Role of interleukin‐1β in postoperative cognitive dysfunction

Abstract

Objective Although postoperative cognitive dysfunction (POCD) often complicates recovery from major surgery, the pathogenic mechanisms remain unknown. We explored whether systemic inflammation, in response to surgical trauma, triggers hippocampal inflammation and subsequent memory impairment, in a mouse model of orthopedic surgery. Methods C57BL/6J, knock out (lacking interleukin [IL]-1 receptor, IL-1R−/−) and wild type mice underwent surgery of the tibia under general anesthesia. Separate cohorts of animals were tested for memory function with fear conditioning tests, or euthanized at different times to assess levels of systemic and hippocampal cytokines and microglial activation; the effects of interventions, designed to interrupt inflammation (specifically and nonspecifically), were also assessed. Results Surgery caused hippocampal-dependent memory impairment that was associated with increased plasma cytokines, as well as reactive microgliosis and IL-1β transcription and expression in the hippocampus. Nonspecific attenuation of innate immunity with minocycline prevented surgery-induced changes. Functional inhibition of IL-1β, both in mice pretreated with IL-1 receptor antagonist and in IL-1R−/− mice, mitigated the neuroinflammatory effects of surgery and memory dysfunction. Interpretation A peripheral surgery-induced innate immune response triggers an IL-1β-mediated inflammatory process in the hippocampus that underlies memory impairment. This may represent a viable target to interrupt the pathogenesis of postoperative cognitive dysfunction.

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.…”