Open AccessANGPTL 4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a
Author(s) -
Jung Kyung Hee,
Son Mi Kwon,
Yan Hong Hua,
Fang Zhenghuan,
Kim Juyoung,
Kim Soo Jung,
Park Jung Hee,
Lee Ji Eun,
Yoon YoungChan,
Seo Myeong Seong,
Han Beom Seok,
Ko Soyeon,
Suh Young Ju,
Lim Joo Han,
Lee DonHaeng,
Teo Ziqiang,
Wee Jonathan Wei Kiat,
Tan Nguan Soon,
Hong SoonSun
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201911222
Subject(s) - downregulation and upregulation , pancreatitis , acinar cell , medicine , microbiology and biotechnology , acute pancreatitis , immunology , chemistry , biology , biochemistry , gene
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 ( ANGPTL 4) as one of the most significantly upregulated genes. Clinically, ANGPTL 4 expression was also increased in the serum and pancreatic tissues of pancreatitis patients. The deficiency in ANGPTL 4 in mice, either by gene deletion or neutralizing antibody, mitigated pancreatitis‐associated pathological outcomes. Conversely, exogenous ANGPTL 4 exacerbated pancreatic injury with elevated cytokine levels and apoptotic cell death. High ANGPTL 4 enhanced macrophage activation and infiltration into the pancreas, which increased complement component 5a (C5a) level through PI 3K/ 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 ANGPTL 4 levels in pancreatitis patients. Taken together, our study suggests that targeting ANGPTL 4 is a potential strategy for the treatment of pancreatitis.