Resolving postoperative neuroinflammation and cognitive decline

Abstract

Objective Cognitive decline accompanies acute illness and surgery, especially in the elderly. Surgery engages the innate immune system that launches a systemic inflammatory response which, 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 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 IKKβ, a central coordinator of TNFα signaling through activation of 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.

The immune response of the human brain to abdominal surgery

“…This observation is in line with results from earlier animal models 2-4 and supports the hypothesis that the postoperative cognitive dysfunction syndrome is related to surgery-induced activation of the brain immune system. [2][3][4] This was further supported by an association between acute changes in systemic IL-6 and long-term cognitive performance at follow-up.…”

“…This observation is in line with results from earlier animal models 2-4 and supports the hypothesis that the postoperative cognitive dysfunction syndrome is related to surgery-induced activation of the brain immune system. [2][3][4] This was further supported by an association between acute changes in systemic IL-6 and long-term cognitive performance at follow-up.The lack of relationship between simultaneous changes in systemic cytokines and brain [ 11 C]PBR28 binding are in agreement with a recent human study showing no correlation between changes in TSPO and systemic cytokine levels after LPS infusion. 28 It may be argued that measured plasma levels of inflammatory mediators reflect the net balance of production and degradation during a prolonged timespan, which is the combined production from multiple cell types, including stromal cells, for example, endothelial cells and hepatocytes, as well as blood-borne immune cells.…”

“…[9][10][11][12] In patients, inflammatory molecules such as TNF-a and interleukins appear in CSF within 12 hours after major surgery. 4,[13][14][15] Although such clinical observations are in line with a series of experimental studies, 2,3,8 the time course pattern beyond the immediate postsurgery phase of immune activation within the human CNS is unknown, and how the systemic pro-and anti-inflammatory response [16][17][18] is associated with cognitive performance is largely unexplored.…”

“…16,43 Upon reaching the brain, the proinflammatory signals interact with the resident brain immune system (eg, microglia and astrocyte populations), 3,9,27 causing a neuroinflammatory reaction and consequent neuronal dysfunction; this was shown in preclinical surgical models to affect CNS plasticity in brain regions relevant for higher cognitive functions. [1][2][3][4] We used plasma tau and NFL as markers of acute neuronal injury 39,40 on postoperative days 3 to 4 and at 3 months. The increase in plasma NFL concentrations with stable plasma tau concentrations over time suggests that no, or very limited, CNS neuronal injury occurred.…”

“…[1][2][3][4] Triggered by surgery-induced damage-associated molecular patterns (DAMPs), an array of proinflammatory mediators and activated blood-borne immune cells orchestrate a rapid spread of this systemic response to the central nervous system (CNS), with inflammatory markers detectable in human cerebrospinal fluid (CSF) within 12 hours. [4][5][6][7] In surgical rodent models, this periphery-to-brain pathway seems critically dependent on NF-jB and proinflammatory cytokine signaling (eg, tumor necrosis factor-a [TNF-a]) associated with a shortlasting disruption of blood-brain barrier integrity, 2,3,8 migration of peripheral macrophages into the CNS, and subsequent hippocampal neuronal dysfunction and cognitive impairment. 8 In addition to an acute and transient response, often referred to as a syndrome of sickness behavior including fatigue, anorexia, and fever, surgery-induced immune activation may be associated with prolonged impairments in learning, memory, and concentration termed postoperative cognitive dysfunction.…”