Acinar Cell-Derived Extracellular Vesicle MiRNA-183-5p Aggravates Acute Pancreatitis by Promoting M1 Macrophage Polarization Through Downregulation of FoxO1

Abstract

Acute pancreatitis (AP) is a common cause of a clinically acute abdomen. Crosstalk between acinar cells and leukocytes (especially macrophages) plays an important role in the development of AP. However, the mechanism mediating the interaction between acinar cells and macrophages is still unclear. This study was performed to explore the role of acinar cell extracellular vesicles (EVs) in the crosstalk between acinar cells and macrophages involved in the pathogenesis of AP. EVs derived from caerulein-treated acinar cells induced macrophage infiltration and aggravated pancreatitis in an AP rat model. Further research showed that acinar cell-derived EV miR-183-5p led to M1 macrophage polarization by downregulating forkhead box protein O1 (FoxO1), and a dual-luciferase reporter assay confirmed that FoxO1 was directly inhibited by miR-183-5p. In addition, acinar cell-derived EV miR-183-5p reduced macrophage phagocytosis. Acinar cell-derived EV miR-183-5p promoted the pancreatic infiltration of M1 macrophages and increased local and systemic damage in vivo. Subsequently, miR-183-5p overexpression in macrophages induced acinar cell damage and trypsin activation, thus further exacerbating the disease. In clinical samples, elevated miR-183-5p levels were detected in serum EVs and positively correlated with the severity of AP. EV miR-183-5p might play an important role in the development of AP by facilitating M1 macrophage polarization, providing a new insight into the diagnosis and targeted management of pancreatitis.Graphical abstract of the present study. In our caerulein-induced AP model, miR-183-5p was upregulated in injured acinar cells and transported by EVs to macrophages. miR-183-5p could induce M1 macrophage polarization through downregulation of FoxO1 and the release of inflammatory cytokines, which could aggravate AP-related injuries. Therefore, a vicious cycle might exist between injured ACs and M1 macrophage polarization, which is fulfilled by EV-transported miR-183-5p, leading to sustainable and progressive AP-related injuries.

METTL14 decreases FTH1 mRNA stability via m6A methylation to promote sorafenib-induced ferroptosis of cervical cancer

“…The lactate produced by tumor glycolysis, serving as a proinflammatory and immunosuppressive mediator within the tumor microenvironment, is modulated by METTL14-mediated m6A methylation, influencing the polarization of macrophages. 27 Our study identifies that METTL14 and m6A modification are significantly downregulated in CC and that there is a correlation between METTL14 levels and poor prognosis in CC. Another study highlighted that hypoxia suppresses METTL14 in a HIF-1α-dependent manner and that METTL14 mediates m6A modification of SLC7A11 mRNA at its 5′-UTR, leading to a decrease in SLC7A11 expression via a YTHDF2-dependent pathway, thus inhibiting ferroptosis in hepatocellular carcinoma.…”

Emodin Ameliorates Severe Acute Pancreatitis-Associated Acute Lung Injury in Rats by Modulating Exosome-Specific miRNA Expression Profiles

“…23,24 The secretion of exosome-specific inflammatory miRNAs by inflammatory cells and exosome-specific antiinflammatory miRNAs by parenchymal cells is only sometimes definitive, and their functions may occasionally be International Journal of Nanomedicine 2023:18 https://doi.org/10.2147/IJN.S428924 DovePress 6755 interchanged. Tang et al 25 discovered that miR-183-5p, specific to EVS and derived from acinar cells, can induce macrophage polarization towards M1. This is achieved through the inhibition of forkhead box transcription factor O1 (FoxO1) expression, which ultimately exacerbates the severity of SAP.…”

The Pivotal Role of Macrophages in the Pathogenesis of Pancreatic Diseases

“…The application of a Notch inhibitor, such as DAPT, has been reported to alleviate symptoms of AP. Additionally, recent studies have shown that the release of extracellular vesicles (EVs) containing miR-183-5p increases in acinar cells during cerulein treatment, inducing the M1 polarization of macrophages and subsequently causing acinar cell damage [ 44 ]. This emerging evidence underscores the complex interplay of molecular signals that modulate macrophage polarization and their potential implications in AP therapy.…”