Macrophage phenotypic switch orchestrates the inflammation and repair/regeneration following acute pancreatitis injury
Background: Impaired or hyperactive pancreas regeneration after injury would cause exocrine insufficiency or recurrent / chronic pancreatitis and potentially carcinogenesis. Macrophages are the most abundant immune cells in the regenerative pancreas, however their phenotype and role remain poorly de...
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doaj-ea53a547d55744cc80605b5d3afef8812020-11-25T03:14:48ZengElsevierEBioMedicine2352-39642020-08-0158102920Macrophage phenotypic switch orchestrates the inflammation and repair/regeneration following acute pancreatitis injuryJinghua Wu0Li Zhang1Juanjuan Shi2Ruizhe He3Wenjuan Yang4Aida Habtezion5Ningning Niu6Ping Lu7Jing Xue8State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai 200127, ChinaState Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai 200127, ChinaState Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai 200127, ChinaDepartment of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, ChinaState Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai 200127, ChinaDivision of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, United StatesState Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai 200127, China; Corresponding author.State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai 200127, ChinaState Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai 200127, China; Corresponding author.Background: Impaired or hyperactive pancreas regeneration after injury would cause exocrine insufficiency or recurrent / chronic pancreatitis and potentially carcinogenesis. Macrophages are the most abundant immune cells in the regenerative pancreas, however their phenotype and role remain poorly defined. Method: Using caerulein-induced acute pancreatitis (AP) model, we examined the dynamic landscape of pancreatic macrophages throughout the acute inflammation to regeneration phases by flow cytometric and RNA-seq analyses. Liposome depletion of macrophages, Il4ra−/− mice as well as inhibitors were used to elucidate the role and regulatory mechanism of macrophages during pancreatic regeneration. Findings: We found that M1 macrophages dominated in the pro-inflammatory phase of AP, while M2-like macrophages dominated during pancreas repair/regeneration. Depletion of macrophages at early or late regenerative stage dramatically blocked the acinar-ductal metaplasia (ADM) or delayed inflammation resolution, respectively. Moreover, alternative activation of macrophages was partially dependent on IL-4RA signaling, and ECM/AKT activation in pancreatic macrophages facilitated inflammation resolution during tissue regeneration. Interpretation: Our findings illustrate a dynamic phenotype and function of macrophages during AP repair/regeneration, helping us better understand the mechanism of pancreatic regeneration and providing clues for novel therapeutic strategy.http://www.sciencedirect.com/science/article/pii/S2352396420302954MacrophageAcute pancreatitisPancreatic regenerationIL-4RA signaling, PI3K-AKT signaling |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jinghua Wu Li Zhang Juanjuan Shi Ruizhe He Wenjuan Yang Aida Habtezion Ningning Niu Ping Lu Jing Xue |
spellingShingle |
Jinghua Wu Li Zhang Juanjuan Shi Ruizhe He Wenjuan Yang Aida Habtezion Ningning Niu Ping Lu Jing Xue Macrophage phenotypic switch orchestrates the inflammation and repair/regeneration following acute pancreatitis injury EBioMedicine Macrophage Acute pancreatitis Pancreatic regeneration IL-4RA signaling, PI3K-AKT signaling |
author_facet |
Jinghua Wu Li Zhang Juanjuan Shi Ruizhe He Wenjuan Yang Aida Habtezion Ningning Niu Ping Lu Jing Xue |
author_sort |
Jinghua Wu |
title |
Macrophage phenotypic switch orchestrates the inflammation and repair/regeneration following acute pancreatitis injury |
title_short |
Macrophage phenotypic switch orchestrates the inflammation and repair/regeneration following acute pancreatitis injury |
title_full |
Macrophage phenotypic switch orchestrates the inflammation and repair/regeneration following acute pancreatitis injury |
title_fullStr |
Macrophage phenotypic switch orchestrates the inflammation and repair/regeneration following acute pancreatitis injury |
title_full_unstemmed |
Macrophage phenotypic switch orchestrates the inflammation and repair/regeneration following acute pancreatitis injury |
title_sort |
macrophage phenotypic switch orchestrates the inflammation and repair/regeneration following acute pancreatitis injury |
publisher |
Elsevier |
series |
EBioMedicine |
issn |
2352-3964 |
publishDate |
2020-08-01 |
description |
Background: Impaired or hyperactive pancreas regeneration after injury would cause exocrine insufficiency or recurrent / chronic pancreatitis and potentially carcinogenesis. Macrophages are the most abundant immune cells in the regenerative pancreas, however their phenotype and role remain poorly defined. Method: Using caerulein-induced acute pancreatitis (AP) model, we examined the dynamic landscape of pancreatic macrophages throughout the acute inflammation to regeneration phases by flow cytometric and RNA-seq analyses. Liposome depletion of macrophages, Il4ra−/− mice as well as inhibitors were used to elucidate the role and regulatory mechanism of macrophages during pancreatic regeneration. Findings: We found that M1 macrophages dominated in the pro-inflammatory phase of AP, while M2-like macrophages dominated during pancreas repair/regeneration. Depletion of macrophages at early or late regenerative stage dramatically blocked the acinar-ductal metaplasia (ADM) or delayed inflammation resolution, respectively. Moreover, alternative activation of macrophages was partially dependent on IL-4RA signaling, and ECM/AKT activation in pancreatic macrophages facilitated inflammation resolution during tissue regeneration. Interpretation: Our findings illustrate a dynamic phenotype and function of macrophages during AP repair/regeneration, helping us better understand the mechanism of pancreatic regeneration and providing clues for novel therapeutic strategy. |
topic |
Macrophage Acute pancreatitis Pancreatic regeneration IL-4RA signaling, PI3K-AKT signaling |
url |
http://www.sciencedirect.com/science/article/pii/S2352396420302954 |
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