Terrando N, Monaco C, Ma D, Foxwell BM, Feldmann M, Maze M. Tumor necrosis factor-α triggers a cytokine cascade yielding postoperative cognitive decline

Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143-0648, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2010; 107(47):20518-22. DOI: 10.1073/pnas.1014557107
Source: PubMed


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.

Download full-text


Available from: Daqing Ma, Jan 13, 2014
  • Source
    • "Chronic CNS disease: pain [77–79, 81, 113, 119–123], Alzheimer's disease [89] [124], Parkinson's disease [125], Huntington disease [126], post-LPS cognition [127], postoperative cognition [108], postirradiation cognition [109], postchemotherapy cognition [110], rheumatoid arthritis cognition [112], sarcoidosis cognition [111], poststroke therapy [69] [87] [97] [98], traumatic brain injury [69] [83]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumor necrosis factor (TNF) is an ancient and widespread cytokine required in small amounts for much physiological function. Higher concentrations are central to innate immunity, but if unchecked this cytokine orchestrates much chronic and acute disease, both infectious and noninfectious. While being a major proinflammatory cytokine, it also controls homeostasis and plasticity in physiological circumstances. For the last decade or so these principles have been shown to apply to the central nervous system as well as the rest of the body. Nevertheless, whereas this approach has been a major success in treating noncerebral disease, its investigation and potential widespread adoption in chronic neurological conditions has inexplicably stalled since the first open trial almost a decade ago. While neuroscience is closely involved with this approach, clinical neurology appears to be reticent in engaging with what it offers patients. Unfortunately, the basic biology of TNF and its relevance to disease is largely outside the traditions of neurology. The purpose of this review is to facilitate lowering communication barriers between the traditional anatomically based medical specialties through recognition of shared disease mechanisms and thus advance the prospects of a large group of patients with neurodegenerative conditions for whom at present little can be done.
    Full-text · Article · Jul 2015 · Neural Plasticity
  • Source
    • "Dysregulated inflammation is a hallmark of several disease states [1]. Systemic inflammation, for example as a result of infection or aseptic surgical trauma, can activate the innate immune system, launching a cascade of physiological and behavioral changes ultimately affecting the central nervous system (CNS) [2], [3]. Release of pro-inflammatory cytokines, namely tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β), together with pathogen-associated molecular patterns (PAMPs) have been classically associated with symptoms of sickness behavior, which includes general fatigue, decreased food intake, fever, somnolence, and hyperalgesia [4]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Inflammation is a hallmark of several disease states ranging from neurodegeneration to sepsis but is also implicated in physiological processes like ageing. Non-resolving inflammation and prolonged neuroinflammation are unclear processes implicated in several conditions, including ageing. In this study we studied the long-term effects of endotoxemia, as systemic lipopolysaccharide (LPS) injection, focusing on the role of astrocyte activation and cytokine release in the brain of aged rats. A single dose of LPS (2 mg/kg) or 0.9% saline was injected intraperitoneally in aged rats. Levels of pro-inflammatory cytokines (TNFα and IL-1β) and NF-κB p65 activation were measured systemically and in hippocampal tissue. Astrocytes and cytokines release in the CNS were detected via double immunofluorescence staining at different time-points up to day 30. Serum levels of TNFα and IL-1β were significantly increased acutely after 30 minutes (p<0.001) and up to 6 hours (p<0.001) following LPS-injection. Centrally, LPS-treated rats showed up-regulated mRNA expression and protein levels of pro-inflammatory cytokines in the hippocampus. These changes associated with astrogliosis in the hippocampus dentate gyrus (DG), IL-1β immunoreactivity and elevated NF-κB p65 expression up to day 30 post LPS exposure. Overall, these data demonstrate that LPS induces prolonged neuroinflammation and astrocyte activation in the hippocampus of aged rats. Hippocampal NF-κB p65 and excessive astrocytes-derived IL-1β release may play a pivotal role in regulating long-lasting neuroinflammation.
    Full-text · Article · Aug 2014 · PLoS ONE
  • Source
    • "The role of cytokines in neurodegenerative diseases is controversial, although TNF has been reported to protect neurons against Aβ [42,43] the majority of studies suggest that elevated concentrations of cytokines increase neurodegeneration. Thus, elevated levels of TNF are reported in neurodegenerative conditions including AD and PD [44,45], inhibition of TNF prevents neuropathology in mouse models of AD and post-operative cognitive decline [46,47] and the TNF inhibitor etanercept causes cognitive improvement in AD patients [48]. Similarly, high levels of IL-6 are raised in the brain tissue or cerebrospinal fluid (CSF) in AD, AIDS dementia complex, multiple sclerosis, stroke, PD and traumatic brain injuries [49] and IL-6 receptors are expressed on neurons at synapses and can regulate neurotransmitter release [50,51]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Activated microglia are associated with deposits of aggregated proteins within the brains of patients with Alzheimer’s disease (AD), Parkinson’s disease (PD) and prion diseases. Since the cytokines secreted from activated microglia are thought to contribute to the pathogenesis of these neurodegenerative diseases, compounds that suppress cytokine production have been identified as potential therapeutic targets. CD14 is a glycosylphosphatidylinositol (GPI)- anchored protein that is part of a receptor complex that mediates microglial responses to peptides that accumulate in prion disease (PrP82-146), AD (amyloid-β (Aβ)42) and PD (α-synuclein (αSN)). As some GPI-anchored proteins are released from cells by treatment with glimepiride, a sulphonylurea used for the treatment of diabetes, the effects of glimepiride upon CD14 expression and cytokine production from cultured macrophages were studied. Methods RAW 264 cells and microglial cells were treated with glimepiride or phosphatidylinositol (PI)-phospholipase C (PLC) and the expression of cell receptors was analysed by ELISA and immunoblot. Treated cells were subsequently incubated with Aβ42, αSN, PrP82-146 or lipopolysaccharide (LPS) and the amounts of Toll-like receptor (TLR)-4, tumour necrosis factor (TNF), interleukin (IL)-1 and IL-6 measured. Results Glimepiride released CD14 from RAW 264 cells and microglial cells. Pre-treatment with glimepiride significantly reduced TNF, IL-1 and IL-6 secretion from RAW 264 and microglial cells incubated with LPS, Aβ42, αSN and PrP82-146. Glimepiride also reduced the LPS, Aβ42, αSN and PrP82-146-induced translocation of TLR-4 into membrane rafts that is associated with cell activation. These effects of glimepiride were also seen after digestion of RAW 264 cells with PI-phospholipase C (PLC). In addition, the effects of glimepiride were blocked by pharmacological inhibition of GPI-PLC. The cytokine production was CD14-dependent; it was reduced in microglia from CD14 knockout mice and was blocked by antiserum to CD14. Conclusions RAW 264 and microglial cell responses to Aβ1–42, αSN, PrP82-146 and LPS are dependent upon CD14 expression. Glimepiride induced the shedding of CD14 from cells by activation of GPI-PLC and consequently reduced cytokine production in response to Aβ42, αSN, PrP82-146 and LPS. These results suggest that glimepiride acts as a novel anti-inflammatory agent that could modify the progression of neurodegenerative diseases.
    Full-text · Article · Jun 2014 · Journal of Neuroinflammation
Show more