Midazolam suppresses the lipopolysaccharide-stimulated immune responses of human macrophages via translocator protein signaling

Horiguchi, Yu; Ohta, Nobuaki; Yamamoto, Satoshi; Koide, Moe; Fujino, Yuji

doi:10.1016/j.intimp.2018.11.050

Cited by 31 publications

(22 citation statements)

References 46 publications

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“…In the human macrophage cell line THP-1, exposure to Midazolam, a TSPO binding agent, suppressed LPS-induced inflammatory responses, including IL-6 expression, NO and NF-κB and MAPK activation. This was specific for TSPO, as TSPO knockout cells did not show this effect [100]. Hence, TSPO interacts with inflammation pathways at the transcriptional level, manifesting in the immunomodulatory effects described in this review.…”

Section: Molecular Pathways Of Tspo Immunomodulationmentioning

confidence: 71%

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

Betlazar

Middleton

Bánati

et al. 2020

Cells

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The translocator protein (TSPO) is an outer mitochondrial membrane protein that is widely used as a biomarker of neuroinflammation, being markedly upregulated in activated microglia in a range of brain pathologies. Despite its extensive use as a target in molecular imaging studies, the exact cellular functions of this protein remain in question. The long-held view that TSPO plays a fundamental role in the translocation of cholesterol through the mitochondrial membranes, and thus, steroidogenesis, has been disputed by several groups with the advent of TSPO knockout mouse models. Instead, much evidence is emerging that TSPO plays a fundamental role in cellular bioenergetics and associated mitochondrial functions, also part of a greater role in the innate immune processes of microglia. In this review, we examine the more direct experimental literature surrounding the immunomodulatory effects of TSPO. We also review studies which highlight a more central role for TSPO in mitochondrial processes, from energy metabolism, to the propagation of inflammatory responses through reactive oxygen species (ROS) modulation. In this way, we highlight a paradigm shift in approaches to TSPO functioning.

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Section: Molecular Pathways Of Tspo Immunomodulationmentioning

confidence: 71%

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

Betlazar

Middleton

Bánati

et al. 2020

Cells

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“…The benzodiazepine midazolam targeted TSPO, a peripheral benzodiazepine receptor [ 14 ], also activated by LPS in the model. Midazolam is known to suppress the LPS-stimulated immune responses of human macrophages via TSPO signaling [ 15 ], but the model did not identify possible neuroprotective pathways for this agent.…”

Section: Discussionmentioning

confidence: 99%

Molecular RNA Correlates of the SOFA Score in Patients with Sepsis

et al. 2021

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The most common scoring system for critically ill patients is the Sequential Organ Failure Assessment (SOFA) score. Little is known about specific molecular signaling networks underlying the SOFA criteria. We characterized these networks and identified specific key regulatory molecules. We prospectively studied seven patients with sepsis and six controls with high-throughput RNA sequencing (RNAseq). Quantitative reverse transcription PCR (RT-qPCR) confirmation was performed in a second independent cohort. Differentially and significantly expressed miRNAs and their target mRNA transcripts were filtered for admission SOFA criteria and marker RNAs for the respective criteria identified. We bioinformatically constructed molecular signaling networks specifically reflecting these criteria followed by RT-qPCR confirmation of RNAs with important regulatory functions in the networks in the second cohort. RNAseq identified 82 miRNAs (45% upregulated) and 3254 mRNAs (50% upregulated) differentially expressed between sepsis patients and controls. Bioinformatic analysis characterized 6 miRNAs and 76 mRNA target transcripts specific for the SOFA criteria. RT-qPCR validated miRNA and mRNAs included IGFBP2 (respiratory system); MMP9 and PDE4B (nervous system); PPARG (cardiovascular system); AKR1B1, ANXA1, and LNC2/NGAL (acute kidney injury); GFER/ALR (liver); and miR-30c-3p (coagulopathy). There are specific canonical networks underlying the SOFA score. Key regulatory miRNA and mRNA transcripts support its biologic validity.

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“…Our animals were premedicated with midazolam and ketamine and were anesthetized with propofol and fentanyl. Midazolam may modulate the immune system by binding to the peripheral receptor of macrophages and inhibiting the proinflammatory responses [ 21 ], while ketamine acts at different levels of inflammation, interacting with inflammatory cell recruitment, cytokine production (IL-6, TNF- α ), and regulation of inflammatory mediators [ 12 ], which could explain in-part the nonsignificant increase in white blood cells. Also, propofol exerts inhibitory effects on neutrophil and monocyte function under different physiological and pathological circumstances, while the effects of cisatracurium and fentanyl are diverse in different disease states and must be further studied [ 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

Baseline Values and Kinetics of IL‐6, Procalcitonin, and TNF‐α in Landrace‐Large White Swine Anesthetized with Propofol‐Based Total Intravenous Anesthesia

Chalkias

Spyropoulos

Γεωργίου

et al. 2021

BioMed Research International

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The baseline levels of various inflammatory mediators and their changes during anesthesia in swine are not known. The aim of this animal study was to measure the baseline values and kinetics of interleukin-6, procalcitonin, and tumor necrosis factor-alpha in healthy Landrace-Large White swine anesthetized with propofol-based total intravenous anesthesia. We included 8 healthy male pigs with an average weight of 19 ± 2 kg (aged 10-15 weeks) that were subjected to propofol-based total intravenous anesthesia for 8 hours. Complete blood count, serum chemistry, and serum levels of interleukin-6, procalcitonin, and tumor necrosis factor-alpha were analyzed, and serum levels were quantified hourly. Blood was also collected for bacterial culturing. Baseline values of interleukin-6 and procalcitonin were 18 pg/ml and 21 ng/ml, respectively, while tumor necrosis factor-alpha was not detectable during collection of baseline samples. A statistically significant difference was observed in interleukin-6 levels between time points ( p < 0.0001 ). Procalcitonin increased with time, but there were no significant differences between time points ( p = 0.152 ). Tumor necrosis factor-alpha increased until the 3rd hour of propofol-based total intravenous anesthesia, while after the 4th hour, it gradually decreased, reaching its baseline undetectable values by the 7th hour ( p < 0.001 ). Our results can serve as the basis for further translational research.

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Midazolam suppresses the lipopolysaccharide-stimulated immune responses of human macrophages via translocator protein signaling

Cited by 31 publications

References 46 publications

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

Molecular RNA Correlates of the SOFA Score in Patients with Sepsis

Baseline Values and Kinetics of IL‐6, Procalcitonin, and TNF‐α in Landrace‐Large White Swine Anesthetized with Propofol‐Based Total Intravenous Anesthesia

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