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Critical Care
Published in: Critical Care 3/2010

Open Access 01-06-2010 | Research

The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction

Authors: Niccolò Terrando, António Rei Fidalgo, Marcela Vizcaychipi, Mario Cibelli, Daqing Ma, Claudia Monaco, Marc Feldmann, Mervyn Maze

Published in: Critical Care | Issue 3/2010

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Abstract

Introduction

The impact of pro-inflammatory cytokines on neuroinflammation and cognitive function after lipopolysaccharide (LPS) challenge remains elusive. Herein we provide evidence that there is a temporal correlation between high-mobility group box 1 (HMGB-1), microglial activation, and cognitive dysfunction. Disabling the interleukin (IL)-1 signaling pathway is sufficient to reduce inflammation and ameliorate the disability.

Methods

Endotoxemia was induced in wild-type and IL-1R-/- mice by intra peritoneal injection of E. Coli LPS (1 mg/kg). Markers of inflammation were assessed both peripherally and centrally, and correlated to behavioral outcome using trace fear conditioning.

Results

Increase in plasma tumor necrosis factor-α (TNFα) peaked at 30 minutes after LPS challenge. Up-regulation of IL-1β, IL-6 and HMGB-1 was more persistent, with detectable levels up to day three. A 15-fold increase in IL-6 and a 6.5-fold increase in IL-1β mRNA at 6 hours post intervention (P < 0.001 respectively) was found in the hippocampus. Reactive microgliosis was observed both at days one and three, and was associated with elevated HMGB-1 and impaired memory retention (P < 0.005). Preemptive administration of IL-1 receptor antagonist (IL-1Ra) significantly reduced plasma cytokines and hippocampal microgliosis and ameliorated cognitive dysfunction without affecting HMGB-1 levels. Similar results were observed in LPS-challenged mice lacking the IL-1 receptor to those seen in LPS-challenged wild type mice treated with IL-1Ra.

