MiR-181a-5p Delivered by Adipose-Derived Mesenchymal Stem Cell Exosomes Alleviates Klebsiella pneumonia Infection-Induced Lung Injury by Targeting STAT3 Signaling

Abstract

Background. Klebsiella pneumoniae (K. pneu) is a leading cause of gram-negative pneumonia, which requires effective treatment. Adipose-derived mesenchymal stem cell- (ADSC-) derived exosomal microRNAs (miRNAs) have presented the inhibitory effect of multiple diseases. However, the function of ADSC-derived exosomal miRNAs in K. pneu remains unclear. Aim. In this study, we aimed to explore the effect of ADSC-derived exosomal miR-181-5p on K. pneu infection-induced lung injury. Methods. C57BL/6 mouse model was established by infection of K. pneu. ADSCs and exosomes were extracted and characterized in vitro. The translocation of ADSC-derived exosomes to bone marrow-derived macrophages (BMDMs) was detected. The level of miR-181a-5p was detected by real-time PCR. The secretion of inflammatory factors was determined by ELISA. The interaction between miR-181a-5p with STAT3 was identified. Results. We successfully isolated the ADSCs that express positive markers CD90 and CD105 rather than CD31 and CD45. The exosomal miR-181a-5p secreted by ADSCs were internalized by BMDM and K. pneu infection stimulated the miR-181a-5p level in bronchoalveolar lavage fluid (BALF) and BMDM. ADSC-derived exosomal miR-181a-5p repressed pulmonary outgrowth and dissemination of K. pneu infection in mice, repressed cellular infiltration in lung tissue, and attenuated the inflammasome activity and the levels of IL-1β and IL-18 in the lung. Mechanically, miR-181a-5p was able to inhibit STAT3 expression at posttranscriptional levels and repressed Nlrp3 and Asc expression in BMDM. Conclusion. Consequently, we concluded that ADSC-derived exosomal miR-181a-5p alleviated Klebsiella pneumonia infection-induced lung injury by targeting STAT3 signaling. ADSC-derived exosomal miR-181a-5p may serve as a potential candidate for the treatment of Klebsiella pneumonia infection-induced lung injury.

LOXL4 Shuttled by Tumor Cells–derived Extracellular Vesicles Promotes Immune Escape in Hepatocellular Carcinoma by Activating the STAT1/PD-L1 Axis

“…Furthermore, to verify whether EV internalization plays a necessary role in the effect on BMDM, we added GW4869 (10 M) to the coculture system of wild-type Hepa 1–6 cells and BMDM to inhibit EV secretion. The treated groups were compared with the untreated group, and after coculturing for 2 days, BMDM was collected for the detection of LOXL4 mRNA levels and protein levels of STAT1, p-STAT1, and PD-L1 29 . The results showed that after GW4869 treatment, the mRNA level of LOXL4 significantly decreased, and the protein levels of LOXL4, STAT1, p-STAT1, and PD-L1 were also significantly downregulated (Fig.…”

“…The treated groups were compared with the untreated group, and after coculturing for 2 days, BMDM was collected for the detection of LOXL4 mRNA levels and protein levels of STAT1, p-STAT1, and PD-L1. 29 The results showed that after GW4869 treatment, the mRNA level of LOXL4 significantly decreased, and the protein levels of LOXL4, STAT1, p-STAT1, and PD-L1 were also significantly downregulated (Fig. 4G-H).…”

Role of microRNAs in Immune Regulation with Translational and Clinical Applications

“…Legionella pneumophila infection caused a pro-inflammatory reaction in murine macrophages through the induction of miR-125a-3p, that targets N-terminal asparagine amidohydrolase 1 (NTAN1) enzyme [73]. Lung injury induced by Klebsiella pneumoniae infection was alleviated by miR-181a-5p, delivered by adipose-derived mesenchymal stem cell (ADSC)released exosomes [74]. Intracellular survival of Brucella abortus was found to be suppressed by miR-125b-5p through targeting the cytoplasmic zinc finger protein A20, resulting in the activation of NFκB signaling and increased production of tumor necrosis factor α (TNFα) [75].…”