Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms.
Animals
Brain
/ metabolism
Brain Injuries
/ immunology
Cognition
/ physiology
Cognition Disorders
/ immunology
Cognitive Dysfunction
/ chemically induced
Cytokines
/ metabolism
Dementia
/ immunology
Female
Hippocampus
/ metabolism
Inflammation
/ complications
Interleukin-1
/ immunology
Lipopolysaccharides
/ pharmacology
Memory Disorders
/ immunology
Memory, Short-Term
/ physiology
Mice
Mice, Inbred C57BL
Neurons
/ metabolism
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
24
04
2017
accepted:
03
04
2018
revised:
12
02
2018
pubmed:
8
6
2018
medline:
22
5
2020
entrez:
8
6
2018
Statut:
ppublish
Résumé
Systemic inflammation can impair cognition with relevance to dementia, delirium and post-operative cognitive dysfunction. Episodes of delirium also contribute to rates of long-term cognitive decline, implying that these acute events induce injury. Whether systemic inflammation-induced acute dysfunction and acute brain injury occur by overlapping or discrete mechanisms remains unexplored. Here we show that systemic inflammation, induced by bacterial LPS, produces both working-memory deficits and acute brain injury in the degenerating brain and that these occur by dissociable IL-1-dependent processes. In normal C57BL/6 mice, LPS (100 µg/kg) did not affect working memory but impaired long-term memory consolidation. However prior hippocampal synaptic loss left mice selectively vulnerable to LPS-induced working memory deficits. Systemically administered IL-1 receptor antagonist (IL-1RA) was protective against, and systemic IL-1β replicated, these working memory deficits. Dexamethasone abolished systemic cytokine synthesis and was protective against working memory deficits, without blocking brain IL-1β synthesis. Direct application of IL-1β to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-dependent fashion. The data suggest that LPS induces working memory dysfunction via circulating IL-1β but direct hippocampal action of IL-1β causes neuronal dysfunction and may drive neuronal death. The data suggest that acute systemic inflammation produces both reversible cognitive deficits, resembling delirium, and acute brain injury contributing to long-term cognitive impairment but that these events are mechanistically dissociable. These data have significant implications for management of cognitive dysfunction during acute illness.
Identifiants
pubmed: 29875474
doi: 10.1038/s41380-018-0075-8
pii: 10.1038/s41380-018-0075-8
pmc: PMC6510649
mid: NIHMS1021981
doi:
Substances chimiques
Cytokines
0
Interleukin-1
0
Lipopolysaccharides
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1533-1548Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : R01 AG050626
Pays : United States
Commentaires et corrections
Type : ErratumIn
Références
Elie M, Cole MG, Primeau FJ, Bellavance F. Delirium risk factors in elderly hospitalized patients. J Gen Intern Med. 1998;13:204–12.
doi: 10.1046/j.1525-1497.1998.00047.x
George J, Bleasdale S, Singleton SJ. Causes and prognosis of delirium in elderly patients admitted to a district general hospital. Age Ageing. 1997;26:423–7.
doi: 10.1093/ageing/26.6.423
Kat MG, Vreeswijk R, de Jonghe JF, van der Ploeg T, van Gool WA, Eikelenboom P, et al. Long-term cognitive outcome of delirium in elderly hip surgery patients. A prospective matched controlled study over two and a half years. Dement Geriatr Cogn Disord. 2008;26:1–8.
doi: 10.1159/000140611
van Munster BC, Korevaar JC, Zwinderman AH, Levi M, Wiersinga WJ, De Rooij SE. Time-course of cytokines during delirium in elderly patients with hip fractures. J Am Geriatr Soc. 2008;56:1704–9.
doi: 10.1111/j.1532-5415.2008.01851.x
Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56.
doi: 10.1038/nrn2297
Gosselin D, Rivest S. MyD88 signaling in brain endothelial cells is essential for the neuronal activity and glucocorticoid release during systemic inflammation. Mol Psychiatry. 2008;13:480–97.
doi: 10.1038/sj.mp.4002122
Cape E, Hall RJ, van Munster BC, de Vries A, Howie SE, Pearson A, et al. Cerebrospinal fluid markers of neuroinflammation in delirium: a role for interleukin-1β in delirium after hip fracture. J Psychosom Res. 2014;77:219–25.
doi: 10.1016/j.jpsychores.2014.06.014
Serantes R, Arnalich F, Figueroa M, Salinas M, Andres-Mateos E, Codoceo R, et al. Interleukin-1 beta enhances GABAA receptor cell-surface expression by a phosphatidylinositol 3-kinase/Akt pathway: relevance to sepsis-associated encephalopathy. J Biol Chem. 2006;281:14632–43.
