Systematic Analysis of Translocator Protein 18 kDa (TSPO) Ligands on Toll-like Receptors-mediated Pro-inflammatory Responses in Microglia and Astrocytes

Lee, Ji Won; Nam, Hyeri; Yu, Sebastian

doi:10.5607/en.2016.25.5.262

Cited by 25 publications

(20 citation statements)

References 16 publications

(35 reference statements)

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“…In rat primary microglia, PK11195 has also been shown to inhibit increases in NO after LPS stimulation [86]. In primary mouse microglia, Etifoxine and PK11195 pre-treatment before toll-like receptor ligand activation were able to reduce microglial activation and production of TNF-α, CCL2 and IL-6 [87]. Vinpocetine, a specific TSPO ligand, was also shown to inhibit the activation and proliferation of LPS-stimulated or oxygen-glucose deprived BV2 cells compared to untreated controls.…”

Section: Microglial Tspo Expression and Modulation By Tspo Ligandsmentioning

confidence: 99%

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: Microglial Tspo Expression and Modulation By Tspo Ligandsmentioning

confidence: 99%

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

Betlazar

Middleton

Bánati

et al. 2020

Cells

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“…To explore the functional consequences of the Psen2 N141I mutation in innate immunity, we examined whether this mutation affects in ammatory functions of immune cells following activation of Toll-like receptors (TLRs) 37 . We treated primary microglia from WT or KI/+ mice with N-palmitoyl-S-dipalmitoylglyceryl Cys-Ser-(Lys) 4 for TLR1/2, heat-killed Listeria monocytogenes for TLR2, polyinosinic-polycytidylic acid (high or low molecular weight) for TLR3, lipopolysaccharide (LPS) from Escherichia coli O111:B4 for TLR4, agellin from Salmonella typhimurium for TLR5, Pam 2 CGDPKHPKSF for TLR6, 20-mer single-strand RNA derived from HIV-1 long terminal repeat for TLR7, and oligonucleotides containing unmethylated CpG dinucleotides for TLR9.…”

Section: Resultsmentioning

confidence: 99%

“…Primary microglia were obtained from 1-3-day-old neonatal mice as described previously 37 and cultured in Dulbecco's modi ed Eagle's medium (DMEM, Corning) supplemented with 10% heat-inactivated fetal bovine serum (HI-FBS, Hyclone) and 1% penicillin-streptomycin (Hyclone). Microglia were isolated at days in vitro 12 by tapping.…”

Section: Cell Culturementioning

confidence: 99%

Presenilin 2 N141I mutation induces hyperactive immune response through the epigenetic repression of REV-ERBα

Nam

Lee

Kim

et al. 2020

Preprint

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Hyperimmunity drives the development of Alzheimer disease (AD). The immune system is under the circadian control, and circadian abnormalities aggravate AD progress. Here, we investigated how an AD-linked mutation deregulates expression of circadian genes and induces cognitive decline using the knock-in (KI) mice heterozygous for presenilin 2 (Psen2) N141I mutation. This mutation causes overproduction of clock-controlled cytokines through the epigenetic repression of the clock protein REV-ERBα in innate immune cells, which show normal circadian period but lower amplitude. The KI/+ mice displayed normal circadian behaviour patterns, but were vulnerable to an otherwise innocuous, mild immune challenge. The antipsychotic chlorpromazine restored the REV-ERBα level and prevented the overexcitation of innate immune cells and cognitive decline in KI/+ mice. These results highlight a new pathogenic link between this AD mutation and immune cell-intrinsic circadian alteration through the epigenetic suppression of REV-ERBα.

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“…7E). However, it is important to note that microglia also produces CCL2 upon inflammatory stimulation; for example, in response to LPS stimulation, microglia may produce 1-5 times more CCL2 than astrocytes (32,33). For this reason, we checked the purity of our astrocyte culture for microglial contamination using immunohistochemistry.…”

Section: Discussionmentioning

confidence: 99%

Roles of the DOCK-D family proteins in a mouse model of neuroinflammation

Namekata

Guo

Kimura

et al. 2020

Journal of Biological Chemistry

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The DOCK-D (dedicator of cytokinesis D) family proteins are atypical guanine nucleotide exchange factors that regulate Rho GTPase activity. The family consists of Zizimin1 (DOCK9), Zizimin2 (DOCK11), and Zizimin3 (DOCK10). Functions of the DOCK-D family proteins are presently not well-explored, and the role of the DOCK-D family in neuroinflammation is unknown. In this study, we generated three mouse lines in which DOCK9 (DOCK9−/−), DOCK10 (DOCK10−/−), or DOCK11 (DOCK11−/−) had been deleted and examined the phenotypic effects of these gene deletions in MOG35–55 peptide-induced experimental autoimmune encephalomyelitis, an animal model of the neuroinflammatory disorder multiple sclerosis. We found that all the gene knockout lines were healthy and viable. The only phenotype observed under normal conditions was a slightly smaller proportion of B cells in splenocytes in DOCK10−/− mice than in the other mouse lines. We also found that the migration ability of macrophages is impaired in DOCK10−/− and DOCK11−/− mice and that the severity of experimental autoimmune encephalomyelitis was ameliorated only in DOCK10−/− mice. No apparent phenotype was observed for DOCK9−/− mice. Further investigations indicated that lipopolysaccharide stimulation up-regulates DOCK10 expression in microglia and that microglial migration is decreased in DOCK10−/− mice. Up-regulation of C–C motif chemokine ligand 2 (CCL2) expression induced by activation of Toll-like receptor 4 or 9 signaling was reduced in DOCK10−/− astrocytes compared with WT astrocytes. Taken together, our findings suggest that DOCK10 plays a role in innate immunity and neuroinflammation and might represent a potential therapeutic target for managing multiple sclerosis.

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Systematic Analysis of Translocator Protein 18 kDa (TSPO) Ligands on Toll-like Receptors-mediated Pro-inflammatory Responses in Microglia and Astrocytes

Cited by 25 publications

References 16 publications

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

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

Presenilin 2 N141I mutation induces hyperactive immune response through the epigenetic repression of REV-ERBα

Roles of the DOCK-D family proteins in a mouse model of neuroinflammation

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