Conclusions

These data suggest that by blocking IL-1 signaling, the inflammatory cascade to LPS is attenuated, thereby reducing microglial activation and preventing the behavioral abnormality.
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Literature
1.
Dantzer R: Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity. Eur J Pharmacol 2004, 500: 399-411. 10.1016/j.ejphar.2004.07.040CrossRefPubMed
2.
Annane D: Hippocampus: a future target for sepsis treatment! Intensive Care Med 2009, 35: 585-586. 10.1007/s00134-009-1395-6CrossRefPubMed
3.
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: 212-229. 10.1006/brbi.1998.0524CrossRefPubMed
4.
Dinarello CA: Biologic basis for interleukin-1 in disease. Blood 1996, 87: 2095-2147.PubMed
5.
Murray CA, Lynch MA: Evidence that increased hippocampal expression of the cytokine interleukin-1 beta is a common trigger for age- and stress-induced impairments in long-term potentiation. J Neurosci 1998, 18: 2974-2981.PubMed
6.
Parnet P, Amindari S, Wu C, Brunke-Reese D, Goujon E, Weyhenmeyer JA, Dantzer R, Kelley KW: Expression of type I and type II interleukin-1 receptors in mouse brain. Brain Res Mol Brain Res 1994, 27: 63-70. 10.1016/0169-328X(94)90185-6CrossRefPubMed
7.
Gemma C, Fister M, Hudson C, Bickford PC: Improvement of memory for context by inhibition of caspase-1 in aged rats. Eur J Neurosci 2005, 22: 1751-1756. 10.1111/j.1460-9568.2005.04334.xCrossRefPubMed
8.
Rachal Pugh C, Fleshner M, Watkins LR, Maier SF, Rudy JW: The immune system and memory consolidation: a role for the cytokine IL-1beta. Neurosci Biobehav Rev 2001, 25: 29-41. 10.1016/S0149-7634(00)00048-8CrossRefPubMed
9.
Chen J, Buchanan JB, Sparkman NL, Godbout JP, Freund GG, Johnson RW: Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav Immun 2008, 22: 301-311. 10.1016/j.bbi.2007.08.014PubMedCentralCrossRefPubMed
10.
Allan SM, Tyrrell PJ, Rothwell NJ: Interleukin-1 and neuronal injury. Nat Rev Immunol 2005, 5: 629-640. 10.1038/nri1664CrossRefPubMed
11.
Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ: HMG-1 as a late mediator of endotoxin lethality in mice. Science 1999, 285: 248-251. 10.1126/science.285.5425.248CrossRefPubMed
12.
Gordon SM, Jackson JC, Ely EW, Burger C, Hopkins RO: Clinical identification of cognitive impairment in ICU survivors: insights for intensivists. Intensive Care Med 2004, 30: 1997-2008. 10.1007/s00134-004-2418-yCrossRefPubMed
13.
Labow M, Shuster D, Zetterstrom M, Nunes P, Terry R, Cullinan EB, Bartfai T, Solorzano C, Moldawer LL, Chizzonite R, McIntyre KW: Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice. J Immunol 1997, 159: 2452-2461.PubMed
14.
Nguyen KT, Deak T, Owens SM, Kohno T, Fleshner M, Watkins LR, Maier SF: Exposure to acute stress induces brain interleukin-1beta protein in the rat. J Neurosci 1998, 18: 2239-2246.PubMed
15.
Colburn RW, DeLeo JA, Rickman AJ, Yeager MP, Kwon P, Hickey WF: Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat. J Neuroimmunol 1997, 79: 163-175. 10.1016/S0165-5728(97)00119-7CrossRefPubMed
16.
Cibelli M, Fidalgo A, Terrando N, Ma D, Monaco C, Feldmann M, Takata M, Lever I, Nanchahal J, Fanselow MS, Maze M: Role of Interleukin-1β in Postoperative Cognitive Dysfunction. Ann Neurol 2010, in press.
17.
Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, Takeda K, Akira S: Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 1999, 162: 3749-3752.PubMed
18.
Andreakos E, Sacre SM, Smith C, Lundberg A, Kiriakidis S, Stonehouse T, Monaco C, Feldmann M, Foxwell BM: Distinct pathways of LPS-induced NF-kappa B activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of MyD88 and Mal/TIRAP. Blood 2004, 103: 2229-2237. 10.1182/blood-2003-04-1356CrossRefPubMed
19.
Van Dam AM, Brouns M, Man AHW, Berkenbosch F: Immunocytochemical detection of prostaglandin E2 in microvasculature and in neurons of rat brain after administration of bacterial endotoxin. Brain Res 1993, 613: 331-336. 10.1016/0006-8993(93)90922-ACrossRefPubMed
20.
Dantzer R: How do cytokines say hello to the brain? Neural versus humoral mediation. Eur Cytokine Netw 1994, 5: 271-273.PubMed
21.
Hansen MK, Taishi P, Chen Z, Krueger JM: Vagotomy blocks the induction of interleukin-1beta (IL-1beta) mRNA in the brain of rats in response to systemic IL-1beta. J Neurosci 1998, 18: 2247-2253.PubMed
22.
23.
Hanisch UK, Kettenmann H: Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 2007, 10: 1387-1394. 10.1038/nn1997CrossRefPubMed
24.
Monje ML, Toda H, Palmer TD: Inflammatory blockade restores adult hippocampal neurogenesis. Science 2003, 302: 1760-1765. 10.1126/science.1088417CrossRefPubMed
25.
Fanselow MS: Conditioned and unconditional components of post-shock freezing. Pavlov J Biol Sci 1980, 15: 177-182.PubMed
26.
Maren S, Aharonov G, Fanselow MS: Neurotoxic lesions of the dorsal hippocampus and Pavlovian fear conditioning in rats. Behav Brain Res 1997, 88: 261-274. 10.1016/S0166-4328(97)00088-0CrossRefPubMed
27.
Vereker E, Campbell V, Roche E, McEntee E, Lynch MA: Lipopolysaccharide inhibits long term potentiation in the rat dentate gyrus by activating caspase-1. J Biol Chem 2000, 275: 26252-26258. 10.1074/jbc.M002226200CrossRefPubMed
28.
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: 291-298. 10.1016/S0166-4328(02)00043-8CrossRefPubMed
29.
30.
31.
Abbate A, Salloum FN, Vecile E, Das A, Hoke NN, Straino S, Biondi-Zoccai GG, Houser JE, Qureshi IZ, Ownby ED, Gustini E, Biasucci LM, Severino A, Capogrossi MC, Vetrovec GW, Crea F, Baldi A, Kukreja RC, Dobrina A: Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction. Circulation 2008, 117: 2670-2683. 10.1161/CIRCULATIONAHA.107.740233CrossRefPubMed
32.
van Zoelen MA, Yang H, Florquin S, Meijers JC, Akira S, Arnold B, Nawroth PP, Bierhaus A, Tracey KJ, Poll T: Role of toll-like receptors 2 and 4, and the receptor for advanced glycation end products in high-mobility group box 1-induced inflammation in vivo. Shock 2009, 31: 280-284. 10.1097/SHK.0b013e318186262dPubMedCentralCrossRefPubMed
33.
Skinner RA, Gibson RM, Rothwell NJ, Pinteaux E, Penny JI: Transport of interleukin-1 across cerebromicrovascular endothelial cells. Br J Pharmacol 2009, 156: 1115-1123. 10.1111/j.1476-5381.2008.00129.xPubMedCentralCrossRefPubMed
34.
D'Mello C, Le T, Swain MG: Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. J Neurosci 2009, 29: 2089-2102. 10.1523/JNEUROSCI.3567-08.2009CrossRefPubMed
35.
Riedemann NC, Guo RF, Ward PA: Novel strategies for the treatment of sepsis. Nat Med 2003, 9: 517-524. 10.1038/nm0503-517CrossRefPubMed
36.
Marshall JC: Such stuff as dreams are made on: mediator-directed therapy in sepsis. Nat Rev Drug Discov 2003, 2: 391-405. 10.1038/nrd1084CrossRefPubMed
Metadata
Title
The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction
Authors
Niccolò Terrando
António Rei Fidalgo
Marcela Vizcaychipi
Mario Cibelli
Daqing Ma
Claudia Monaco
Marc Feldmann
Mervyn Maze
Publication date
01-06-2010
Publisher
BioMed Central
Published in
Critical Care / Issue 3/2010
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/cc9019

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