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 significantly upregulated genes. Clinically,ANGPTL4 expression was also increased in the serum and pancreatic tissues of pancreatitis patients. The deficiency inANGPTL4 in mice, either by gene deletion or neutralizing antibody, mitigated pancreatitis-associated pathological outcomes. Conversely, exogenousANGPTL4 exacerbated pancreatic injury with elevated cytokine levels and apoptotic cell death. HighANGPTL4 enhanced macrophage activation and infiltration into the pancreas, which increased complement component 5a (C5a) level throughPI3K/AKTsignaling. The activation of the C5a receptor led to hypercytokinemia that accelerated acinar cell damage and furthered pancreatitis. Indeed, C5a neutralizing antibody decreased inflammatory response inLPS-activated macrophages and alleviated pancreatitis severity. In agreement, there was a significant positive correlation between C5a andANGPTL4 levels in pancreatitis patients. Taken together, our study suggests that targetingANGPTL4 is a potential strategy for the treatment of pancreatitis.