B cells with aberrant activation of Notch1 signaling promote Treg and Th2 cell–dominant T-cell responses via IL-33

Arima, Hiroshi; Nishikori, Momoko; Otsuka, Yuichi; Kishimoto, Wataru; Izumi, Kunihide; Yasuda, Koubun; Yoshimoto, Tomohiro; Takaori‐Kondo, Akifumi

doi:10.1182/bloodadvances.2018019919

“…Notch pathway is also critical in B cells and monocytes (28)(29)(30)(31)(32), which are also characterized by EZH2 overexpression in lupus in our study.…”

Section: Cells the Reduction In Cd4-cd8-t Cells (Dn T Cells) Is Of Psupporting

confidence: 62%

Inhibition of EZH2 ameliorates lupus-like disease inMRL/lprmice

Rohraff

¹

,

He

²

,

Farkash

³

et al. 2018

Preprint

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Objective. We previously identified a role for EZH2, a transcriptional regulator in inducing proinflammatory epigenetic changes in lupus CD4+ T cells. This study was undertaken to investigate whether inhibiting EZH2 ameliorates lupus-like disease in MRL/lpr mice.Methods. EZH2 expression levels in multiple cell types in lupus patients were evaluated using flow cytometry and messenger RNA expression data. Inhibition of EZH2 in MRL/lpr mice was achieved by intraperitoneal 3′-deazaneplanocin (DZNep) administration using a preventative and a therapeutic treatment model. Effects of DZNep on animal survival, anti-double-stranded DNA (anti-dsDNA) antibody production, proteinuria, renal histopathology, cytokine production, and T and B cell numbers and percentages were assessed.Results. EZH2 expression levels were increased in whole blood, neutrophils, monocytes, B cells, and CD4+ T cells in lupus patients. In MRL/lpr mice, inhibition of EZH2 by DZNep was confirmed by significant reduction of EZH2 and H3K27me3 in splenocytes. Inhibiting EZH2 with DZNep treatment before or after disease onset improved survival and significantly reduced anti-dsDNA antibody production. DZNep-treated mice displayed a significant reduction in renal involvement, splenomegaly, and lymphadenopathy. Lymphoproliferation and numbers of double-negative T cells were significantly reduced in DZNep-treated mice. Concentrations of circulating cytokines and chemokines, including tumor necrosis factor, interferonγ, CCL2, RANTES/CCL5, interleukin-10 (IL-10), keratinocyte-derived chemokine/ CXCL1, IL-12, IL-12p40, and CCL4/macrophage inflammatory protein 1β, were decreased in DZNep-treated mice.Conclusion. EZH2 is up-regulated in multiple cell types in lupus patients. Therapeutic inhibition of EZH2 abrogates lupus-like disease in MRL/lpr mice, suggesting that EZH2 inhibitors may be repurposed as a novel therapeutic option for lupus patients.

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“…EZH2 has been shown to inhibit T cell Notch repressors, promoting Notch activation and thus effector T cell polyfunctionality and survival . The Notch pathway is also critical in B cells and monocytes , which were characterized by EZH2 overexpression in lupus in our study.…”

