RNA sequencing reveals resistance of TLR4 ligand-activated microglial cells to inflammation mediated by the selective jumonji H3K27 demethylase inhibitor

Das, Amitabh; Arifuzzaman, Sarder; Yoon, Tae-Ho; Kim, Sun Hwa; Chai, Jin Choul; Lee, Young Seek; Jung, Kyoung Hwa; Chai, Young Gyu

doi:10.1038/s41598-017-06914-5

Cited by 29 publications

(22 citation statements)

References 67 publications

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“…Induction of reactive gliosis in an animal model of intraventricular hemorrhage (IVH). (a) Representative images of P11 brain sections from normal control (NC) with PBS injection, IVH control (IC), IVH‐fibroblast (Das et al, ), IVH‐MSC (IM) groups immunostained for GFAP. Scale bar: 500 μm.…”

Section: Resultsmentioning

confidence: 99%

Reactive microglia and astrocytes in neonatal intraventricular hemorrhage model are blocked by mesenchymal stem cells

Kim

Hong

et al. 2019

Glia

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Severe intraventricular hemorrhage (IVH) in premature infants triggers reactive gliosis, causing acute neuronal death and glial scar formation. Transplantation of mesenchymal stem cells (MSCs) has often showed improved CNS recovery in an IVH model, but whether this response is related to reactive glial cells is still unclear. Herein, we suggest that MSCs impede the response of reactive microglia rather than astrocytes, thereby blocking neuronal damage. Astrocytes alone showed mild reactiveness under hemorrhagic conditions mimicked by thrombin treatment, and this was not blocked by MSC‐conditioned medium (MSC‐CM) in vitro. In contrast, thrombin‐induced microglial activation and release of proinflammatory cytokines were inhibited by MSC‐CM. Interestingly, astrocytes showed greater reactive response when co‐cultured with microglia, and this was abolished in the presence of MSC‐CM. Gene expression profiles in microglia revealed that transcript levels of genes for immune response and proinflammatory cytokines were altered by thrombin treatment. This result coincided with the robust phosphorylation of STAT1 and p38 MAPK, which might be responsible for the production and release of proinflammatory cytokines. Furthermore, application of MSC‐CM diminished thrombin‐mediated phosphorylation of STAT1 and p38 MAPK, supporting the acute anti‐inflammatory role of MSCs under hemorrhagic conditions. In line with this, activation of microglia and consequent cytokine release were impaired in Stat1‐null mice. However, reactive response in Stat1‐deficient astrocytes was maintained. Taken together, our results demonstrate that MSCs mainly block the activation of microglia involving STAT1‐mediated cytokine release and subsequent reduction of reactive astrocytes.

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Section: Resultsmentioning

confidence: 99%

Reactive microglia and astrocytes in neonatal intraventricular hemorrhage model are blocked by mesenchymal stem cells

Kim

Hong

et al. 2019

Glia

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“…; Das et al . ). Moreover, GSK‐J4 modifies the H3K27me3 and H3K4me3 levels on specific gene promoters in dendritic cells, which prevents autoimmune encephalomyelitis (Donas et al .…”

Section: Discussionmentioning

confidence: 97%

“…In addition, GSK-J4 inhibits paediatric brainstem glioma by targeting the oncogenic mutation in histone variant H3.3 (Hashizume et al 2014). Furthermore, GSK-J4 also modulates inflammatory responses in macrophage and microglia by inhibiting demethylase activity, which is critical for the activation of proinflammatory genes (Kruidenier et al 2012;Das et al 2017). Moreover, GSK-J4 modifies the H3K27me3 and H3K4me3 levels on specific gene promoters in dendritic cells, which prevents autoimmune encephalomyelitis (Donas et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

Hong

Huang

Xiu-qin

et al. 2018

The Journal of Physiology

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Key points Diabetic kidney disease (DKD) is a major complication of diabetes. We found that UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase, was upregulated in the renal mesangial and tubular cells of diabetic mice and DKD patients. In cultured renal mesangial and tubular cells, UTX overexpression promoted palmitic acid‐induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. We found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes and apoptosis; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal abnormalities in db/db mice, an animal model of type 2 diabetes. These results revealed the possible mechanisms underlying the regulation of histone methylation in DKD and suggest UTX as a potential therapeutic target for DKD. Abstract Diabetic kidney disease (DKD) is a microvascular complication of diabetes and the leading cause of end‐stage kidney disease worldwide without effective therapy available. UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase that removes the di‐ and tri‐methyl groups from histone H3K27, plays important biological roles in gene activation, cell fate control and life span regulation in Caenorhabditis elegans. In the present study, we report upregulated UTX in the kidneys of diabetic mice and DKD patients. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal dysfunction, abnormal morphology, inflammation, apoptosis and DNA damage in db/db mice, comprising an animal model of type 2 diabetes. In cultured renal mesanglial and tubular cells, UTX overexpression promoted palmitic acid induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. Mechanistically, we found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Collectively, our results suggest UTX as a potential therapeutic target for DKD.

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“…We consider these observations to be relevant findings. Frequently, reports only focus on gene upregulation due to pro-inflammatory stimuli 12 , 36 . However, according to our data, 9,343 genes out of 14,337 tend to be downregulated, without this trend emerging as statistically significantresult, by both treatments.…”

Section: Discussionmentioning

confidence: 99%

RNA-Seq transcriptomic profiling of primary murine microglia treated with LPS or LPS + IFNγ

Pulido-Salgado

Vidal-Taboada

Barriga

et al. 2018

Sci Rep

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Microglia, the main resident immune cells in the CNS, are thought to participate in the pathogenesis of various neurological disorders. LPS and LPS + IFNγ are stimuli that are widely used to activate microglia. However, the transcriptomic profiles of microglia treated with LPS and LPS + IFNγ have not been properly compared. Here, we treated murine primary microglial cultures with LPS or LPS + IFNγ for 6 hours and then performed RNA-Sequencing. Gene expression patterns induced by the treatments were obtained by WGCNA and 11 different expression profiles were found, showing differential responses to LPS and LPS + IFNγ in many genes. Interestingly, a subset of genes involved in Parkinson’s, Alzheimer’s and Huntington’s disease were downregulated by both treatments. By DESeq analysis we found differentially upregulated and downregulated genes that confirmed LPS and LPS + IFNγ as inducers of microglial pro-inflammatory responses, but also highlighted their involvement in specific cell functions. In response to LPS, microglia tended to be more proliferative, pro-inflammatory and phagocytic; whereas LPS + IFNγ inhibited genes were involved in pain, cell division and, unexpectedly, production of some inflammatory mediators. In summary, this study provides a detailed description of the transcriptome of LPS- and LPS + IFNγ treated primary microglial cultures. It may be useful to determine whether these in vitro phenotypes resemble microglia in in vivo pathological conditions.

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RNA sequencing reveals resistance of TLR4 ligand-activated microglial cells to inflammation mediated by the selective jumonji H3K27 demethylase inhibitor

Cited by 29 publications

References 67 publications

Reactive microglia and astrocytes in neonatal intraventricular hemorrhage model are blocked by mesenchymal stem cells

Reactive microglia and astrocytes in neonatal intraventricular hemorrhage model are blocked by mesenchymal stem cells

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

RNA-Seq transcriptomic profiling of primary murine microglia treated with LPS or LPS + IFNγ

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