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.
Highlights
Sepsis is a fatal syndrome featured by abnormal host response to invasive pathogens, which involves hemodynamic changes and leads to a variety of life-threatening organ dysfunction [1]
We used flow cytometry was used to detect the level of Interleukin 27 (IL-27) in bone marrow-derived macrophages (BMDMs) and the results indicated that the ratio of F4/80+ IL-27 +BMDMs was RESULTS Knockout of IL-27 attenuated lung injury induced by cecal ligation and puncture (CLP) To explore the relationship between IL-27 and CLP-induced acute lung injury, we first detected the level of IL-27 in serum using notably decreased after adipose-derived MSCs (ADMSCs)-exosomes incubation compared with LPS treatment alone (Fig. 3F)
Recent evidence has indicated the crucial role of IL-27 in the pathogenesis of sepsis, and blocking IL-27 may be an alternative therapy for sepsis [22]
Summary
Sepsis is a fatal syndrome featured by abnormal host response to invasive pathogens, which involves hemodynamic changes and leads to a variety of life-threatening organ dysfunction [1]. Antibiotics and supportive measures remain the available treatments for patients with sepsis-induced ALI, but these measures have limited effects on reducing the mortality of sepsis [3], highlighting the urgent need to develop innovative and potent therapies for sepsis-induced ALI. In the process of sepsis-induced ALI, the activation of inflammatory pathways results in the destruction of alveolar epithelial cells, the enhancement of epithelial permeability, and the flow of edema fluid into the alveolar cavity [4]. Emerging evidence has indicated that the excessive secretion of inflammatory cytokines contributes to the occurrence and development of ALI/ARDS, and the degree and duration of the inflammatory response can eventually determine the prognosis of patients with sepsis-induced ALI/ARDS [5, 6]. The existing findings suggest that IL-27 inhibition may become a prospective therapeutic target for patients with sepsis-induced ALI
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