LRG1 inhibition promotes acute pancreatitis recovery by inducing cholecystokinin Type 1 receptor expression via Akt

• Published in: Theranostics Vol. 15; no. 10; pp. 4247 - 4269
• Main Authors: Lim, Seok Ting, Zhao, Xinmei, Liu, Shuqing, Zhang, Wenjuan, Tan, Yuanyang, Mullappilly, Nidula, Swain, Sandip M, Leong, Mei Ling, Rajarethinam, Ravisankar, Wan, Kah Fei, Ruedl, Christiane, Liddle, Rodger A., Li, Liang, Wang, Xiaomeng
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher 01.01.2025
• Subjects: Acinar Cells - metabolism; Animals; Ceruletide; Disease Models, Animal; Female; Glycoproteins - antagonists & inhibitors; Glycoproteins - genetics; Glycoproteins - metabolism; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pancreas - metabolism; Pancreas - pathology; Pancreatitis - drug therapy; Pancreatitis - metabolism; Pancreatitis - pathology; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Cholecystokinin - metabolism; Research Paper; Transforming-growth factor-beta; Leucine-rich alpha-2 glycoprotein 1; Cholecystokinin Type 1 receptor; Acute pancreatitis; Pancreatic regeneration
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.110116

Acute pancreatitis (AP) is a common gastrointestinal disease affecting nearly 3 million people annually worldwide. Although AP is typically self-limiting, up to 20% of patients may develop life-threatening complications. Individuals who suffer from AP also have an increased likelihood of developing other exocrine and endocrine pancreatic disorders. However, to date, there are no specific, targeted treatment modalities that can effectively improve the clinical outcomes of AP. Leucine-rich alpha-2 glycoprotein 1 (LRG1) is a multifunctional protein with established roles in inflammation and cell mitosis. This study aims to investigate the functional role of LRG1 in AP progression and develop LRG1-targeted AP therapeutics. Levels of circulating and tissue LRG1 were determined in human patient samples and mouse models of caerulein-induced AP and pancreatic duct ligation-induced AP. Histopathological grading, amylase assay, real-time polymerase chain reaction analysis and Western blotting were used to evaluate the extent of pancreatic damage and recovery following caerulein-induced AP in both wild-type and mice. Primary acinar cells were also isolated from mice for in-vitro mechanistic studies. LRG1 neutralizing antibody was administered post-AP induction to evaluate its therapeutic potential in improving AP outcomes. LRG1 is markedly increased in serum and acinar cells of AP patients and C57BL/6 mice subjected to caerulein-induced AP or pancreatic duct ligation-induced AP. Despite demonstrating no obvious pancreatic dysfunction, mice exhibited more severe pancreatic damage and inflammation during the early stages of caerulein-induced AP. However, the resolution of AP was accelerated in the absence of Lrg1, which is at least partially due to LRG1's role in regulating the expression of trophic cholecystokinin (CCK) Type 1 receptor (CCK1R) via the TGFβ/ALK5/AKT pathway in acinar cells. Importantly, the administration of an LRG1-blocking antibody promoted AP recovery, evidenced by reduced overall inflammation and increased acinar cell proliferation. Our data provide compelling evidence for targeting LRG1 as a potential innovative therapy for promoting AP recovery.