Exosomes from adipose-derived mesenchymal stem cells alleviate sepsis-induced lung injury in mice by inhibiting the secretion of IL-27 in macrophages

Abstract

Acute lung injury (ALI) represents a frequent sepsis-induced inflammatory disorder. Mesenchymal stromal cells (MSCs) elicit anti-inflammatory effects in sepsis. This study investigated the mechanism of exosomes from adipose-derived MSCs (ADMSCs) in sepsis-induced ALI. The IL-27r−/− (WSX-1 knockout) or wild-type mouse model of sepsis was established by cecal ligation and puncture (CLP). The model mice and lipopolysaccharide (LPS)-induced macrophages were treated with ADMSC-exosomes. The content of Dil-labeled exosomes in pulmonary macrophages, macrophages CD68+ F4/80+ in whole lung tissues, and IL-27 content in macrophages were detected. The mRNA expression and protein level of IL27 subunits P28 and EBI3 in lung tissue and the levels of IL-6, TNF-α, and IL-1β were measured. The pulmonary edema, tissue injury, and pulmonary vascular leakage were measured. In vitro, macrophages internalized ADMSC-exosomes, and ADMSC-exosomes inhibited IL-27 secretion in LPS-induced macrophages. In vivo, IL-27 knockout attenuated CLP-induced ALI. ADMSC-exosomes suppressed macrophage aggregation in lung tissues and inhibited IL-27 secretion. ADMSC-exosomes decreased the contents of IL-6, TNF-α, and IL-1β, reduced pulmonary edema and pulmonary vascular leakage, and improved the survival rate of mice. Injection of recombinant IL-27 reversed the protective effect of ADMSC-exosomes on sepsis mice. Collectively, ADMSC-exosomes inhibited IL-27 secretion in macrophages and alleviated sepsis-induced ALI in mice.

Advances in the use of exosomes for the treatment of ALI/ARDS

“…MSCs-derived exosomes have shown good therapeutic effects in preclinical models of ALI/ARDS. MSCs-derived exosomes have been shown to inhibit macrophage aggregation in lung tissue, suppress IL-27 secretion, reduce the levels of pro-inflammatory factors in lung tissue, and improve the survival rate of mice ( 79 ). Wei et al.…”

“…In addition, exosomes can also bind to specific receptors on the surface of target cells. Wang et al found that MSCs-derived exosomes could inhibit the aggregation of pulmonary macrophages and suppressed the synthesis and release of IL-27, and decrease the contents of IL-6, TNF-a, and IL-1b, thus alleviating sepsis-induced lung injury (79). Injection of recombinant IL-27 reversed the protective effect of exosomes on sepsis-induced lung injury.…”

“…MSCs-derived exosomes have shown good therapeutic effects in preclinical models of ALI/ARDS. MSCs-derived exosomes have been shown to inhibit macrophage aggregation in lung tissue, suppress IL-27 secretion, reduce the levels of pro-inflammatory factors in lung tissue, and improve the survival rate of mice (79). Wei et al reported that human umbilical cord MSCs-derived exosomes reduced the levels of inflammatory factors and inhibited lung inflammation and oxidative stress in LPS-induced ALI by inducing autophagy in vivo (141).. Lastly, Tian et al demonstrated the therapeutic effects of exosomes (primarily improved pathological injury and promoted M2 macrophage polarization) derived from adipose-derived MSCs on septic lung injury in mice (100).…”

Molecular Insight into the Therapeutic Effects of Stem Cell-Derived Exosomes in Respiratory Diseases and the Potential for Pulmonary Delivery

“…IL-27 is a cytokine that increases during sepsis, and its suppression could be a potential target in treating sepsis [ 92 ]. ASC-Exos have been shown to attenuate lung injury in septic mice by decreasing pulmonary macrophages and reducing their IL-27 expression [ 93 ]. The molecular mechanism of action of SC-Exos could be related to their miRNA content.…”

“…A study identified exosomal miR-16-5p derived from ASC as a regulator of TLR4 in septic mice. By this mechanism, ASC-Exos promoted macrophage polarization and alleviated sepsis-induced lung injury [ 93 ].…”