doi: 10.1074/jbc.M512489200
Davis DH, Skelly DT, Murray C, Hennessy E, Bowen J, Norton S, et al. Worsening cognitive impairment and neurodegenerative pathology progressively increase risk for delirium. Am J Geriatr Psychiatry. 2015;23:403–15.
doi: 10.1016/j.jagp.2014.08.005
Fong TG, Davis D, Growdon ME, Albuquerque A, Inouye SK. The interface between delirium and dementia in elderly adults. Lancet Neurol. 2015;14:823–32.
doi: 10.1016/S1474-4422(15)00101-5
Davis DH,Muniz Terrera G,Keage H,Rahkonen T,Oinas M,Matthews FE, et al. Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study. Brain. 2012;135:2809–16.
doi: 10.1093/brain/aws190
MacLullich AM, Beaglehole A, Hall RJ, Meagher DJ. Delirium and long-term cognitive impairment. Int Rev Psychiatry. 2009;21:30–42.
doi: 10.1080/09540260802675031
Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, et al. Long-term cognitive impairment after critical illness. N Engl J Med. 2013;369:1306–16.
doi: 10.1056/NEJMoa1301372
Fong TG, Jones RN, Shi P, Marcantonio ER, Yap L, Rudolph JL, et al. Delirium accelerates cognitive decline in Alzheimer disease. Neurology. 2009;72:1570–5.
doi: 10.1212/WNL.0b013e3181a4129a
Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, et al. Systemic inflammation and disease progression in Alzheimer’s disease. Neurology. 2009;73:768–74.
doi: 10.1212/WNL.0b013e3181b6bb95
Leslie DL, Marcantonio ER, Zhang Y, Leo-Summers L, Inouye SK. One-year health care costs associated with delirium in the elderly population. Arch Intern Med. 2008;168:27–32.
doi: 10.1001/archinternmed.2007.4
Cunningham C, Sanderson DJ. Malaise in the water maze: untangling the effects of LPS and IL-1 beta on learning and memory. Brain Behav Immun. 2008;22:1117–27.
doi: 10.1016/j.bbi.2008.05.007
Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun. 2011;25:181–213.
doi: 10.1016/j.bbi.2010.10.015
Barrientos RM, Higgins EA, Sprunger DB, Watkins LR, Rudy JW, Maier SF. Memory for context is impaired by a post context exposure injection of interleukin-1 beta into dorsal hippocampus. Behav Brain Res. 2002;134:291–8.
doi: 10.1016/S0166-4328(02)00043-8
Cibelli M, Fidalgo AR, Terrando N, Ma D, Monaco C, Feldmann M, et al. Role of interleukin-1 beta in postoperative cognitive dysfunction. Ann Neurol. 2010;68:360–8.
doi: 10.1002/ana.22082
Goshen I, Kreisel T, Ounallah-Saad H, Renbaum P, Zalzstein Y, Ben-Hur T, et al. A dual role for interleukin-1 in hippocampal-dependent memory processes. Psychoneuroendocrinology. 2007;32:1106–15.
doi: 10.1016/j.psyneuen.2007.09.004
Barrientos RM, Hein AM, Frank MG, Watkins LR, Maier SF. Intracisternal interleukin-1 receptor antagonist prevents postoperative cognitive decline and neuroinflammatory response in aged rats. J Neurosci. 2012;32:14641–8.
doi: 10.1523/JNEUROSCI.2173-12.2012
Terrando N, Rei Fidalgo A, Vizcaychipi M, Cibelli M, Ma D, Monaco C, et al. The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction. Crit Care. 2010;14:R88.
doi: 10.1186/cc9019
Brown LJ, Ferner HS, Robertson J, Mills NL, Pessotto R, Deary IJ, et al. Differential effects of delirium on fluid and crystallized cognitive abilities. Arch Gerontol Geriatr. 2011;52:153–8.
doi: 10.1016/j.archger.2010.03.005
Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci. 2005;25:9275–84.
doi: 10.1523/JNEUROSCI.2614-05.2005
Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493:674–8.
doi: 10.1038/nature11729
Holmes C, El-Okl M, Williams AL, Cunningham C, Wilcockson D, Perry VH. Systemic infection, interleukin 1 beta, and cognitive decline in Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2003;74:788–9.
