Interleukin-1α and HMGB1 Mediate Hippocampal Dysfunction in SIGIRR-Deficient Mice

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 SIGIRRϪ/Ϫ mice more susceptible to inflammatory challenge. This susceptibility extends to the brain, where increased responsiveness to lipopolysaccharide has been observed in SIGIRR-deficient mice. While this is likely due to enhanced TLR4-mediated signaling, 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 Ϫ/Ϫ mice. These changes were accompanied by increased expression of IL-1RI and TLR4, and upregulation of their downstream signaling events, namely IRAK1 (IL-1R-associated kinase 1), c-Jun N-terminal protein kinase (JNK), and nuclear factor B (NF-B). 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 NF-B. We propose that IL-1RI is activated by IL-1␣ 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 SIGIRRϪ/Ϫ mice. Additionally, application of HMGB1 increased the activation of JNK and NF-B and was found to be detrimental to LTP in a TLR4-dependent manner. These findings highlight the functional role of SIGIRR in regulating inflammatorymediated synaptic and cognitive decline, and describe evidence of the key role of HMGB1 in this process.

Toll-like receptor 4 enhancement of non-NMDA synaptic currents increases dentate excitability after brain injury

“…The ongoing basal neurophysiological effects of TLR4 could underlie the recently identified contribution of TLR4 to hippocampal long-term potentiation and memory function (Costello et al, 2011; Okun et al, 2012). The cellular mechanisms underlying TLR4 modulation of neurophysiology in the normal brain remain to be elucidated.…”

Long Term Potentiation Is Impaired in Membrane Glycoprotein CD200-deficient Mice

“…Analysis of CD200, GFAP, pIB␣, IL-1␣, IL-1␤, and TNF␣ by Western Immunoblotting-Hippocampal lysate was assessed for expression of IL-1␣, IL-1␤, and TNF␣; glial cell lysate was evaluated for expression of pIB␣; and membrane and cytosolic preparations obtained from purified astrocytes were evaluated for expression of CD200 and GFAP using standard Western immunoblotting methods (8,18). Primary antibodies directed against CD200 (anti-goat; 1:500; Santa Cruz Biotechnology, Inc., Santa Cruz, CA), GFAP (anti-rabbit; 1:1000; Invitrogen), pIB␣ (Ser-32) (anti-rabbit; 1:1000; Cell Signaling), IL-1␣ (antigoat; 1:1000; R&D Systems), IL-1␤ (anti-goat; 1:500; Santa Cruz Biotechnology, Inc.), and TNF␣ (anti-rabbit; 1:500; Cell Signaling) were incubated overnight at 4°C.…”

“…The secondary antibodies were conjugated to horseradish peroxidase (1:5000; Jackson Immunoresearch), and after a 2-h incubation step, membranes were washed, and protein complexes were visualized (Immobilon Western chemiluminescent substrate, Millipore). Membranes were stripped and probed for ␤-actin (to confirm equal loading) as described previously (8,18). Images were captured using the Fujifilm LAS-3000 imager, and densitometric analysis was used to quantify expression of the proteins.…”

HMGB1 in health and disease

“…CXCR3 −/− , but not CCR1 −/− , CCR5 −/− mice and NK cell-depleted mice display severe liver damage after CCl4 injection partly through increased HMGB1 expression in the liver (Zaldivar et al, 2012); HO1 −/− mice show increased mortality in sepsis partly through increased HMGB1 expression in response to LPS or IL-1β (Garcia-Arnandis et al, 2010a; Takamiya et al, 2009); PI3Kγ −/− mice ameliorated the LPS-induced decrease in myocardial contractility and HMGB1 mycocardial expression (Xu et al, 2010); Single-Ig-interleukin-1 related receptor (SIGIRR) −/− mice show cognitive deficiencies and hippocampal dysfunction with enhanced expression of HMGB1 (Costello et al, 2011); Metalloproteinase Zmpste24 −/− mice exhibit lipodystrophy with upregulated HMGB1 expression (Peinado et al, 2011). …”