期刊
MOLECULAR IMMUNOLOGY
卷 142, 期 -, 页码 63-75出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2021.12.012
关键词
Severe acute pancreatitis; Spleen injury; TLR4; ROS; PI3K; AKT; mTOR signaling; Autophagy
资金
- National Natural Science Foundation of China [81973580, 81803966]
- West China Hospital, Sichuan University [2019HXBH024]
- West China Hospital, Sichuan University [HXYS19001, HXYS19002]
- Post-Doctor Research Project, West China Hospital, Sichuan University [2019HXBH024]
- China Postdoctoral Science Foundation [2019M663533]
- Sichuan Province COVID-19 Science and Technology Emergency Project [2021YFS0408]
- Key Technology Research and Development Program of Sichuan Province of China [22ZDYF2101, 22ZDYF1549]
This study investigated the mechanism of spleen injury caused by severe acute pancreatitis (SAP) and explored the potential use of tuftsin in treating spleen damage. The researchers found that the up-regulation of Toll-like receptor 4 (TLR4) in the spleen leads to the accumulation of reactive oxygen species (ROS) and mitochondrial dysfunction under SAP conditions. They also discovered that N-acetylcysteine (NAC) treatment or knocking out TLR4 can improve splenic ROS and mitochondrial dysfunction in SAP mice. Furthermore, they verified that spleen injury is caused by splenic ROS affecting the PI3K/p-AKT/mTOR pathway-mediated autophagy. The study also showed that tuftsin supplementation can ameliorate the pathological damage, ROS accumulation, impaired autophagy, inflammation expression, and apoptosis in damaged spleen.
Severe acute pancreatitis (SAP) is complicated by systemic inflammatory response syndrome and multiple organ dysfunction, the disease will eventually result in death in almost half of the case. The spleen, as the largest immune organ adjacent to the pancreas, is prone to damage in SAP, thereby aggravating the damage of other organs and increasing mortality. However, to date, the research on the mechanism and treatment of spleen injury caused by SAP is still in its infancy. Herein, we investigated the mechanism of spleen injury, and explored the application potential of tuftsin for relieving spleen damage in SAP mice. Firstly, SAP mice model was constructed via the retrograde infusion of 3.5 % sodium taurocholate into the biliopancreatic duct. Then, we proved that the up-regulation of Toll-like receptor 4 (TLR4) in spleen would lead to the accumulation of reactive oxygen species (ROS) and mitochondrial dysfunction under SAP conditions. The splenic ROS and mitochondrial dysfunction could be improved by N-acetylcysteine (NAC) treatment or knocking out TLR4 in SAP mice. Meanwhile, we found that NAC treatment could also improve the autophagy of spleen tissue, suggesting that splenic ROS may affect impaired autophagy, causing the accumulation of damaged mitochondria, aggravating spleen damage. Furthermore, we verified the mechanism of spleen injury is caused by splenic ROS affecting PI3K/p-AKT/mTOR pathway-mediated autophagy. In addition, we detected the spleen injury caused by SAP could decrease the concentration of tuftsin in the serum of mice. Whereas, exogenous supplementation of tuftsin ameliorated the pathological damage, ROS accumulation, impaired autophagy, inflammation expression and apoptosis in damaged spleen. In summary, we verified the new mechanism of SAP-caused spleen damage that TLR4-induced ROS provoked mitophagy impairment and mitochondrial dysfunction in spleen via PI3K/p-AKT mTOR signaling, and the application potential of tuftsin in treating spleen injury, which might expand novel ideas and methods for the treatment of pancreatitis.
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