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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.

Type

Journal article

Journal

Annals of neurology

Publication Date

12/2011

Volume

70

Pages

986 - 995

Addresses

Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, CA, USA.

Keywords

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