Epithelial‑derived exosomes promote M2 macrophage polarization via Notch2/SOCS1 during mechanical ventilation

Abstract

Alveolar macrophages (AMs) play an essential role in ventilator-induced lung injury (VILI). Exosomes and their cargo, including microRNAs (miRNAs/miRs) serve as regulators of the intercellular communications between macrophages and epithelial cells (ECs), and are involved in maintaining homeostasis in lung tissue. The present study found that exosomes released by ECs subjected to cyclic stretching promoted M2 macrophage polarization. It was demonstrated that miR-21a-5p, upregulated in epithelial-derived exosomes, increased the percentage of M2 macrophages by suppressing the expression of Notch2 and the suppressor of cytokine signaling 1 (SOCS1). The overexpression of Notch2 decreased the percentage of M2 macrophages. However, these effects were reversed by the downregulation of SOCS1. The percentage of M2 macrophages was increased in both short-term high- and low-tidal-volume mechanical ventilation, and the administration of exosomes-derived from cyclically stretched ECs had the same function. However, the administration of miR-21a-5p antagomir decreased M2 macrophage activation induced by cyclically stretched ECs or ventilation. Thus, the present study demonstrates that the intercellular transferring of exosomes from ECs to AMs promotes M2 macrophage polarization. Exosomes may prove to be a novel treatment for VILI.

Exosomal Non-Coding RNAs: Novel Regulators of Macrophage-Linked Intercellular Communication in Lung Cancer and Inflammatory Lung Diseases

“…Exosomal ncRNAs also display positive or negative roles in inflammatory lung disorders ( Table 2 ). In ALI, exosomal ncRNAs from MSCs [ 105 , 106 ], epithelial cells [ 107 , 109 ], PMNs [ 99 ], endothelial cells [ 112 ], monocytes [ 100 ], serum [ 110 ], and BALFs [ 111 ] can be transmitted into macrophages. Exosomal ncRNAs from different sources can control the M1/M2 polarization of macrophages ( Figure 2 ) [ 99 , 106 , 109 , 110 ].…”

“…In ALI, exosomal ncRNAs from MSCs [ 105 , 106 ], epithelial cells [ 107 , 109 ], PMNs [ 99 ], endothelial cells [ 112 ], monocytes [ 100 ], serum [ 110 ], and BALFs [ 111 ] can be transmitted into macrophages. Exosomal ncRNAs from different sources can control the M1/M2 polarization of macrophages ( Figure 2 ) [ 99 , 106 , 109 , 110 ]. In pulmonary fibrosis, exosomal ncRNAs from macrophages can be transferred into fibroblasts [ 124 , 126 , 127 ].…”

“…Exosomes from epithelial cells that have undergone cyclic stretching (CS) exhibit increased miR-21a-5p expression. CS-treated epithelial cell-derived exosomes transmit miR-21a-5p into recipient macrophages and elevate miR-21a-5p expression [ 109 ]. Exosomal miR-21a-5p subsequently reduces Notch2 and SOCS1 to enhance M2 macrophage polarization, which can exert protective anti-inflammatory effects in mechanical ventilation [ 109 ].…”

“…CS-treated epithelial cell-derived exosomes transmit miR-21a-5p into recipient macrophages and elevate miR-21a-5p expression [ 109 ]. Exosomal miR-21a-5p subsequently reduces Notch2 and SOCS1 to enhance M2 macrophage polarization, which can exert protective anti-inflammatory effects in mechanical ventilation [ 109 ]. In response to mechanical ventilation in mice, over-expressed miR-21a-5p increases the percentage of M2 macrophages.…”

“…In response to mechanical ventilation in mice, over-expressed miR-21a-5p increases the percentage of M2 macrophages. These suggest a negative relationship between epithelial cell-derived exosomal miR-21a-5p and mechanical ventilation-related lung injury [ 109 ]. Exosomal ncRNAs from epithelial cells can show positive or negative effects on macrophage inflammation.…”