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?-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance.

ABSTRACT: Innate immune memory is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to microbial components such as lipopolysaccharide (LPS). We apply an integrated epigenomic approach to characterize the molecular events involved in LPS-induced tolerance in a time-dependent manner. Mechanistically, LPS-treated monocytes fail to accumulate active histone marks at promoter and enhancers of genes in the lipid metabolism and phagocytic pathways. Transcriptional inactivity in response to a second LPS exposure in tolerized macrophages is accompanied by failure to deposit active histone marks at promoters of tolerized genes. In contrast, ?-glucan partially reverses the LPS-induced tolerance in vitro. Importantly, ex vivo ?-glucan treatment of monocytes from volunteers with experimental endotoxemia re-instates their capacity for cytokine production. Tolerance is reversed at the level of distal element histone modification and transcriptional reactivation of otherwise unresponsive genes. VIDEO ABSTRACT.

SUBMITTER: Novakovic B

PROVIDER: S-EPMC5927328 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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β-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance.

Novakovic Boris B Habibi Ehsan E Wang Shuang-Yin SY Arts Rob J W RJW Davar Robab R Megchelenbrink Wout W Kim Bowon B Kuznetsova Tatyana T Kox Matthijs M Zwaag Jelle J Matarese Filomena F van Heeringen Simon J SJ Janssen-Megens Eva M EM Sharifi Nilofar N Wang Cheng C Keramati Farid F Schoonenberg Vivien V Flicek Paul P Clarke Laura L Pickkers Peter P Heath Simon S Gut Ivo I Netea Mihai G MG Martens Joost H A JHA Logie Colin C Stunnenberg Hendrik G HG

Cell 20161101 5

Innate immune memory is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to microbial components such as lipopolysaccharide (LPS). We apply an integrated epigenomic approach to characterize the molecular events involved in LPS-induced tolerance in a time-dependent manner. Mechanistically, LPS-treated monocytes fail to accumulate active histone marks at promoter and enhancers of genes in the lipid metabolism and phagocytic ...[more]

PMID: 27863248

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Project description:BACKGROUND AND PURPOSE: ??-Adrenoceptor agonists are important therapeutic agents in the treatment of asthma and chronic obstructive pulmonary disease. The regular use of these drugs has been associated with proasthmatic-like changes that limit their efficacy and increase the risk of severe adverse reactions. We investigated whether the peroxisome-proliferator-activated receptor (PPAR)? agonist rosiglitazone modulated salbutamol-induced ??-adrenoceptor desensitization in vivo and in vitro. EXPERIMENTAL APPROACH: An in vivo model of homologous ??-adrenoceptor desensitization, established in guinea-pigs by administering salbutamol continuously, was used to study the ability of rosiglitazone to prevent ??-adrenoceptor tolerance. In vitro experiments on human bronchial smooth muscle cells were performed to increase the clinical relevance of the study. KEY RESULTS: In tracheal smooth muscle tissues from desensitized animals, we observed a decrease in the protective effect of salbutamol on carbachol-induced contraction, a hyperresponsiveness to cholinergic stimuli, a modest underexpression of ??-adrenoceptor gene and a marked decrease in ?-adrenoceptor number, relative to control values. Treatment with rosiglitazone preserved salbutamol relaxant activity, mitigated carbachol hyperresponsiveness and partially restored ??-adrenoceptor binding sites in tracheal tissues from homologously desensitized animals. The highly selective PPAR? agonist, GW1929, reproduced the effect of rosiglitazone, in vivo. In vitro ??-adrenoceptor desensitization decreased salbutamol-mediated cAMP production, without affecting forskolin responses and ??-adrenoceptor expression. Rosiglitazone and 15-deoxy-?¹²(,)¹?-prostaglandin J? restored salbutamol sensitivity in homologously desensitized cells. CONCLUSIONS AND IMPLICATIONS: These data suggest a potential pharmacodynamic interaction between PPAR? agonists and salbutamol on airway smooth muscle responsiveness, supporting the therapeutic potential of this combination in chronic airway disease.

Project description:In multiple myeloma, osteolytic lesions rarely heal because of persistent suppressed osteoblast differentiation resulting in a high fracture risk. Herein, chromatin immunoprecipitation analyses reveal that multiple myeloma cells induce repressive epigenetic histone changes at the Runx2 locus that prevent osteoblast differentiation. The most pronounced multiple myeloma-induced changes were at the Runx2-P1 promoter, converting it from a poised bivalent state to a repressed state. Previously, it was observed that multiple myeloma induces the transcription repressor GFI1 in osteoblast precursors, which correlates with decreased Runx2 expression, thus prompting detailed characterization of the multiple myeloma and TNF?-dependent GFI1 response element within the Runx2-P1 promoter. Further analyses reveal that multiple myeloma-induced GFI1 binding to Runx2 in osteoblast precursors and recruitment of the histone modifiers HDAC1, LSD1, and EZH2 is required to establish and maintain Runx2 repression in osteogenic conditions. These GFI1-mediated repressive chromatin changes persist even after removal of multiple myeloma. Ectopic GFI1 is sufficient to bind to Runx2, recruit HDAC1 and EZH2, increase H3K27me3 on the gene, and prevent osteogenic induction of endogenous Runx2 expression. Gfi1 knockdown in MC4 cells blocked multiple myeloma-induced recruitment of HDAC1 and EZH2 to Runx2, acquisition of repressive chromatin architecture, and suppression of osteoblast differentiation. Importantly, inhibition of EZH2 or HDAC1 activity in pre-osteoblasts after multiple myeloma exposure in vitro or in osteoblast precursors from patients with multiple myeloma reversed the repressive chromatin architecture at Runx2 and rescued osteoblast differentiation.Implications: This study suggests that therapeutically targeting EZH2 or HDAC1 activity may reverse the profound multiple myeloma-induced osteoblast suppression and allow repair of the lytic lesions. Mol Cancer Res; 15(4); 405-17. ©2017 AACR.

Dataset Information

?-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance.

Publications

β-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance.

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