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ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a
Pancreatitis is the inflammation of the pancreas. However, little is known about the genes associated with pancreatitis severity. Our microarray analysis of pancreatic tissues from mild and severe acute pancreatitis mice models identified angiopoietin‐like 4 (ANGPTL4) as one of the most significantl...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411571/ https://www.ncbi.nlm.nih.gov/pubmed/32638512 http://dx.doi.org/10.15252/emmm.201911222 |
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author | Jung, Kyung Hee Son, Mi Kwon Yan, Hong Hua Fang, Zhenghuan Kim, Juyoung Kim, Soo Jung Park, Jung Hee Lee, Ji Eun Yoon, Young‐Chan Seo, Myeong Seong Han, Beom Seok Ko, Soyeon Suh, Young Ju Lim, Joo Han Lee, Don‐Haeng Teo, Ziqiang Wee, Jonathan Wei Kiat Tan, Nguan Soon Hong, Soon‐Sun |
author_facet | Jung, Kyung Hee Son, Mi Kwon Yan, Hong Hua Fang, Zhenghuan Kim, Juyoung Kim, Soo Jung Park, Jung Hee Lee, Ji Eun Yoon, Young‐Chan Seo, Myeong Seong Han, Beom Seok Ko, Soyeon Suh, Young Ju Lim, Joo Han Lee, Don‐Haeng Teo, Ziqiang Wee, Jonathan Wei Kiat Tan, Nguan Soon Hong, Soon‐Sun |
author_sort | Jung, Kyung Hee |
collection | PubMed |
description | Pancreatitis is the inflammation of the pancreas. However, little is known about the genes associated with pancreatitis severity. Our microarray analysis of pancreatic tissues from mild and severe acute pancreatitis mice models identified angiopoietin‐like 4 (ANGPTL4) as one of the most significantly upregulated genes. Clinically, ANGPTL4 expression was also increased in the serum and pancreatic tissues of pancreatitis patients. The deficiency in ANGPTL4 in mice, either by gene deletion or neutralizing antibody, mitigated pancreatitis‐associated pathological outcomes. Conversely, exogenous ANGPTL4 exacerbated pancreatic injury with elevated cytokine levels and apoptotic cell death. High ANGPTL4 enhanced macrophage activation and infiltration into the pancreas, which increased complement component 5a (C5a) level through PI3K/AKT signaling. The activation of the C5a receptor led to hypercytokinemia that accelerated acinar cell damage and furthered pancreatitis. Indeed, C5a neutralizing antibody decreased inflammatory response in LPS‐activated macrophages and alleviated pancreatitis severity. In agreement, there was a significant positive correlation between C5a and ANGPTL4 levels in pancreatitis patients. Taken together, our study suggests that targeting ANGPTL4 is a potential strategy for the treatment of pancreatitis. |
format | Online Article Text |
id | pubmed-7411571 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-74115712020-08-10 ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a Jung, Kyung Hee Son, Mi Kwon Yan, Hong Hua Fang, Zhenghuan Kim, Juyoung Kim, Soo Jung Park, Jung Hee Lee, Ji Eun Yoon, Young‐Chan Seo, Myeong Seong Han, Beom Seok Ko, Soyeon Suh, Young Ju Lim, Joo Han Lee, Don‐Haeng Teo, Ziqiang Wee, Jonathan Wei Kiat Tan, Nguan Soon Hong, Soon‐Sun EMBO Mol Med Articles Pancreatitis is the inflammation of the pancreas. However, little is known about the genes associated with pancreatitis severity. Our microarray analysis of pancreatic tissues from mild and severe acute pancreatitis mice models identified angiopoietin‐like 4 (ANGPTL4) as one of the most significantly upregulated genes. Clinically, ANGPTL4 expression was also increased in the serum and pancreatic tissues of pancreatitis patients. The deficiency in ANGPTL4 in mice, either by gene deletion or neutralizing antibody, mitigated pancreatitis‐associated pathological outcomes. Conversely, exogenous ANGPTL4 exacerbated pancreatic injury with elevated cytokine levels and apoptotic cell death. High ANGPTL4 enhanced macrophage activation and infiltration into the pancreas, which increased complement component 5a (C5a) level through PI3K/AKT signaling. The activation of the C5a receptor led to hypercytokinemia that accelerated acinar cell damage and furthered pancreatitis. Indeed, C5a neutralizing antibody decreased inflammatory response in LPS‐activated macrophages and alleviated pancreatitis severity. In agreement, there was a significant positive correlation between C5a and ANGPTL4 levels in pancreatitis patients. Taken together, our study suggests that targeting ANGPTL4 is a potential strategy for the treatment of pancreatitis. John Wiley and Sons Inc. 2020-07-07 2020-08-07 /pmc/articles/PMC7411571/ /pubmed/32638512 http://dx.doi.org/10.15252/emmm.201911222 Text en © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Jung, Kyung Hee Son, Mi Kwon Yan, Hong Hua Fang, Zhenghuan Kim, Juyoung Kim, Soo Jung Park, Jung Hee Lee, Ji Eun Yoon, Young‐Chan Seo, Myeong Seong Han, Beom Seok Ko, Soyeon Suh, Young Ju Lim, Joo Han Lee, Don‐Haeng Teo, Ziqiang Wee, Jonathan Wei Kiat Tan, Nguan Soon Hong, Soon‐Sun ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a |
title |
ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a |
title_full |
ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a |
title_fullStr |
ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a |
title_full_unstemmed |
ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a |
title_short |
ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a |
title_sort | angptl4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of c5a |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411571/ https://www.ncbi.nlm.nih.gov/pubmed/32638512 http://dx.doi.org/10.15252/emmm.201911222 |
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