IL-1alpha and HMGB1 mediate hippocampal dysfunction in SIGIRR-deficient mice
Citation:
Derek A. Costello, Melanie B. Watson, Thelma R. Cowley, Niamh Murphy, Ciaran Murphy Royal, Cecilia Garlanda & Marina A. Lynch, IL-1alpha and HMGB1 mediate hippocampal dysfunction in SIGIRR-deficient mice, Journal of Neuroscience, 31, 10, 2011, 3871-3879Download Item:
Abstract:
Single-Ig-interleukin-1 related receptor (SIGIRR) is a member of the interleukin (IL)-1/Toll-like receptor (TLR) family. It negatively regulates inflammation, rendering SIGIRR-/- mice more susceptible to inflammatory challenge. This susceptibility extends to the brain, where increased responsiveness to lipopolysaccharide (LPS) has been observed in SIGIRR-deficient mice. While this is likely due to enhanced TLR4-mediated signalling, the functional consequences of these changes have not yet been described. In the current study, we have investigated the impact of SIGIRR deficiency on hippocampal function, and show that novel object recognition, spatial reference memory and long-term potentiation (LTP) were impaired in SIGIRR-/- mice. These changes were accompanied by increased expression of IL-1RI and TLR4, and up-regulation of their downstream signalling events, namely IRAK1, JNK and NFkappaB. The deficit in LTP was attenuated by the endogenous IL-1 receptor antagonist (IL-1ra) and an anti-TLR4 antibody, and also by inhibition of JNK and NFkappaB. We propose that IL-1RI is activated by IL-1alpha and TLR4 is activated by the endogenous agonist, high mobility group box 1 (HMGB1), as we identified enhanced expression of both cytokines in the hippocampus of SIGIRR-/- mice. Additionally, application of HMGB1 increased the activation of JNK and NFkappaB and was found to be detrimental to LTP in a TLR4-dependent manner. These findings highlight the functional role of SIGIRR in regulating inflammatory-mediated synaptic and cognitive decline, and describe evidence of the key role of HMGB1 in this process.
Sponsor
Grant Number
European Commission
005203
Science Foundation Ireland
Author's Homepage:
http://people.tcd.ie/decostelhttp://people.tcd.ie/lynchma
Description:
PUBLISHEDPubMed ID: 21389242
Author: LYNCH, MARINA ANNETTA; COSTELLO, DEREK
Type of material:
Journal ArticleSeries/Report no:
Journal of Neuroscience31
10
Availability:
Full text availableKeywords:
Long-term potentiation, TIR8, IL-1RI, TLR4, NeuroscienceMetadata
Show full item recordLicences: