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OBJECTIVE: Cognitive decline accompanies acute illness and surgery, especially in the elderly. Surgery engages the innate immune system that launches a systemic inflammatory response that, if unchecked, can cause multiple organ dysfunction. We sought to understand the mechanisms whereby the brain is targeted by the inflammatory response and how this can be resolved. METHODS: C57BL/6J, Ccr2(RFP/+)Cx3cr1(GFP/+), Ikk(F/F) mice and LysM-Cre/Ikk(F/F) mice underwent stabilized tibial fracture operation under analgesia and general anesthesia. Separate cohorts of mice were tested for systemic and hippocampal inflammation, integrity of the blood-brain barrier (BBB), and cognition. The putative resolving effects of the cholinergic pathway on these postoperative responses were also studied. RESULTS: Peripheral surgery disrupts the BBB via release of tumor necrosis factor-alpha (TNFα), which facilitates the migration of macrophages into the hippocampus. Macrophage-specific deletion of Ikappa B kinase (IKK)β, a central coordinator of TNFα signaling through activation of nuclear factor (NF) κB, prevents BBB disruption and macrophage infiltration in the hippocampus following surgery. Activation of the α7 subtype of nicotinic acetylcholine receptors, an endogenous inflammation-resolving pathway, prevents TNFα-induced NF-κB activation, macrophage migration into the hippocampus, and cognitive decline following surgery. INTERPRETATION: These data reveal the mechanisms for bidirectional communication between the brain and immune system following aseptic trauma. Pivotal molecular mechanisms can be targeted to prevent and/or resolve postoperative neuroinflammation and cognitive decline.

Original publication

DOI

10.1002/ana.22664

Type

Journal article

Journal

Ann neurol

Publication Date

12/2011

Volume

70

Pages

986 - 995

Keywords

Animals, Aza Compounds, Behavior, Animal, CD11b Antigen, CX3C Chemokine Receptor 1, Cell Movement, Cells, Cultured, Cognition Disorders, Conditioning (Psychology), Cytokines, Dioxins, Disease Models, Animal, Drug Administration Schedule, Encephalitis, Fear, HMGB1 Protein, Hippocampus, I-kappa B Kinase, Luminescent Proteins, Macrophages, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, NF-kappa B, Nicotinic Agonists, Postoperative Complications, Receptors, CCR2, Receptors, Chemokine, Tumor Necrosis Factor-alpha