Resolving postoperative neuroinflammation and cognitive decline

N Terrando, LI Eriksson, J Kyu Ryu, T Yang… - Annals of …, 2011 - Wiley Online Library
N Terrando, LI Eriksson, J Kyu Ryu, T Yang, C Monaco, M Feldmann, M Jonsson Fagerlund…
Annals of neurology, 2011Wiley Online Library
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, Ccr2RFP/+ Cx3cr1GFP/+, IkkF/F mice and LysM‐
Cre/IkkF/F mice underwent stabilized tibial fracture operation under analgesia and general …
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, Ccr2RFP/+Cx3cr1GFP/+, IkkF/F mice and LysM‐Cre/IkkF/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. ANN NEUROL 2011;70:986–995
Wiley Online Library