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

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机构： [1]Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China. [2]Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China. [3]Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China. [4]Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, China. [5]Department of Breast Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.

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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.Copyright © 2022 Tang, Cao, Yan, Cui, Guo, Cheng, Li, Li, Ma, Fang, Gao, Ren, Sun, Wang and Ji.

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出版当年[2021]版：

大类 | 2 区

医学

小类 | 2 区免疫学

最新[2023]版：

大类 | 2 区医学

小类 | 2 区免疫学

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出版当年[2020]版：

Q1 IMMUNOLOGY

最新[2023]版：

Q1 IMMUNOLOGY

影响因子： 5.7 最新[2023版] 6.8 最新五年平均 7.561 出版当年[2020版] 7.624 出版当年五年平均 5.085 出版前一年[2019版] 8.787 出版后一年[2021版]

第一作者：

第一作者机构： [1]Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China. [2]Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.

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通讯作者：

通讯机构： [1]Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China. [2]Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China. [5]Department of Breast Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.

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