TLR4 signaling pathway mediates the LPS/ischemia-induced expression of monocytechemotactic protein-induced protein 1 in microglia

Chen, Shumin; Lyu, Chenfei; Zhou, Junming; Huang, Shaofei; Zhang, Yongfang; Liu, Guanghui; Liu, Kewei; Chen, Danqi; Y, Hu; Zhou, Liang; Gu, Yong

doi:10.1016/j.neulet.2018.08.052

Cited by 17 publications

(7 citation statements)

References 30 publications

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“…Thus, in this part, we mainly focused on correlation between TLR2/TLR4 and macrophage activation induced by SYQP on TLR2/TLR4 antagonist-treated cells (RAW264.7 and MPMs). TAK-242 and C29, antagonists of TLR4 and TLR2 respectively, have been proven to exhibit effective specific blocking properties ( Chen et al, 2018 ). Firstly, we measured pro-inflammatory cytokines in TLR2/TLR4 antagonist-treated RAW264.7 cells ( Figures 2A,B ) and MPMs after SYQP stimulation ( Figures 2C,D ).…”

Section: Resultsmentioning

confidence: 99%

Polysaccharides From the Aerial Parts of Tetrastigma Hemsleyanum Diels et Gilg Induce Bidirectional Immunity and Ameliorate LPS-Induced Acute Respiratory Distress Syndrome in Mice

Zhu

Zhou

et al. 2022

Front. Pharmacol.

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Tetrastigma hemsleyanum Diels et Gilg (Sanyeqing, SYQ) has traditionally been used to treat inflammation, high fever and improve immune function of patients. Polysaccharides have been proved to be one of the important components of SYQ. Previous studies have confirmed the antipyretic and antitumor effects of polysaccharides from SYQ (SYQP), and clarified that SYQP could enhance immunity through TLR4 signalling pathway. However, there were more possibilities for the mechanism by which SYQP exerted immunomodulatory effects and the role of SYQP in acute respiratory distress syndrome (ARDS) is elusive. The purpose of this study was further to explain the bidirectional modulation of immunity mechanism of SYQP in vitro and its effect in LPS-induced ARDS in vivo. Experimental results showed that SYQP significantly stimulated gene expressions of TLR1, TLR2 and TLR6 and secretion of cytokines in RAW264.7 cells. Individual or combined application of TLR2 antagonist C29 and TLR4 antagonist TAK-242 could reduce SYQP-mediated stimulation of cytokine secretion in RAW264.7 cells and mouse peritoneal macrophages (MPMs) to varying degrees. On the other hand, SYQP markedly inhibited the expression levels of inflammatory cytokines, NO, iNOS and COX-2 in LPS-treatment RAW264.7 cells. Moreover, in vivo results indicated that SYQP significantly reduced LPS-induced damage in ARDS mice through alleviating LPS-induced pulmonary morphological damage, inhibiting myeloperoxidase (MPO) expression levels, ameliorating the inflammatory cells in bronchoalveolar lavage fluid (BALF) and improving hematological status. Meanwhile, SYQP evidently reduced IL-6, TNF-α and IFN-γ secretion, the overexpression levels of TLR2 and TLR4, as well as the phosphorylation of NF-κB p65. In addition, SYQP reduced the phosphorylation of JAK2 and STAT1 and the overexpression of NLRP3, caspase-1, caspase-3 and caspase-8 in lung tissues of ARDS mice. In summary, our study confirmed that SYQP induced bidirectional immunity and ameliorated LPS-induced acute respiratory distress syndrome in mice through TLR2/TLR4-NF-κB, NLRP3/caspase and JAK/STAT signaling pathways, which provided a theoretical basis for further use of SYQP.

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Section: Resultsmentioning

confidence: 99%

Polysaccharides From the Aerial Parts of Tetrastigma Hemsleyanum Diels et Gilg Induce Bidirectional Immunity and Ameliorate LPS-Induced Acute Respiratory Distress Syndrome in Mice

Zhu

Zhou

et al. 2022

Front. Pharmacol.

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“…TLR4 and RAGE signal via a common downstream messenger MyD88 and trigger inflammation. To investigate whether LPS exerted its effect through activating TLR4 and RAGE signaling, we used TAK‐242 (3 mg/kg), a selective inhibitor of TLR4 that effectively attenuates inflammation in endotoxin shock, 26 or FPS‐ZM1 (1 mg/kg), a RAGE antagonist that inhibits RAGE receptors and signaling induced by LPS/ ischemia 27,28 . Primed DBA/1 mice were injected with TAK‐242 (3 mg/kg, ip) or FPS‐ZM1 (1.5 mg/kg, ip) 35 minutes before injection of 10 mg/kg of LPS.…”

Section: Resultsmentioning

confidence: 99%

Intraperitoneal injection of lipopolysaccharide prevents seizure‐induced respiratory arrest in a DBA/1 mouse model of SUDEP

Adhikari

Jin

2020

Epilepsia Open

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Objective Sudden unexpected death in epilepsy (SUDEP) is the cause of premature death of 50% patients with chronic refractory epilepsy. Respiratory failure during seizures is regarded as an important mechanism of SUDEP. Previous studies have shown that abnormal serotonergic neurotransmission is involved in the pathogenesis of seizure‐induced respiratory failure, while enhancing serotonergic neurotransmission in the brainstem suppresses it. Because peripheral inflammation is known to enhance serotonergic neuron activation and 5‐HT synthesis and release, we investigated the effect of intraperitoneal lipopolysaccharide (LPS)‐induced inflammation on the S‐IRA susceptibility during audiogenic seizures in DBA/1 mice. Methods After DBA/1 mice were primed by exposing to sound stimulation for three consecutive days, they were tested for seizure severity and seizure‐induced respiratory arrest (S‐IRA) induced by sound stimulation under different conditions. We determined the dose and time course of the effects of intraperitoneal administration of LPS on audiogenic seizures and S‐IRA. The effects of blocking TLR4 or RAGE receptors and blocking 5‐HT receptors on the LPS‐induced effect on S‐IRA were investigated. Statistical significance was evaluated using the Kruskal‐Wallis test. Results Intraperitoneal injection of LPS significantly had dose‐dependent effects in reducing the incidence of S‐IRA as well as seizure severity in DBA/1 mice. The protective effect of LPS on S‐IRA peaked at 8‐12 hours after LPS injection and was related to both reducing seizure severity and enhancing autoresuscitation. Blocking TLR4 or RAGE receptor with TAK‐242 or FPS‐ZM1, respectively, prior to LPS injection attenuated its effects on S‐IRA and seizure severity. Injection of a nonselective 5‐HT receptor antagonist, cyproheptadine, or a 5‐HT3 receptor antagonist, ondansetron, was effective in blocking LPS‐induced effect on S‐IRA. Immunostaining results showed a significant increase in c‐Fos‐positive serotonergic neurons in the dorsal raphe. Significance This is the first study that demonstrates the effect of intraperitoneal LPS injection‐induced inflammation on reducing S‐IRA susceptibility and provides additional evidence supporting the serotonin hypothesis on SUDEP. Our study suggests that inflammation may enhance brainstem 5‐HT neurotransmission to promote autoresuscitation during seizure and prevent SUDEP.

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“…For the TLR inhibitor and agonist studies, male ApoE −/− mice were intraperitoneally (i.p.) administered vehicle (20% DMSO in phosphate‐buffered saline (PBS), Ctrl), C29 (50 mg kg −1 daily) (BioVision, Milpitas, CA), [ 45 ] TAK‐242 (3 mg kg −1 daily) (Sigma, St. Louis, MO), [ 46 ] Pam (15 µg (0.01 µmol) weekly) (Sigma), [ 47 ] or LPS (50 µg (0.01 µmol) weekly) (Sigma) for 14 weeks. [ 48 ] For lipid metabolic studies, male WT, HEMI, and Sub1 KO mice were fed standard rodent chow or a HFD (60% fat, TD06414, Harlan) for 20 weeks.…”

Section: Methodsmentioning

confidence: 99%

The Transcription Factor SUB1 Is a Master Regulator of the Macrophage TLR Response in Atherosclerosis

Huang

Chen

et al. 2021

Advanced Science

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Toll-like receptor 2 and 4 (TLR2, TLR4) signaling is implicated in atherosclerotic plaque formation. The two-stage master regulator Virtual Inference of Protein-activity by Enriched Regulon (VIPER) analysis of macrophage TLR2 and TLR4 signature genes integrated with coexpression network genes derived from 371 patient-derived carotid specimens identifies activated RNA polymerase II transcriptional coactivator p15 (SUB1/Sub1, PC4) as a master regulon in the atherogenic TLR response. It is found that TLR2 and TLR4 signaling is proinflammatory and proatherosclerotic in chow-fed apolipoprotein E-deficient (ApoE −/− ) mice. Through transgenic myeloid-specific Sub1 knockout in ApoE −/− mice, it is discovered that these proatherosclerotic effects of TLR2 and TLR4 signaling are mediated by Sub1. Sub1 knockout in macrophages enhances anti-inflammatory M2 macrophage polarization and cholesterol efflux. Irradiated low density lipoprotein receptor-deficient (Ldlr −/− ) mice transplanted with Sub1 −/− murine bone marrow display reduced atherosclerosis. Promoter analysis reveals Sub1-dependent activation of interferon regulatory factor 1 (Irf1) transcription in a casein kinase 2 (Ck2)-dependent manner, and Sub1-knockout macrophages display decreased Irf1 expression. Artificial Irf1 overexpression in Sub1-knockout macrophages enhances proinflammatory M1 skewing and lowers cholesterol clearance. In conclusion, the TLR master regulon Sub1, and its downstream effect on the transcription factor Irf1, promotes a proinflammatory M1 macrophage phenotype and enhances atherosclerotic burden in vivo.

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TLR4 signaling pathway mediates the LPS/ischemia-induced expression of monocytechemotactic protein-induced protein 1 in microglia

Cited by 17 publications

References 30 publications

Polysaccharides From the Aerial Parts of Tetrastigma Hemsleyanum Diels et Gilg Induce Bidirectional Immunity and Ameliorate LPS-Induced Acute Respiratory Distress Syndrome in Mice

Polysaccharides From the Aerial Parts of Tetrastigma Hemsleyanum Diels et Gilg Induce Bidirectional Immunity and Ameliorate LPS-Induced Acute Respiratory Distress Syndrome in Mice

Intraperitoneal injection of lipopolysaccharide prevents seizure‐induced respiratory arrest in a DBA/1 mouse model of SUDEP

The Transcription Factor SUB1 Is a Master Regulator of the Macrophage TLR Response in Atherosclerosis

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