Rosiglitazone as a Modulator of TLR4 and TLR3 Signaling Pathways in Rat Primary Neurons and Astrocytes

Chistyakov, Dmitry V.; Azbukina, Nadezhda V.; Лопачев, А. В.; Куличенкова, К.Н.; Astakhova, A. A.; Sergeeva, Marina G.

doi:10.3390/ijms19010113

Cited by 27 publications

(23 citation statements)

References 43 publications

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“…Similar role of TLR3 activation as an amplifier of the early inflammatory responses have been reported in the kidney and the liver (Patole et al, 2005; Lang et al, 2006). Activation of TLR3 with poly I:C induces a prolonged inflammatory response from cultured astrocytes (Chistyakov et al, 2018), microglia (Dupuis et al, 2016; Yousif et al, 2018), and brain endothelial cells (Johnson et al, 2018). The prolonged inflammatory response induced by TLR3 activation in microglia and astrocytes biologically serves to control or to enhance insidious viral infections such as Chikungunya (Priya et al, 2014) and HIV-1 (Bhargavan and Kanmogne, 2018) and non-viral infections such as Borrelia burgdorferi (Greenmyer et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Evidence for Sexual Dimorphism in the Response to TLR3 Activation in the Developing Neonatal Mouse Brain: A Pilot Study

et al. 2019

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Toll-like receptor (TLR)3 activation during the neonatal period produces responses linked to the origins of neuropsychiatric disorders. Although there is sexual dimorphism in neuropsychiatric disorders, it is unknown if brain responses to TLR3 activation are sex-specific. We hypothesized that poly I:C in a post-natal day (P)8 model induces a sexually dimorphic inflammatory responses. C57BL6 mice received intraperitoneal injection of poly I:C (10 mg/kg) or vehicle [normal saline (NS)] at P8. Pups were killed at 6 or 14 h for caspase 3 and 8 activity assays, NFkB ELISA, IRF3, AP1, and GFAP western blotting and cytokines/chemokines gene expression real time qRT-PCR (4–6/group). A second group of pups were killed at 24 h (P9) or 7 days (P15) after poly I:C to assess astrocytic (GFAP) and microglia (Iba1) activation in the hippocampus, thalamus and cortex using immunohistochemistry, and gene and protein expression of cytokines/chemokines using real time RT-PCR and MSD, respectively (4–6/group). Non-parametric analysis was applied. Six hours after poly I:C, caspase-3 and -8 activities in cytosolic fractions were 1.6 and 2.8-fold higher in poly I:C-treated than in NS-treated female mice, respectively, while gene expressions of pro-inflammatory cytokines were upregulated in both sexes. After poly I:C, IRF3 nuclear translocation occurred earlier (6 h) in female mice and later (14 h) in male mice. At 14 h after poly I:C, only male mice also had increased nuclear NFκB levels (88%, p < 0.001) and GFAP expression coinciding with persistent IL-6 and FAS gene upregulation (110 and 77%, respectively; p < 0.001) and IL-10 gene downregulation (-42%, p < 0.05). At 24 h after poly I:C, IL-1β, CXCL-10, TNF-α, and MCP-1 were similarly increased in both sexes but at 7 days after exposure, CXCL-10 and INFγ were increased and IL-10 was decreased only in female mice. Accordingly, microglial activation persisted at 7 days after poly I:C in the hippocampus, thalamus and cortex of female mice. This preliminary study suggests that TLR3 activation may produce in the developing neonatal mouse brain a sexually dimorphic response with early activation of caspase-dependent pathways in female mice, activation of inflammatory cascades in both sexes, which then persists in female mice. Further well-powered studies are essential to confirm these sex-specific findings.

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Section: Discussionmentioning

confidence: 99%

Evidence for Sexual Dimorphism in the Response to TLR3 Activation in the Developing Neonatal Mouse Brain: A Pilot Study

et al. 2019

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“…An important finding of the present data concerns sex difference in the LPS-induced prostaglandin (PG) synthesis. Although there are still questions concerning the precise roles of various PGs in inflammation or in the resolution of inflammation, there is no doubt that signaling lipids are major regulatory participants of inflammation, developing of neurodegenerative diseases and mood disorders [ 16 , 18 , 30 , 45 ]. We have found only one work with correlations between PGF 2α and PGE 2 synthases, TLR4 and 3β-hydroxysteroid dehydrogenase in a model, where LPS was given in vivo and then the structure and function of the bovine corpus luteum were investigated [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