doi: 10.1136/jnnp.74.6.788
Murray C, Sanderson DJ, Barkus C, Deacon RM, Rawlins JN, Bannerman DM, et al. Systemic inflammation induces acute working memory deficits in the primed brain: relevance for delirium. Neurobiol Aging. 2012;33:603–16. e3
doi: 10.1016/j.neurobiolaging.2010.04.002
Teeling JL, Cunningham C, Newman TA, Perry VH. The effect of non-steroidal anti-inflammatory agents on behavioural changes and cytokine production following systemic inflammation: implications for a role of COX-1. Brain Behav Immun. 2010;24:409–19.
doi: 10.1016/j.bbi.2009.11.006
Murray CL, Skelly DT, Cunningham C. Exacerbation of CNS inflammation and neurodegeneration by systemic LPS treatment is independent of circulating IL-1 beta and IL-6. J Neuroinflamm. 2011;8:50.
doi: 10.1186/1742-2094-8-50
Murray CL, Obiang P, Bannerman D, Cunningham C. Endogenous IL-1 in cognitive function and anxiety: a study in IL-1RI-/- mice. PLoS ONE. 2013;8:e78385.
doi: 10.1371/journal.pone.0078385
Czerniawski J, Guzowski JF. Acute neuroinflammation impairs context discrimination memory and disrupts pattern separation processes in hippocampus. J Neurosci. 2014;34:12470–80.
doi: 10.1523/JNEUROSCI.0542-14.2014
Pugh CR, Kumagawa K, Fleshner M, Watkins LR, Maier SF, Rudy JW. Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning. Brain Behav Immun. 1998;12:212–29.
doi: 10.1006/brbi.1998.0524
Fanselow MS. Contextual fear, gestalt memories, and the hippocampus. Behav Brain Res. 2000;110:73–81.
doi: 10.1016/S0166-4328(99)00186-2
Cunningham C, Campion S, Teeling J, Felton L, Perry VH. The sickness behaviour and CNS inflammatory mediator profile induced by systemic challenge of mice with synthetic double-stranded RNA (poly I:C). Brain Behav Immun. 2007;21:490–502.
doi: 10.1016/j.bbi.2006.12.007
Pugh CR, Nguyen KT, Gonyea JL, Fleshner M, Wakins LR, Maier SF, et al. Role of interleukin-1 beta in impairment of contextual fear conditioning caused by social isolation. Behav Brain Res. 1999;106:109–18.
doi: 10.1016/S0166-4328(99)00098-4
Skelly DT, Hennessy E, Dansereau MA, Cunningham C. A systematic analysis of the peripheral and CNS effects of systemic LPS, IL-1 beta, [corrected] TNF-alpha and IL-6 challenges in C57BL/6 mice. PLoS ONE. 2013;8:e69123.
doi: 10.1371/journal.pone.0069123
Cunningham C, Wilcockson DC, Boche D, Perry VH. Comparison of inflammatory and acute-phase responses in the brain and peripheral organs of the ME7 model of prion disease. J Virol. 2005;79:5174–84.
doi: 10.1128/JVI.79.8.5174-5184.2005
Greenhalgh AD, Galea J, Denes A, Tyrrell PJ, Rothwell NJ. Rapid brain penetration of interleukin-1 receptor antagonist in rat cerebral ischaemia: pharmacokinetics, distribution, protection. Br J Pharmacol. 2010;160:153–9.
doi: 10.1111/j.1476-5381.2010.00684.x
Glaccum MB, Stocking KL, Charrier K, Smith JL, Willis CR, Maliszewski C, et al. Phenotypic and functional characterization of mice that lack the type I receptor for IL-1. J Immunol. 1997;159:3364–71.
pubmed: 9317135
Konsman JP, Veeneman J, Combe C, Poole S, Luheshi GN, Dantzer R. Central nervous action of interleukin-1 mediates activation of limbic structures and behavioural depression in response to peripheral administration of bacterial lipopolysaccharide. Eur J Neurosci. 2008;28:2499–510.
doi: 10.1111/j.1460-9568.2008.06549.x
Bluthe RM, Laye S, Michaud B, Combe C, Dantzer R, Parnet P. Role of interleukin-1beta and tumour necrosis factor-alpha in lipopolysaccharide-induced sickness behaviour: a study with interleukin-1 type I receptor-deficient mice. Eur J Neurosci. 2000;12:4447–56.
