Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline.
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.
Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143-0648, USA.
Niccolò
N
Terrando
Claudia
C
Monaco
Daqing
D
Ma
Brian M J
BM
Foxwell
Marc
M
Feldmann
Mervyn
M
Maze
D000818:Animals; D003072:Cognition Disorders / Q000209:etiology* / Q000276:immunology; D016207:Cytokines / Q000378:metabolism / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D024243:HMGB1 Protein / Q000378:metabolism; D007249:Inflammation / Q000150:complications* / Q000209:etiology; D007375:Interleukin-1 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D011183:Postoperative Complications / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016207:Cytokines; D024243:HMGB1 Protein; D007375:Interleukin-1; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha