Interleukin17A Promotes Postoperative Cognitive Dysfunction by Triggering β-Amyloid Accumulation via the Transforming Growth Factor-β (TGFβ)/Smad Signaling Pathway.
Although postoperative cognitive dysfunction (POCD) is relatively common in elderly patients who have undergone major surgery, the mechanisms underlying this postoperative complication are unclear. Previously, we have investigated the role of cytokine-mediated hippocampal inflammation in the development of POCD in a rat model. Here, we sought to determine in mice the role of cytokine interleukin17A (IL17A) in POCD and to characterize the associated signaling pathways. Old mice underwent hepatectomy surgery in the presence or absence of IL17A monoclonal antibody, and cognitive function, hippocampal neuroinflammation, and pathologic markers of Alzheimer's disease (AD) were assessed. We found that the level of IL17A in the hippocampus was increased in hepatectomy mice and that cognitive impairment after surgery was associated with the appearance of certain pathological hallmarks of AD: activation of astrocytes, β-amyloid1-42 (Aβ1-42) production, upregulation of transforming growth factor-β (TGFβ), and increased phosphorylation of signaling mother against decapentaplegic peptide 3 (Smad3) protein in the hippocampus. Surgery-induced changes in cognitive dysfunction and changes in Aβ1-42 and TGFβ/Smad signaling were prevented by the administration of IL17A monoclonal antibody. In addition, IL17A-stimulated TGFβ/Smad activation and Aβ1-42 expression were reversed by IL17A receptor small interfering RNA and a TGFβ receptor inhibitor in cultured astrocytes. Our findings suggest that surgery can provoke IL17A-related hippocampal damage, as characterized by activation of astrocytes and TGFβ/Smad pathway dependent Aβ1-42 accumulation in old subjects. These changes likely contribute to the cognitive decline seen in POCD.
Department of Anesthesiology, the first Affiliated Hospital of China Medical University, Nanjing North Street 155, Shenyang, Liaoning, China.
Ayong
A
Tian
Department of Anesthesiology, the first Affiliated Hospital of China Medical University, Nanjing North Street 155, Shenyang, Liaoning, China.
Hong
H
Ma
Department of Gerontology and Geriatrics, the first Affiliated Hospital of China Medical University, Nanjing North Street 155, Shenyang, Liaoning, China.
Rongwei
R
Zhang
Department of Anesthesiology, the first Affiliated Hospital of China Medical University, Nanjing North Street 155, Shenyang, Liaoning, China.
Wenfei
W
Tan
Department of Anesthesiology, the first Affiliated Hospital of China Medical University, Nanjing North Street 155, Shenyang, Liaoning, China.
Xiaolong
X
Wang
Department of Anesthesiology, the first Affiliated Hospital of China Medical University, Nanjing North Street 155, Shenyang, Liaoning, China.
Binyang
B
Wu
Department of Neurology, the first Affiliated Hospital of China Medical University, Nanjing North Street 155, Shenyang, Liaoning, China.
Jun
J
Wang
Department of Pain Medicine, the first Affiliated Hospital of China Medical University, Nanjing North Street 155, Shenyang, Liaoning, China.
Chengfu
C
Wan
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism; D015415:Biomarkers; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006498:Hepatectomy / Q000009:adverse effects; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D018782:Maze Learning; D008570:Memory, Short-Term; D051379:Mice; D010766:Phosphorylation; D011183:Postoperative Complications; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D065852:Spatial Memory; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; D015415:Biomarkers; D016207:Cytokines; D020381:Interleukin-17; D051785:Smad Proteins; D016212:Transforming Growth Factor beta