pubmed: 11122355
Hennessy E, Gormley S, Lopez-Rodriguez AB, Murray C, Cunningham C. Systemic TNF-alpha produces acute cognitive dysfunction and exaggerated sickness behavior when superimposed upon progressive neurodegeneration. Brain Behav Immun. 2017;59:233–44.
doi: 10.1016/j.bbi.2016.09.011
Davis DH, Muniz Terrera G, Keage H, Stephan BC, Fleming J, Ince PG, et al. Association of delirium with cognitive decline in late life: a neuropathologic study of 3 population-based cohort studies. JAMA Psychiatry. 2017;74:244–51.
doi: 10.1001/jamapsychiatry.2016.3423
Cunningham C, Maclullich AM. At the extreme end of the psychoneuroimmunological spectrum: delirium as a maladaptive sickness behaviour response. Brain Behav Immun. 2013;28:1–13.
doi: 10.1016/j.bbi.2012.07.012
Tong L, Prieto GA, Kramar EA, Smith ED, Cribbs DH, Lynch G, et al. Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-1 via p38 mitogen-activated protein kinase. J Neurosci. 2012;32:17714–24.
doi: 10.1523/JNEUROSCI.1253-12.2012
Frank MG, Barrientos RM, Hein AM, Biedenkapp JC, Watkins LR, Maier SF. IL-1RA blocks E. coli-induced suppression of Arc and long-term memory in aged F344xBN F1 rats. Brain Behav Immun. 2010;24:254–62.
doi: 10.1016/j.bbi.2009.10.005
Chapman TR, Barrientos RM, Ahrendsen JT, Maier SF, Patterson SL. Synaptic correlates of increased cognitive vulnerability with aging: peripheral immune challenge and aging interact to disrupt theta-burst late-phase long-term potentiation in hippocampal area CA1. J Neurosci. 2010;30:7598–603.
doi: 10.1523/JNEUROSCI.5172-09.2010
Bannerman DM, Sprengel R, Sanderson DJ, McHugh SB, Rawlins JN, Monyer H, et al. Hippocampal synaptic plasticity, spatial memory and anxiety. Nat Rev Neurosci. 2014;15:181–92.
doi: 10.1038/nrn3677
Czerniawski J, Miyashita T, Lewandowski G, Guzowski JF. Systemic lipopolysaccharide administration impairs retrieval of context-object discrimination, but not spatial, memory: evidence for selective disruption of specific hippocampus-dependent memory functions during acute neuroinflammation. Brain Behav Immun. 2015;44:159–66.
doi: 10.1016/j.bbi.2014.09.014
Gutierrez EG, Banks WA, Kastin AJ. Blood-borne interleukin-1 receptor antagonist crosses the blood-brain barrier. J Neuroimmunol. 1994;55:153–60.
doi: 10.1016/0165-5728(94)90005-1
Singh AK, Jiang Y. How does peripheral lipopolysaccharide induce gene expression in the brain of rats? Toxicology. 2004;201:197–207.
doi: 10.1016/j.tox.2004.04.015
Chakravarty S, Herkenham M. Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines. J Neurosci. 2005;25:1788–96.
doi: 10.1523/JNEUROSCI.4268-04.2005
Chen Z, Jalabi W, Shpargel KB, Farabaugh KT, Dutta R, Yin X, et al. Lipopolysaccharide-induced microglial activation and neuroprotection against experimental brain injury is independent of hematogenous TLR4. J Neurosci. 2012;32:11706–15.
doi: 10.1523/JNEUROSCI.0730-12.2012
Serrats J, Schiltz JC, Garcia-Bueno B, van Rooijen N, Reyes TM, Sawchenko PE. Dual roles for perivascular macrophages in immune-to-brain signaling. Neuron. 2010;65:94–106.
doi: 10.1016/j.neuron.2009.11.032
Cawthorne C, Prenant C, Smigova A, Julyan P, Maroy R, Herholz K, et al. Biodistribution, pharmacokinetics and metabolism of interleukin-1 receptor antagonist (IL-1RA) using [18F]-IL1RA and PET imaging in rats. Br J Pharmacol. 2011;162:659–72.
doi: 10.1111/j.1476-5381.2010.01068.x
Ericsson A, Liu C, Hart RP, Sawchenko PE. Type 1 interleukin-1 receptor in the rat brain: distribution, regulation, and relationship to sites of IL-1-induced cellular activation. J Comp Neurol. 1995;361:681–98.
