title: S100A8 contributes to postoperative cognitive dysfunction in mice undergoing tibial fracture surgery by activating the TLR4/MyD88 pathway.
abstract: Neuro-inflammation plays a key role in the occurrence and development of postoperative cognitive dysfunction (POCD). Although S100A8 and Toll-like receptor 4 (TLR4) have been increasingly recognized to contribute to neuro-inflammation, little is known about the interaction between S100A8 and TLR4/MyD88 signaling in the process of systemic inflammation that leads to neuro-inflammation. Firstly, we demonstrated that C57BL/6 wide-type mice exhibit cognitive deficit 24h after the tibial fracture surgery. Subsequently, increased S100A8 and S100A9 expression was found in the peripheral blood mononuclear cells (PBMCs), spleen, and hippocampus of C57BL/6 wide-type mice within 48h after the surgery. Pre-operative administration of S100A8 antibody significantly inhibited hippocampal microgliosis and improved cognitive function 24h after the surgery. Secondly, we also observed TLR4/MyD88 activation in the PBMCs, spleen, and hippocampus after the surgery. Compared with those in their corresponding wide-type mice, TLR4(-/-) and MyD88(-/-) mice showed lower immunoreactive area of microglia in the hippocampal CA3 region after operation. TLR4 deficiency also led to reduction of CD45(hi)CD11b(+) cells in the brain and better performance in both Y maze and open field test after surgery, suggesting a new regulatory mechanism of TLR4-dependent POCD. At last, the co-location of S100A8 and TLR4 expression in spleen after operation suggested a close relationship between them. On the one hand, S100A8 could induce TLR4 activation of CD11b(+) cells in the blood and hippocampus via intraperitoneal or intracerebroventricular injection. On the other hand, TLR4 deficiency conversely alleviated S100A8 protein-induced hippocampal microgliosis. Furthermore, the increased expression of S100A8 protein in the hippocampus induced by surgery sharply decreased in both TLR4 and MyD88 genetically deficient mice. Taken together, these data suggest that S100A8 exerts pro-inflammatory effect on the occurrence and development of neuro-inflammation and POCD by activating TLR4/MyD88 signaling in the early pathological process of the postoperative stage.
authors.affiliation: Department of Anesthesiology, 1st Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Shun-Mei
authors.initials: SM
authors.lastname: Lu
authors.affiliation: Department of Anesthesiology, Affiliated Tumor Hospital, Xinjiang Medical University, Urumqi 830011, China.
authors.forename: Chan-Juan
authors.initials: CJ
authors.lastname: Yu
authors.affiliation: Department of Anesthesiology, Affiliated Tumor Hospital, Xinjiang Medical University, Urumqi 830011, China.
authors.forename: Ya-Hua
authors.initials: YH
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, 1st Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Hong-Quan
authors.initials: HQ
authors.lastname: Dong
authors.affiliation: Department of Anesthesiology, 1st Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, 1st Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Su-Su
authors.initials: SS
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, 1st Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Liu-Qing
authors.initials: LQ
authors.lastname: Hu
authors.affiliation: Department of Intensive Care Unit, Wuxi First People's Hospital, Nanjing Medical University, Wuxi 214023, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, 1st Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China. Electronic address: yanning_qian@163.com.
authors.forename: Yan-Ning
authors.initials: YN
authors.lastname: Qian
authors.affiliation: Department of Anesthesiology, 1st Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China. Electronic address: guibosy@163.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Gui
mesh_terms: D000818:Animals; D000906:Antibodies; D001007:Anxiety / Q000209:etiology / Q000378:metabolism; D040501:Calgranulin A / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D040502:Calgranulin B / Q000097:blood / Q000378:metabolism; D003071:Cognition / Q000502:physiology*; D004660:Encephalitis / Q000209:etiology / Q000378:metabolism*; D005911:Gliosis / Q000209:etiology / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D011183:Postoperative Complications / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism; D013978:Tibial Fractures / Q000378:metabolism / Q000523:psychology / Q000601:surgery; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D000906:Antibodies; D040501:Calgranulin A; D040502:Calgranulin B; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C576329:S100A9 protein, mouse; C086145:S100a8 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
keywords: Microglia; Postoperative cognitive dysfunction; S100A8; TLR4/MyD88 pathway; Tibial fracture surgery