Section: Discussionmentioning

confidence: 48%

Inhibition of EZH2 Ameliorates Lupus‐Like Disease in MRL/lpr Mice

Rohraff

¹

,

He

²

,

Farkash

³

et al. 2019

Arthritis & Rheumatology

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Objective. We previously identified a role for EZH2, a transcriptional regulator in inducing proinflammatory epigenetic changes in lupus CD4+ T cells. This study was undertaken to investigate whether inhibiting EZH2 ameliorates lupus-like disease in MRL/lpr mice.Methods. EZH2 expression levels in multiple cell types in lupus patients were evaluated using flow cytometry and messenger RNA expression data. Inhibition of EZH2 in MRL/lpr mice was achieved by intraperitoneal 3′-deazaneplanocin (DZNep) administration using a preventative and a therapeutic treatment model. Effects of DZNep on animal survival, anti-double-stranded DNA (anti-dsDNA) antibody production, proteinuria, renal histopathology, cytokine production, and T and B cell numbers and percentages were assessed.Results. EZH2 expression levels were increased in whole blood, neutrophils, monocytes, B cells, and CD4+ T cells in lupus patients. In MRL/lpr mice, inhibition of EZH2 by DZNep was confirmed by significant reduction of EZH2 and H3K27me3 in splenocytes. Inhibiting EZH2 with DZNep treatment before or after disease onset improved survival and significantly reduced anti-dsDNA antibody production. DZNep-treated mice displayed a significant reduction in renal involvement, splenomegaly, and lymphadenopathy. Lymphoproliferation and numbers of double-negative T cells were significantly reduced in DZNep-treated mice. Concentrations of circulating cytokines and chemokines, including tumor necrosis factor, interferonγ, CCL2, RANTES/CCL5, interleukin-10 (IL-10), keratinocyte-derived chemokine/ CXCL1, IL-12, IL-12p40, and CCL4/macrophage inflammatory protein 1β, were decreased in DZNep-treated mice.Conclusion. EZH2 is up-regulated in multiple cell types in lupus patients. Therapeutic inhibition of EZH2 abrogates lupus-like disease in MRL/lpr mice, suggesting that EZH2 inhibitors may be repurposed as a novel therapeutic option for lupus patients.

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“…Such IL-33-induced immunotolerance has been observed in breast, colorectal, and certain lung cancers (47). Most notably, another group has similarly shown selection for increased IL33 expression in DLBCL, which, in mice, promoted T regulatory cell activation (48). Additionally, whereas a large proportion of B-CLL samples (79%) had a decrease in IL33 expression, there were samples that displayed an increase in IL33 mRNA compared with healthy controls, suggesting that additional factors, including tumor genetics and the tumor microenvironment, may influence the relative benefit of modulated IL33 expression.…”

Section: Discussionmentioning

confidence: 91%

IL-33 Is a Cell-Intrinsic Regulator of Fitness during Early B Cell Development

Stier

¹

,

Mitra

²

,

Nyhoff

³

et al. 2019

The Journal of Immunology

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IL-33 is an IL-1 family member protein that is a potent driver of inflammatory responses in both allergic and nonallergic disease. This proinflammatory effect is mediated primarily by extracellular release of IL-33 from stromal cells and binding of the C-terminal domain of IL-33 to its receptor ST2 on targets such as CD4+ Th2 cells, ILC2, and mast cells. Notably, IL-33 has a distinct N-terminal domain that mediates nuclear localization and chromatin binding. However, a defined in vivo cell-intrinsic role for IL-33 has not been established. We identified IL-33 expression in the nucleus of progenitor B (pro-B) and large precursor B cells in the bone marrow, an expression pattern unique to B cells among developing lymphocytes. The IL-33 receptor ST2 was not expressed within the developing B cell lineage at either the transcript or protein level. RNA sequencing analysis of wild-type and IL-33–deficient pro-B and large precursor B cells revealed a unique, IL-33–dependent transcriptional profile wherein IL-33 deficiency led to an increase in E2F targets, cell cycle genes, and DNA replication and a decrease in the p53 pathway. Using mixed bone marrow chimeric mice, we demonstrated that IL-33 deficiency resulted in an increased frequency of developing B cells via a cell-intrinsic mechanism starting at the pro-B cell stage paralleling IL-33 expression. Finally, IL-33 was detectable during early B cell development in humans and IL33 mRNA expression was decreased in B cell chronic lymphocytic leukemia samples compared with healthy controls. Collectively, these data establish a cell-intrinsic, ST2-independent role for IL-33 in early B cell development.

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B cells with aberrant activation of Notch1 signaling promote Treg and Th2 cell–dominant T-cell responses via IL-33

Cited by 19 publications

References 77 publications

Inhibition of EZH2 ameliorates lupus-like disease inMRL/lprmice

Inhibition of EZH2 ameliorates lupus-like disease inMRL/lprmice

Inhibition of EZH2 Ameliorates Lupus‐Like Disease in MRL/lpr Mice

IL-33 Is a Cell-Intrinsic Regulator of Fitness during Early B Cell Development

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