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Prevention of LPS-induced microglia activation, cytokine production and sickness behavior with TLR4 receptor interfering peptides.

ABSTRACT: The innate immune receptor Toll-like 4 (TLR4) is the receptor activated by lipopolysaccharide (LPS), and TLR4-LPS interaction is well known to induce an innate immune response, triggering sickness behavior. Within the brain, TLR4 is highly expressed in brain microglia, and excessive inflammation resulting from activation of this pathway in the brain has been implicated in depressive disorders and neurodegenerative pathologies. We hypothesized that blocking LPS-induced activation of TLR4 would prevent downstream immune signaling in the brain and suppress the induction of sickness behavior. We used interfering peptides to block TLR4 activation and confirmed their efficacy in preventing second messenger activation and cytokine production normally induced by LPS treatment. Further, these peptides blocked morphological changes in microglia that are typically induced by LPS. We also demonstrated that intraperitoneal (i.p.) injection of Tat-TLR4 interfering peptides prevented LPS-induced sickness behavior, as assessed in home cage behavior and with the intracranial self-stimulation paradigm. These newly synthesised peptides inhibit TLR4 signaling thereby preventing changes in behavior and motivation caused by inflammatory stimuli. These peptides highlight the roll of TLR4 and microglia morphology changes in sickness behavior, and thus may be of therapeutic value in limiting the deleterious impact of excessive inflammation in specific CNS pathologies.

SUBMITTER: Hines DJ

PROVIDER: S-EPMC3610686 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Prevention of LPS-induced microglia activation, cytokine production and sickness behavior with TLR4 receptor interfering peptides.

Hines Dustin J DJ Choi Hyun B HB Hines Rochelle M RM Phillips Anthony G AG MacVicar Brian A BA

PloS one 20130328 3

The innate immune receptor Toll-like 4 (TLR4) is the receptor activated by lipopolysaccharide (LPS), and TLR4-LPS interaction is well known to induce an innate immune response, triggering sickness behavior. Within the brain, TLR4 is highly expressed in brain microglia, and excessive inflammation resulting from activation of this pathway in the brain has been implicated in depressive disorders and neurodegenerative pathologies. We hypothesized that blocking LPS-induced activation of TLR4 would pr ...[more]

PMID: 23555964

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Project description:Siglec-E is a murine CD33-related siglec that functions as an inhibitory receptor and is expressed mainly on neutrophils and macrophage populations. Recent studies have suggested that siglec-E is an important negative regulator of LPS-TLR4 signalling and one report (Wu et al 2016) claimed that siglec-E is required for TLR4 endocytosis following uptake of Escherichia coli by macrophages and dendritic cells (DCs). Our attempts to reproduce these observations using cells from wildtype (WT) and siglec E deficient mice were unsuccessful. We used a variety of assays to determine if siglec-E expressed by different macrophage populations can regulate TLR-4 signalling in response to LPS, but found no consistent differences in cytokine secretion in vitro and in vivo, comparing 3 different strains of siglec-E-deficient mice with matched WT controls. No evidence was found that the siglec-E deficiency was compensated by expression of siglecs-F and –G, the other murine inhibitory CD33-related siglecs. Quantitative proteomics was used as an unbiased approach and provided additional evidence that siglec-E does not suppress inflammatory TLR4 signaling. Interestingly, proteomics revealed a siglec E dependent alteration in macrophage phenotype that could be relevant to functional responses in host defence. In support of this, siglec-E-deficient mice exhibited enhanced growth of Salmonella enterica serovar Typhimurium in the liver following intravenous infection, but macrophages lacking siglec-E did not show altered uptake or killing of bacteria in vitro. Using various cell types including bone marrow derived DCs (BMDC), splenic DCs and macrophages from WT and siglec-E-deficient mice, we showed that siglec-E is not required for TLR4 endocytosis following E.coli uptake or LPS challenge. We failed to see expression of siglec-E by BMDC even after LPS-induced maturation, but confirmed previous studies that splenic DCs express low levels of siglec-E. Taken together, our findings do not support a major role of siglec-E in regulation of TLR4 signalling functions or TLR4 endocytosis in macrophages or DCs. Instead, they reveal that induction of siglec-E by LPS can modulate the phenotype of macrophages, the functional significance of which is currently unclear.

Dataset Information

Prevention of LPS-induced microglia activation, cytokine production and sickness behavior with TLR4 receptor interfering peptides.

Publications

Prevention of LPS-induced microglia activation, cytokine production and sickness behavior with TLR4 receptor interfering peptides.

Similar Datasets

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