IL-17A contributes to perioperative neurocognitive disorders through blood-brain barrier disruption in aged mice

• Published in: Journal of neuroinflammation Vol. 15; no. 1; p. 332
• Main Authors: Ni, Pengfei, Dong, Hongquan, Wang, Yiwei, Zhou, Qin, Xu, Mengmeng, Qian, Yanning, Sun, Jie
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 30.11.2018; BioMed Central; BMC
• Subjects: Aging; Animal cognition; Animals; Antibodies - therapeutic use; Blood-brain barrier; Blood-Brain Barrier - physiopathology; Brain research; Breakdowns; Claudin-5 - metabolism; Cognition; Cognition Disorders - drug therapy; Cognition Disorders - etiology; Cognition Disorders - metabolism; Cognition Disorders - pathology; Cognitive ability; Cytokines; Disease; Disease Models, Animal; Enzyme-linked immunosorbent assay; Fear conditioning; Fractures; Gelatinase A; Gelatinase B; Hippocampus; Hippocampus - metabolism; IL-17A; IL-1β; Immunofluorescence; Immunohistochemistry; Inflammation; Inflammatory diseases; Interleukin 6; Interleukin-17 - immunology; Interleukin-17 - metabolism; Ischemia; Male; Matrix metalloproteinase; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; Memory; Metalloproteinase; Mice; Mice, Inbred C57BL; Multiple sclerosis; Nervous system; Neurodegeneration; Neuroinflammation; Occludin - metabolism; Pathogenesis; Perioperative neurocognitive disorders; Permeability; Postoperative Complications - drug therapy; Postoperative Complications - metabolism; Rodents; Surgery; Tibial Fractures - surgery; Tight junctions; Tight Junctions - metabolism; Tight Junctions - pathology; Trauma; Up-Regulation - physiology; Monaco; United States > US; Neuroinflammation; Blood-brain barrier; IL-17A; Neurodegeneration; Perioperative neurocognitive disorders
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-018-1374-3

Perioperative neurocognitive disorders (PND) occur frequently after surgery, especially in aged patients. Surgery-induced neuroinflammation and blood-brain barrier (BBB) dysfunction play a crucial role in the pathogenesis of PND. Interleukin-17A (IL-17A) increases after surgical stress and will be involved in BBB dysfunction. However, the effect of IL-17A on BBB function during PND remains poorly understood. Male wild-type C57BL/6J mice (15 months old) received tibial fracture surgery and fixation to establish the PND model. All the mice were injected intraperitoneally with an IL-17A-neutralizing antibody (Abs) or isotype-control Abs 30 min before tibial fracture surgery. Animal behaviour tests conducted 24 h after surgery included the contextual fear conditioning and Y maze tests. Serum and hippocampus IL-17A levels and hippocampus IL-6 and IL-1β levels were detected by ELISA. BBB function was detected by Evans blue (EB) test. Hippocampus matrix metalloproteinase-2 (MMP-2)- and MMP-9-positive cells were detected by immunohistochemistry. Hippocampus albumin, occludin, claudin-5 and IL-17A receptors were detected by Western blot. For the in vitro experiment, bEnd.3 cells were incubated with IL-17A. Cell IL-17A receptors were detected by immunofluorescence. Cellular MMP-2, MMP-9, occludin, and claudin-5 were detected by Western blot. Tibial fracture surgery promoted memory impairment, increased levels of IL-17A and IL-17A receptors, inflammatory factor production and BBB dysfunction. IL-17A Abs inhibited this effect, including improving memory function, decreasing inflammatory factor production and alleviating BBB disruption, indicated by decreased tight junctions (TJs) and increased MMPs after surgery. The in vitro study suggested that recombinant IL-17A could upregulate the expression of IL-17A receptors, decrease TJs and increase the level of MMPs in bEnd.3 cells. Our results suggested that IL-17A-promoted BBB disruption might play an important role in the pathogenesis of PND.