A small molecule binding HMGB1 and HMGB2 inhibits microglia-mediated neuroinflammation

Lee, Sang‐Hee; Nam, Youngpyo; Koo, Ja Young; Lim, Donghyun; Park, Jong-Min; Ock, Jiyeon; Kim, Jae Hong; Suk, Kyoungho; Park, Seung Bum

doi:10.1038/nchembio.1669

Cited by 103 publications

(131 citation statements)

References 30 publications

(45 reference statements)

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“…Confirming our observations of disrupted Troma-I expression in the GIT2KO model it has also been demonstrated that reductions in Troma-I can also modulate HMGCS2 expression and in doing so modulate energy metabolism and ketogenic activity [103]. HMGB2 is also critically involved in regulatory mechanisms that, control DNA damage [125], cell senescence [126], innate immune responses and neuroinflammation [127, 128] as well as stem cell proliferation and neurogenesis [129]. In addition to the specific GIT2-dependent alteration of HMG proteins multiple additional proteins that regulate age-related energy metabolism (Prcp [130], age-related DNA damage (Bach2 [131], age-related hematopoietic network regulation (Irf8 [132], immunosenescence (Pecam1 [133] and ER stress/amyloid related regulation of insulin secretion (Herpud1 [134-136]) were altered in GIT2KOs.…”

Section: Discussionsupporting

confidence: 72%

Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption

Siddiqui

Lustig²,

Carter³

et al. 2017

Aging

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Recent research has proposed that GIT2 (G protein-coupled receptor kinase interacting protein 2) acts as an integrator of the aging process through regulation of ‘neurometabolic’ integrity. One of the commonly accepted hallmarks of the aging process is thymic involution. At a relatively young age, 12 months old, GIT2−/− mice present a prematurely distorted thymic structure and dysfunction compared to age-matched 12 month-old wild-type control (C57BL/6) mice. Disruption of thymic structure in GIT2−/− (GIT2KO) mice was associated with a significant reduction in the expression of the cortical thymic marker, Troma-I (cytokeratin 8). Double positive (CD4+CD8+) and single positive CD4+ T cells were also markedly reduced in 12 month-old GIT2KO mice compared to age-matched control wild-type mice. Coincident with this premature thymic disruption in GIT2KO mice was the unique generation of a novel cervical ‘organ’, i.e. ‘parathymic lobes’. These novel organs did not exhibit classical peripheral lymph node-like characteristics but expressed high levels of T cell progenitors that were reflexively reduced in GIT2KO thymi. Using signaling pathway analysis of GIT2KO thymus and parathymic lobe transcriptomic data we found that the molecular signaling functions lost in the dysfunctional GIT2KO thymus were selectively reinstated in the novel parathymic lobe – suggestive of a compensatory effect for the premature thymic disruption. Broader inspection of high-dimensionality transcriptomic data from GIT2KO lymph nodes, spleen, thymus and parathymic lobes revealed a systemic alteration of multiple proteins (Dbp, Tef, Per1, Per2, Fbxl3, Ddit4, Sin3a) involved in the multidimensional control of cell cycle clock regulation, cell senescence, cellular metabolism and DNA damage. Altered cell clock regulation across both immune and non-immune tissues therefore may be responsible for the premature ‘aging’ phenotype of GIT2KO mice.

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Section: Discussionsupporting

confidence: 72%

Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption

Siddiqui

Lustig²,

Carter³

et al. 2017

Aging

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“…A high percentage of the identified UPF1-regulated genes such as S100A9, CDC42, HMGB2 and members of 14-3-3 protein family are related to cell differentiation and inflammation19202122232425. In order to investigate the mechanism behind the UPF1 effects we selected S100A9, an important regulator for myeloid cell functions, for further analysis26.…”

Section: Resultsmentioning

confidence: 99%

UPF1 regulates myeloid cell functions and S100A9 expression by the hnRNP E2/miRNA-328 balance

Saul

Stein²,

Grez³

et al. 2016

Sci Rep

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UPF1 is a key player in nonsense mediated mRNA decay (NMD) but also involved in posttranscriptional gene regulation. In this study we found that UPF1 regulates the expression of genes with functions in inflammation and myeloid cell differentiation via hnRNP E2. The majority of the UPF1-regulated genes identified in monocytic cells contain a binding site for hnRNP E2 within 5′ UTR located introns with hnRNP E2 acting here as splicing regulator. We found that miRNA-328 which is significantly induced during monocytic cell differentiation acts independently from its gene silencing function as RNA decoy for hnRNP E2. One representative gene controlled by the hnRNP E2/miRNA-328 balance is S100A9 which plays an important role in cell differentiation and oxidative stress response of monocytes. Induction of miRNA-328 expression during cell differentiation antagonizes the blockade by hnRNP E2 which results in the upregulation of CD11b expression and ROS production in monocytic cells. Taken together, our data indicate that upregulation of miR-328 is responsible for the induction of hnRNP E2 target genes during myeloid cell differentiation.

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“…Though not itself a transcription factor, high mobility group protein B1 (HMG1) is a DNA-binding protein that regulates gene transcription through its interactions with nucleosomes, transcription factors and histones 142–144 . Crucially, HMG1 is involved in proinflammatory cytokine gene transcription 143 and is secreted by haem-stimulated microglia in vitro 145 .…”

Section: Modulators Of Microglial Polarizationmentioning

confidence: 99%

Modulators of microglial activation and polarization after intracerebral haemorrhage

et al. 2017

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Intracerebral haemorrhage (ICH) is the most lethal subtype of stroke but currently lacks effective treatment. Microglia are among the first non-neuronal cells on the scene during the innate immune response to ICH. Microglia respond to acute brain injury by becoming activated and developing classic M1-like (proinflammatory) or alternative M2-like (anti-inflammatory) phenotypes. This polarization implies as yet unrecognized actions of microglia in ICH pathology and recovery, perhaps involving microglial production of proinflammatory or anti-inflammatory cytokines and chemokines. Furthermore, alternatively activated M2-like microglia might promote phagocytosis of red blood cells and tissue debris, a major contribution to haematoma clearance. Interactions between microglia and other cells modulate microglial activation and function, and are also important in ICH pathology. This Review summarizes key studies on modulators of microglial activation and polarization after ICH, including M1-like and M2-like microglial phenotype markers, transcription factors and key signalling pathways. Microglial phagocytosis, haematoma resolution, and the potential crosstalk between microglia and T lymphocytes, neurons, astrocytes, and oligodendrocytes in the ICH brain are described. Finally, the clinical and translational implications of microglial polarization in ICH are presented, including the evidence that therapeutic approaches aimed at modulating microglial function might mitigate ICH injury and improve brain repair.

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A small molecule binding HMGB1 and HMGB2 inhibits microglia-mediated neuroinflammation

Cited by 103 publications

References 30 publications

Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption

Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption

UPF1 regulates myeloid cell functions and S100A9 expression by the hnRNP E2/miRNA-328 balance

Modulators of microglial activation and polarization after intracerebral haemorrhage

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