SIGIRR modulates the inflammatory response in the brain

Watson, Melanie B.; Costello, Derek A.; Carney, Dónal G.; McQuillan, Keith; Lynch, Marina A.

doi:10.1016/j.bbi.2010.04.002

Cited by 27 publications

(28 citation statements)

References 37 publications

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“…SIGIRR deficiency has been associated with increased inflammation in several experimental models (Drexler et al, 2010;Gulen et al, 2010), and recent data indicate that LPS induces a more profound effect on proinflammatory cytokine production in SI-GIRR Ϫ/Ϫ , compared with wild-type mice in vitro and in vivo (Watson et al, 2010). These changes are paralleled by, and probably due to, increased microglial activation in SIGIRR Ϫ/Ϫ mice (Watson et al, 2010).…”

Section: Resultsmentioning

confidence: 60%

“…These changes are paralleled by, and probably due to, increased microglial activation in SIGIRR Ϫ/Ϫ mice (Watson et al, 2010). …”

Section: Resultsmentioning

confidence: 99%

“…A previous report from our laboratory identified that SIGIRR deficiency was associated with increased expression of TLR4 mRNA and CD14 mRNA, coupled with NF-B activation (Watson et al, 2010). Here we demonstrate a significant increase in TLR4 protein in hippocampal tissue of SIGIRR Ϫ/Ϫ relative to wild-type mice (**p Ͻ 0.01; unpaired Student's t test; Fig.…”

Section: Resultsmentioning

confidence: 99%

“…A recent report demonstrated that LPS exerted an enhanced response in glial cells and hippocampal tissue from SIGIRR Ϫ/Ϫ , compared with wild-type mice (Watson et al, 2010). In addition, intraperitoneal injection of LPS decreased exploratory behavior to a greater extent in SIGIRR Ϫ/Ϫ , compared with wild-type, mice (Watson et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…A recent report from this laboratory provides the first evidence that these effects are extended to the brain, demonstrating exaggerated microglial activation and inflammatory regulation in hippocampus of SIGIRR Ϫ/Ϫ mice in response to LPS (Watson et al, 2010). In addition to analysis in SIGIRR-deficient mice, overexpression of SIGIRR has proven beneficial to our understanding of how its anti-inflammatory effects may be mediated (Wald et al, 2003;Qin et al, 2005;Zhang et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

Costello¹,

Watson²,

Cowley³

et al. 2011

J. Neurosci.

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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.

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Section: Resultsmentioning

confidence: 60%

“…These changes are paralleled by, and probably due to, increased microglial activation in SIGIRR Ϫ/Ϫ mice (Watson et al, 2010). …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Costello¹,

Watson²,

Cowley³

et al. 2011

J. Neurosci.

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Toll‐like receptor 3 activation modulates hippocampal network excitability, via glial production of interferon‐β

Costello

Lynch

2013

Hippocampus

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The family of toll-like receptors (TLR) plays a major role in innate immunity due to their pathogen-recognition abilities. TLR3 is a sensor for double-stranded RNA, and regulates host-defense responses to several viruses, via the production of type I interferons. Interferon-β (IFNβ) is a primary product of TLR3 activation, and its transcription is elevated in the CNS response to the synthetic TLR3 ligand, polyinosinic-polycytidylic acid (poly(I:C)). Peripheral infections, along with TLR-induced inflammatory mediators, are known to have detrimental effects on brain function, exerting a negative impact on cognition and enhancing seizure susceptibility. In this study, we assessed hippocampal function in vitro, in response to systemic delivery of a TLR3 agonist. Unlike agonists of other TLRs, intraperitoneal injection of poly(I:C) did not adversely affect evoked short- and long-term synaptic plasticity in mouse hippocampal slices. However, sustained and interictal-like spontaneous activity was observed in CA1 pyramidal cells in response to poly(I:C) and this was associated with alterations in the expression of phosphorylated NR2B subunit-containing NMDA receptors and an astrocyte-specific glutamate/aspartate transporter (GLAST) which impact on extracellular glutamate concentration and contribute to the genesis of epileptiform activity. We provide evidence for the production of IFNβ from microglia and astrocytes, and using mice deficient in the type I IFN receptor α 1 (IFNAR1), demonstrate that its subsequent activation is likely to underlie the TLR3-mediated modulation of hippocampal excitability.

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Regulation of Immunity and Disease by the IL-1 Receptor Family Members IL-1R2 and IL-1R8

Molgora

Supino

Garlanda

2018

Immunopharmacology and Inflammation

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SIGIRR modulates the inflammatory response in the brain

Cited by 27 publications

References 37 publications

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

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

Toll‐like receptor 3 activation modulates hippocampal network excitability, via glial production of interferon‐β

Regulation of Immunity and Disease by the IL-1 Receptor Family Members IL-1R2 and IL-1R8

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