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Acinar ATP8b1/LPC pathway promotes macrophage efferocytosis and clearance of inflammation during chronic pancreatitis development

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机构： [1]Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China. [2]Nanfang PET Center, Nanfang Hospital, Southern Medical University, Guangzhou, China. [3]Department of the Electronic Microscope Room, Central Laboratory, Southern Medical University, Guangzhou, China. [4]School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China. [5]Department of Pathophysiology, Southern Medical University, Guangzhou, China. [6]Department of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China. [7]Laboratory Animal Research Center of Nanfang Hospital, Southern Medical University, Guangzhou, China. [8]Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou, China. [9]Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China. [10]Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China. [11]Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Institute, Guangzhou, China. [12]Southern Medical University, Guangzhou, China. [13]Department of Gynaecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, China.

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Noninflammatory clearance of dying cells by professional phagocytes, termed efferocytosis, is fundamental in both homeostasis and inflammatory fibrosis disease but has not been confirmed to occur in chronic pancreatitis (CP). Here, we investigated whether efferocytosis constitutes a novel regulatory target in CP and its mechanisms. PRSS1 transgenic (PRSS1Tg) mice were treated with caerulein to mimic CP development. Phospholipid metabolite profiling and epigenetic assays were performed with PRSS1Tg CP models. The potential functions of Atp8b1 in CP model were clarified using Atp8b1-overexpressing adeno-associated virus, immunofluorescence, enzyme-linked immunosorbent assay(ELISA), and lipid metabolomic approaches. ATAC-seq combined with RNA-seq was then used to identify transcription factors binding to the Atp8b1 promoter, and ChIP-qPCR and luciferase assays were used to confirm that the identified transcription factor bound to the Atp8b1 promoter, and to identify the specific binding site. Flow cytometry was performed to analyze the proportion of pancreatic macrophages. Decreased efferocytosis with aggravated inflammation was identified in CP. The lysophosphatidylcholine (LPC) pathway was the most obviously dysregulated phospholipid pathway, and LPC and Atp8b1 expression gradually decreased during CP development. H3K27me3 ChIP-seq showed that increased Atp8b1 promoter methylation led to transcriptional inhibition. Atp8b1 complementation substantially increased the LPC concentration and improved CP outcomes. Bhlha15 was identified as a transcription factor that binds to the Atp8b1 promoter and regulates phospholipid metabolism. Our study indicates that the acinar Atp8b1/LPC pathway acts as an important "find-me" signal for macrophages and plays a protective role in CP, with Atp8b1 transcription promoted by the acinar cell-specific transcription factor Bhlha15. Bhlha15, Atp8b1, and LPC could be clinically translated into valuable therapeutic targets to overcome the limitations of current CP therapies.© 2022. The Author(s).

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出版当年[2021]版：

大类 | 1 区

生物学

小类 | 2 区细胞生物学

最新[2025]版：

大类 | 1 区

生物学

小类 | 2 区细胞生物学

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第一作者机构： [1]Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.

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