“…Sex differences in the responses of astrocytes to lipopolysaccharide (LPS) as an agonist of toll-like receptors type 4 (TLR4) were demonstrated on the mRNA level [ 13 ]. It has previously been shown that TLR4 activation in astrocytes simultaneously induced, on a protein level, both the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) and anti-inflammatory cytokine interleukin-10 (IL-10) [ 15 , 16 ]. The modulation of the cyclooxygenase (COX)-2 expression by LPS induces synthesis of various prostaglandins (PG) [ 17 , 18 ], which, modifies both the pro-inflammatory and anti-inflammatory processes, depending on the cellular context [ 19 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Sex-Mediated Differences in LPS Induced Alterations of TNFα, IL-10 Expression, and Prostaglandin Synthesis in Primary Astrocytes

Chistyakov

Azbukina

Astakhova

et al. 2018

IJMS

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Although many neurological and psychiatric disorders reveal clear sex-dependent variations, the molecular mechanism of this process is not clear enough. Astrocytes are involved in the response of neural tissue to injury and inflammation, produce steroid hormones, and sense steroid presence. To explore the hypothesis that astrocytes may participate in sex-mediated differences of inflammatory responses, we have examined whether male and female primary rat astrocytes show different responses to lipopolysaccharide (LPS) as a toll-like receptor 4 (TLR4) agonist. Levels of mRNA and proteins of tumor necrosis factor alpha (TNFα), interleukin-10 (IL-10), and cyclooxygenase (COX)-2 were assessed using qPCR, immunoblotting, and ELISA. UPLC-MS/MS was used to detect prostaglandins (PGs). LPS stimulation resulted in different levels of cytokine production; more TNFα and less IL-10 were produced in female cells compared with male astrocytes. Although the levels of the COX-2 expression were not altered, LPS significantly induced the synthesis of PGs with notable sex-related differences. PGE2 and PGD2 were less and 6-keto-PGF1α was more upregulated in female astrocytes, and TXB2 had similar levels in cells obtained from males and females. Trilostane, an inhibitor of 3β-Hydroxysteroid dehydrogenase (3β-HSD), inhibited the LPS-induced TNFα production and the release of PGE2, PGD2, and 6-keto-PGF1α in female astrocytes. Thus, male and female astrocytes differentially respond to inflammatory challenges on the level of production of cytokines and steroid hormones. Sex-mediated differences in pro- and anti-inflammatory responses should be taken into consideration for the effective treatment of disorders with neuroinflammation.

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“…Although most of the work in this field uses LPS in order to stimulate glial cells, mainly microglia, it is known that neurons also express TLR4. Indeed, activation of this receptor leads to the neuronal production of different inflammatory mediators [10,11,12,13].…”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide-Induced Neuroinflammation as a Bridge to Understand Neurodegeneration

Batista

Gomes

Candelario‐Jalil

et al. 2019

IJMS

390

233

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A large body of experimental evidence suggests that neuroinflammation is a key pathological event triggering and perpetuating the neurodegenerative process associated with many neurological diseases. Therefore, different stimuli, such as lipopolysaccharide (LPS), are used to model neuroinflammation associated with neurodegeneration. By acting at its receptors, LPS activates various intracellular molecules, which alter the expression of a plethora of inflammatory mediators. These factors, in turn, initiate or contribute to the development of neurodegenerative processes. Therefore, LPS is an important tool for the study of neuroinflammation associated with neurodegenerative diseases. However, the serotype, route of administration, and number of injections of this toxin induce varied pathological responses. Thus, here, we review the use of LPS in various models of neurodegeneration as well as discuss the neuroinflammatory mechanisms induced by this toxin that could underpin the pathological events linked to the neurodegenerative process.

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Rosiglitazone as a Modulator of TLR4 and TLR3 Signaling Pathways in Rat Primary Neurons and Astrocytes

Cited by 27 publications

References 43 publications

Evidence for Sexual Dimorphism in the Response to TLR3 Activation in the Developing Neonatal Mouse Brain: A Pilot Study

Evidence for Sexual Dimorphism in the Response to TLR3 Activation in the Developing Neonatal Mouse Brain: A Pilot Study

Sex-Mediated Differences in LPS Induced Alterations of TNFα, IL-10 Expression, and Prostaglandin Synthesis in Primary Astrocytes

Lipopolysaccharide-Induced Neuroinflammation as a Bridge to Understand Neurodegeneration

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