Role of interleukin-1beta in postoperative cognitive dysfunction.
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-1beta transcription and expression in the hippocampus. Nonspecific attenuation of innate immunity with minocycline prevented surgery-induced changes. Functional inhibition of IL-1beta, both in mice pretreated with IL-1 receptor antagonist and in IL-1R(-/-) mice, mitigated the neuroinflammatory effects of surgery and memory dysfunction.


CONCLUSIONS
A peripheral surgery-induced innate immune response triggers an IL-1beta-mediated inflammatory process in the hippocampus that underlies memory impairment. This may represent a viable target to interrupt the pathogenesis of postoperative cognitive dysfunction.
Cibelli
Mario
M
Department of Anesthetics, Pain Medicine, and Intensive Care, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom.
Fidalgo
Antonio Rei
AR
Terrando
Niccolò
N
Ma
Daqing
D
Monaco
Claudia
C
Feldmann
Marc
M
Takata
Masao
M
Lever
Isobel J
IJ
Nanchahal
Jagdeep
J
Fanselow
Michael S
MS
Maze
Mervyn
M
D000704:Analysis of Variance; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D003213:Conditioning, Psychological / Q000502:physiology; D004192:Discrimination, Psychological / Q000502:physiology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005239:Fear; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D011939:Mental Recall / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009830:Olfactory Bulb / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D011183:Postoperative Complications / Q000473:pathology / Q000503:physiopathology*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000172:deficiency; D012919:Social Behavior; D014059:Tongue / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D039481:CD11b Antigen; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha
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