associated factor 6 (TRAF6) and IL-1R-associated kinase-1 (IRAK1), two key factors of the TLR4 signalling.…”

Exosomes in Sepsis

“…Caspase-1 encapsulated in exosomes released from LPS-challenged macrophages induced lung endothelial cell apoptosis, indicating their contribution to the disruption of the alveolar-capillary barrier (30). The injection of exosomes isolated from the serum of LPS-challenged mice increased the number of total and M1 macrophages and the levels of TNF-α and IL-6 in the lungs, which was associated with the increase of miR-155 (52). Although ARDS has attracted clinical attention for decades, none of the proposed therapies for ARDS including sivelestat sodium, neutrophil elastase inhibitor, have yet to show its clinical effect sufficiently (64).…”

“…After both in vitro and in vivo LPS stimulation, exosomes contained increased amount of miR-146a and miR-155 (51). Exosomal miR-155 induced IL-6 and TNF-α production via NF-kB activation by targeting suppressor of cytokine signaling-1 (SOCS-1), and promoted macrophage proliferation by targeting SHIP1 (52). Exosomal miR-19b-3p was also increased by LPS stimulation and promoted M1 polarization and cytokine production (53).…”

“…Although ARDS has attracted clinical attention for decades, none of the proposed therapies for ARDS including sivelestat sodium, neutrophil elastase inhibitor, have yet to show its clinical effect sufficiently (64). We might have overlooked the significance of exosomes as they cause inflammatory response and cell death in lungs independent of neutrophil activity (30,52).…”