Macrophage microvesicle-derived circ_YTHDF2 in methamphetamine-induced chronic lung injury

Abstract

Long-term abuse of methamphetamine (MA) can cause lung toxicity. Intercellular communication between macrophages and alveolar epithelial cells (AECs) is critical for maintaining lung homeostasis. Microvesicles (MVs) are an important medium of intercellular communication. However, the mechanism of macrophage MVs (MMVs) in MA-induced chronic lung injury remains unclear. This study aimed to investigate if MA can augment the activity of MMVs and if circ_YTHDF2 is a key factor in MMV-mediated macrophage-AEC communication, and to explore the mechanism of MMV-derived circ_YTHDF2 in MA-induced chronic lung injury. MA elevated peak velocity of the pulmonary artery and pulmonary artery accelerate time, reduced the number of alveolar sacs, thickened the alveolar septum, and accelerated the release of MMVs and the uptake of MMVs by AECs. Circ_YTHDF2 was downregulated in lung and MMVs induced by MA. The immune factors in MMVs were increased by si-circ_YTHDF. Circ_YTHDF2 knockdown in MMVs induced inflammation and remodelling in the internalised AECs by MMVs, which was reversed by circ_YTHDF2 overexpression in MMVs. Circ_YTHDF2 bound specifically to and sponged miRNA-145-5p. Runt-related transcription factor 3 (RUNX3) was identified as potential target of miR-145-5p. RUNX3 targeted zinc finger E-box-binding homeobox 1 (ZEB1)-related inflammation and EMT of AECs. In vivo, circ_YTHDF2 overexpression-MMVs attenuated MA-induced lung inflammation and remodelling by the circ_YTHDF2-miRNA-145-5p-RUNX3 axis. Therefore, MA abuse can induce pulmonary dysfunction and alveolus injury. The immunoactivity of MMVs is regulated by circ_YTHDF2. Circ_YTHDF2 in MMVs is the key to communication between macrophages and AECs. Circ_YTHDF2 sponges miR-145-5p targeting RUNX3 to participate in ZEB1-related inflammation and remodelling of AECs. MMV-derived circ_YTHDF2 would be an important therapeutic target for MA-induced chronic lung injury. KEY POINTS: Methamphetamine (MA) abuse induces pulmonary dysfunction and alveoli injury. The immunoactivity of macrophage microvesicles (MMVs) is regulated by circ_YTHDF2. Circ_YTHDF2 in MMVs is the key to MMV-mediated intercellular communication between macrophages and alveolar epithelial cells. Circ_YTHDF2 sponges miR-145-5p targeting runt-related transcription factor 3 (RUNX3) to participate in zinc finger E-box-binding homeobox 1 (ZEB1)-related inflammation and remodelling. MMV-derived circ_YTHDF2 would be an important therapeutic target for MA-induced chronic lung injury.

Keywords: RUNX3; alveolar epithelial cells; circ_YTHDF2; intercellular communication; macrophage; methamphetamine; miR-145-5p; microvesicles.