doi: 10.1002/cne.903610410
Liu X, Yamashita T, Chen Q, Belevych N, McKim DB, Tarr AJ, et al. Interleukin 1 type 1 receptor restore: a genetic mouse model for studying interleukin 1 receptor-mediated effects in specific cell types. J Neurosci: Off J Soc Neurosci. 2015;35:2860–70.
doi: 10.1523/JNEUROSCI.3199-14.2015
Wong ML, Licinio J. Localization of interleukin 1 type I receptor mRNA in rat brain. Neuroimmunomodulation. 1994;1:110–5.
doi: 10.1159/000097143
Griffin EW, Skelly DT, Murray CL, Cunningham C. Cyclooxygenase-1-dependent prostaglandins mediate susceptibility to systemic inflammation-induced acute cognitive dysfunction. J Neurosci. 2013;33:15248–58.
doi: 10.1523/JNEUROSCI.6361-11.2013
Chen Q, Zhang H, Li Q, An Y, Herkenham M, Lai W, et al. Three promoters regulate tissue- and cell type-specific expression of murine interleukin-1 receptor type I. J Biol Chem. 2009;284:8703–13.
doi: 10.1074/jbc.M808261200
Engler H, Doenlen R, Engler A, Riether C, Prager G, Niemi MB, et al. Acute amygdaloid response to systemic inflammation. Brain Behav Immun. 2011;25:1384–92.
doi: 10.1016/j.bbi.2011.04.005
Nadjar A, Combe C, Laye S, Tridon V, Dantzer R, Amedee T, et al. Nuclear factor kappaB nuclear translocation as a crucial marker of brain response to interleukin-1. A study in rat and interleukin-1 type I deficient mouse. J Neurochem. 2003;87:1024–36.
doi: 10.1046/j.1471-4159.2003.02097.x
Ota K, Wildmann J, Ota T, Besedovsky HO, Del Rey A. Interleukin-1beta and insulin elicit different neuroendocrine responses to hypoglycemia. Ann N Y Acad Sci. 2009;1153:82–8.
doi: 10.1111/j.1749-6632.2008.03981.x
Godbout JP, Chen J, Abraham J, Richwine AF, Berg BM, Kelley KW, et al. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J. 2005;19:1329–31.
doi: 10.1096/fj.05-3776fje
Palin K, Cunningham C, Forse P, Perry VH, Platt N. Systemic inflammation switches the inflammatory cytokine profile in CNS Wallerian degeneration. Neurobiol Dis. 2008;30:19–29.
doi: 10.1016/j.nbd.2007.11.012
Pott-Godoy MC, Tarelli R, Ferrari CC, Sarchi MI, Pitossi FJ. Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson’s disease. Brain. 2008;131:1880–94.
doi: 10.1093/brain/awn101
Combrinck MI, Perry VH, Cunningham C. Peripheral infection evokes exaggerated sickness behaviour in pre-clinical murine prion disease. Neuroscience. 2002;112:7–11.
doi: 10.1016/S0306-4522(02)00030-1
Coogan A, O’Connor JJ. Inhibition of NMDA receptor-mediated synaptic transmission in the rat dentate gyrus in vitro by IL-1 beta. Neuroreport. 1997;8:2107–10.
doi: 10.1097/00001756-199707070-00004
Ferri CC, Ferguson AV. Interleukin-1 beta depolarizes paraventricular nucleus parvocellular neurones. J Neuroendocrinol. 2003;15:126–33.
doi: 10.1046/j.1365-2826.2003.00870.x
Balosso S,Maroso M,Sanchez-Alavez M,Ravizza T,Frasca A,Bartfai T, et al. A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1 beta. Brain. 2008;131:3256–65.
doi: 10.1093/brain/awn271
Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, et al. Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci. 2003;23:8692–700.
doi: 10.1523/JNEUROSCI.23-25-08692.2003
Prieto GA, Snigdha S, Baglietto-Vargas D, Smith ED, Berchtold NC, Tong L, et al. Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1 beta in the aged hippocampus. Proc Natl Acad Sci USA. 2015;112:E5078–87.
doi: 10.1073/pnas.1514486112
Cunningham C, Campion S, Lunnon K, Murray CL, Woods JF, Deacon RM, et al. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry. 2009;65:304–12.
doi: 10.1016/j.biopsych.2008.07.024
Schreuder L, Eggen J, Biber K, Schoemaker R, Laman J, de Rooij S. Pathophysiological and behavioral effects of systemic inflammation in aged and diseased rodents with relevance to delirium: a systematic review. Brain Behav Immun. 2017;62:362–81.
doi: 10.1016/j.bbi.2017.01.010