ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a

• Published in: EMBO molecular medicine Vol. 12; no. 8; pp. e11222 - n/a
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England EMBO Press 07.08.2020; John Wiley and Sons Inc; Springer Nature
• Subjects: 1-Phosphatidylinositol 3-kinase; Acinar Cells; Acute Disease; acute pancreatitis; AKT protein; Angiopoietin; Angiopoietin-Like Protein 4 - genetics; ANGPTL4; Animal models; Animals; Apoptosis; C5a; Cell activation; Cell death; Cell injury; Chemokines; Complement activation; Complement component C5a; Cytokines; DNA microarrays; Gene deletion; Humans; Inflammation; Inflammatory diseases; Lipopolysaccharides; macrophage; Macrophages; Metabolism; Mice; Mice, Inbred C57BL; Mortality; Pancreas; Pancreatitis; Pathophysiology; Phosphatidylinositol 3-Kinases; Up-Regulation; macrophage; ANGPTL4; C5a; acute pancreatitis
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201911222

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. Synopsis This study identifies ANGPTL4 as a potential pathological mediator that induces pancreatitis. Targeting ANGPTL4 by a neutralizing antibody is shown to be an effective strategy for the treatment of pancreatitis in mice. ANGPTL4 induces pancreatitis in mice and its expression is correlated with pancreatitis severity in acute pancreatitis patients. ANGPTL4 expression induces acinar cell injury as well as a massive release of inflammatory cytokines. ANGPTL4 plays a critical role in the regulation of C5a via PI3K/AKT signaling in macrophages. A neutralizing antibody against ANGPTL4 alleviates macrophage activation and improves pancreatitis severity in mice. This study identifies ANGPTL4 as a potential pathological mediator that induces pancreatitis. Targeting ANGPTL4 by a neutralizing antibody is shown to be an effective strategy for the treatment of pancreatitis in mice.