The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction.
BACKGROUND
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-alpha (TNFalpha) peaked at 30 minutes after LPS challenge. Up-regulation of IL-1beta, 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-1beta 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.
Terrando
Niccolò
N
Department of Anesthetics, Pain Medicine and Intensive Care, Imperial College London, Chelsea & Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. n.terrando@imperial.ac.uk
Rei Fidalgo
António
A
Vizcaychipi
Marcela
M
Cibelli
Mario
M
Ma
Daqing
D
Monaco
Claudia
C
Feldmann
Marc
M
Maze
Mervyn
M
D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced* / Q000276:immunology / Q000517:prevention & control*; D016207:Cytokines / Q000097:blood; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism; D004926:Escherichia coli / Q000276:immunology / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000187:drug effects
D016207:Cytokines; D024243:HMGB1 Protein; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha
Eur J Neurosci. 2005 Oct;22(7):1751-6
16197515
Behav Brain Res. 1997 Nov;88(2):261-74
9404635
Blood. 2004 Mar 15;103(6):2229-37
14630816
Ann Neurol. 2010 Sep;68(3):360-8
20818791
J Neurosci. 1998 Mar 15;18(6):2247-53
9482809
Behav Brain Res. 2002 Aug 21;134(1-2):291-8
12191816
Neurosci Biobehav Rev. 2001 Jan;25(1):29-41
11166076
J Neurosci. 1998 Apr 15;18(8):2974-81
9526014
J Neurosci. 1998 Mar 15;18(6):2239-46
9482808
J Exp Med. 2005 May 2;201(9):1355-9
15867089
Intensive Care Med. 2009 Apr;35(4):585-6
19156398
J Immunol. 1999 Apr 1;162(7):3749-52
10201887
Nat Neurosci. 2007 Nov;10(11):1387-94
17965659
Brain Behav Immun. 2008 Mar;22(3):301-11
17951027
Brain Behav Immun. 1998 Sep;12(3):212-29
9769157
Pavlov J Biol Sci. 1980 Oct-Dec;15(4):177-82
7208128
J Biol Chem. 2000 Aug 25;275(34):26252-8
10856294
Nat Rev Drug Discov. 2003 May;2(5):391-405
12750742
Science. 1999 Jul 9;285(5425):248-51
10398600
Nat Med. 2003 May;9(5):517-24
12724763
Circulation. 2008 May 20;117(20):2670-83
18474815
J Clin Invest. 1991 Nov;88(5):1445-51
1834696
Intensive Care Med. 2004 Nov;30(11):1997-2008
15549252
Shock. 2009 Mar;31(3):280-4
19218854
Blood. 1996 Mar 15;87(6):2095-147
8630372
J Immunol. 1997 Sep 1;159(5):2452-61
9278338
Brain Res. 1993 Jun 11;613(2):331-6
8186987
Br J Pharmacol. 2009 Apr;156(7):1115-23
19298391
Brain Res Mol Brain Res. 1994 Nov;27(1):63-70
7877456
J Neuroimmunol. 1997 Nov;79(2):163-75
9394789
Science. 2003 Dec 5;302(5651):1760-5
14615545
Eur J Pharmacol. 2004 Oct 1;500(1-3):399-411
15464048
Eur Cytokine Netw. 1994 May-Jun;5(3):271-3
7948764
Glia. 2001 Nov;36(2):165-79
11596125
Nat Rev Immunol. 2005 Aug;5(8):629-40
16034365
J Neurosci. 2009 Feb 18;29(7):2089-102
19228962