LncRNA HCG18 loaded by polymorphonuclear neutrophil-secreted exosomes aggravates sepsis acute lung injury by regulating macrophage polarization

Abstract

Polymorphonuclear neutrophils (PMNs) exert significant roles in septic acute lung injury (ALI). Accumulating evidence suggests that PMN-derived exosomes (PMN-exo) are a novel subcellular entity that is the fundamental link between PMN-driven inflammation and tissue damage. However, the role of PMN-exo in septic ALI and the underlying mechanisms remain unclear. Tumor necrosis factor-α (TNF-α), a key regulator of innate immunity in septic ALI, was used to induce PMN activation in vitro. Using an in vitro co-culture system, the rat alveolar macrophage cell line NR8383 was co-cultured with TNF-α-stimulated PMN-released exosomes (TNF-α-exo) to further confirm the results of the in vitro studies and explore the underlying mechanisms involved. A septic lung injury model was established by cecal ligation and puncture surgery, and PMN-exo were injected into septic mice through the tail vein, and then lung injury, inflammatory release, macrophage polarization, and apoptosis were examined. The results reported that TNF-α-exo promoted the activation of M1 macrophages after i.p. injection in vivo or co-culture in vitro. Furthermore, TNF-α-exo affected alveolar macrophage polarization by delivering HCG18. Mechanistic studies indicated that HCG18 mediated the function of TNF-α-exo by targeting IL-32 in macrophages. In addition, tail vein injection of si-HCG18 in septic mice significantly reduced TNF-α-exo-induced M1 macrophage activation and lung macrophage death, as well as histological lesions. In conclusion, TNF-α-exo-loaded HCG18 contributes to septic ALI by regulating macrophage polarization. These findings may provide new insights into novel mechanisms of PMN-macrophage polarization interactions in septic ALI and may provide new therapeutic strategies for patients with sepsis.

Identification and analysis of MSC-Exo-derived LncRNAs related to the regulation of EMT in hypospadias

“…lncRNAs play an important role in different biological processes through sponge adsorption of miRNAs. For example, exosomes secreted by polymorphonuclear neutrophils may affect the polarization of alveolar macrophages by transferring HCG18 and adsorbing miR-146b, thus resulting in acute pulmonary injury [ 34 ]. Exosome-derived lncRNA HCG18 could promote the growth and metastasis of cholangiocarcinoma cells through the miR-424-5p/SOX9 axis of the PI3K/AKT pathway [ 35 ].…”