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PNAS 107 (47): 20518-20522

Copyright © 2010 by the National Academy of Sciences.

From the Cover

BIOLOGICAL SCIENCES / NEUROSCIENCE

Tumor necrosis factor-α triggers a cytokine cascade yielding postoperative cognitive decline

Niccolò Terrandoa,b, Claudia Monacoc, Daqing Mab, Brian M. J. Foxwellc,1, Marc Feldmannc,2, and Mervyn Mazea,b,2

aDepartment of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143-0648; bDepartment of Anesthetics, Pain Medicine and Intensive Care, Imperial College London, Chelsea and Westminster Hospital, London SW10 9NH, United Kingdom; and cKennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London W6 8LH, United Kingdom

Contributed by Marc Feldmann, September 30, 2010 (sent for review August 2, 2010)

Abstract: Cognitive decline following surgery in older individuals is a major clinical problem of uncertain mechanism; a similar cognitive decline also follows severe infection, chemotherapy, or trauma and is currently without effective therapy. A variety of mechanisms have been proposed, and exploring the role of inflammation, we recently reported the role of IL-1β in the hippocampus after surgery in mice with postoperative cognitive dysfunction. Here, we show that TNF-α is upstream of IL-1 and provokes its production in the brain. Peripheral blockade of TNF-α is able to limit the release of IL-1 and prevent neuroinflammation and cognitive decline in a mouse model of surgery-induced cognitive decline. TNF-α appears to synergize with MyD88, the IL-1/TLR superfamily common signaling pathway, to sustain postoperative cognitive decline. Taken together, our results suggest a unique therapeutic potential for preemptive treatment with anti-TNF antibody to prevent surgery-induced cognitive decline.

Key Words: innate immunity • surgical complications • delirium • dementia

Author contributions: N.T., C.M., D.M., B.M.J.F., M.F., and M.M. designed research; N.T. performed research; N.T., C.M., D.M., M.F., and M.M. analyzed data; and N.T., C.M., D.M., M.F., and M.M. wrote the paper.

The authors declare no conflict of interest.

1Deceased December 16, 2008.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1014557107/-/DCSupplemental.

2To whom correspondence may be addressed. E-mail: m.feldmann{at}imperial.ac.uk or mazem{at}anesthesia.ucsf.edu.

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