Inhibition of CD53 Reduces the Formation of ROS-Induced Neutrophil Extracellular Traps and Protects Against Inflammatory Injury in Acute Pancreatitis

Tianqi Xia,1,2 Fei Han,1,2 Yaning Wang,1,2 Xinyue Xie,1,2 Chenchen Yuan,1,2 Guotao Lu,1,2 Weiming Xiao,1,2 Bo Tu,3 Hongbo Ren,4 Weijuan Gong,1,2 Yaodong Wang5 1Pancreatic Center, Department of Gastroenterology, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People’s Republic of China; 2Yangzhou Key Laboratory of Pancreatic Disease, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People’s Republic of China; 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 4Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, People’s Republic of China; 5Department of Gastroenterology, Kunshan Hospital of Traditional Chinese Medicine, Suzhou Key Laboratory of Integrated Traditional Chinese and Western Medicine of Digestive Diseases, Kunshan Affiliated Hospital of Yangzhou University, Kunshan, 215300, People’s Republic of ChinaCorrespondence: Yaodong Wang; Weijuan Gong, Email [email protected]; [email protected]: The tetraspanin CD53 transmembrane protein is vital in immune cells like B cells and T cells, playing a crucial role in various inflammatory conditions. However, its involvement in neutrophils regarding inflammation remains uncertain. This study aims to examine the impact of CD53 on neutrophil extracellular traps (NETs) formation.Methods: Phorbol 12-myristate 13-acetate (PMA) was utilized to establish an in vitro classical NETs model to investigate the influence of CD53 on NETs formation and its regulatory mechanisms. Subsequently, the link between CD53 and acute pancreatitis (AP), a model of aseptic inflammatory responses connected to NETs, was verified. Peripheral blood neutrophils from clinical AP patients were collected to explore the role of CD53 in AP, while an AP mouse model induced by caerulein was employed to confirm the impact of CD53 inhibition on AP mice pancreatic tissue.Results: Our study has shown that CD53 is significantly elevated in in vitro NETs models and neutrophils from AP patients. The expression of CD53 is closely related to the clinical prognosis of AP patients. At the same time, CD53 neutralizing antibody (Anti-CD53) can significantly inhibit the formation of NETs in vitro, inflammatory injury in AP mice and the formation of NETs in damaged tissues. Mechanistically, CD53 can modulate the PI3K/AKT pathway and promote the formation of NETs. Finally, targeted regulation of CD53 can effectively reduce inflammatory injury and NETs formation in damaged tissues of AP mice.Conclusion: The results of this study mark the first confirmation that CD53 plays a crucial role in NETs formation. Targeting CD53 inhibition could potentially serve as a novel therapeutic approach for the treatment of AP. Keywords: CD53, neutrophil extracellular traps, acute pancreatitis, PI3K/AKT