Dissecting the Role of BET Bromodomain Proteins BRD2 and BRD4 in Human NK Cell Function

Cribbs, Adam P.; Filippakopoulos, P.; Philpott, Martin; Wells, Graham; Penn, Henry; Oerum, Henrik; Valge-Archer, Viia; Feldmann, Marc; Oppermann, U.

doi:10.3389/fimmu.2021.626255

Cited by 17 publications

(12 citation statements)

References 61 publications

(76 reference statements)

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“…We found that NK cells treated with butyrate expressed higher levels of the BET bromodomain containing protein, BRD2. BRD2 controls inflammatory cytokine production by NK cells 34 . We also found that NK cells differentially express the ubiquitin-binding selective autophagy receptor p62/SQSTM1, and the RNA helicase DDX21 following butyrate treatment.…”

Section: Discussionmentioning

confidence: 99%

Butyrate limits human natural killer cell effector function

Zaiatz-Bittencourt

Jones

Tosetto

et al. 2023

Sci Rep

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The gut microbiota regulates chronic inflammation and has been implicated in the pathogenesis of a broad spectrum of disease including autoimmunity and cancer. Microbial short-chain fatty acids (SCFAs) e.g., butyrate have demonstrated immunomodulatory effects and are thought to be key mediators of the host-microbiome interaction. Here, we investigated the effect of butyrate on effector functions of blood derived human NK cells stimulated for 18 h with a combination of IL-12/IL-15, a potent mix of cytokines that drive NK cell activation. We show that butyrate has a strong anti-inflammatory effect on NK cells. NK cells cultured in the presence of butyrate expressed lower levels of activating receptors (TRAIL, NKp30, NKp44) and produced lower levels of cytokines (IFNγ, TNF-α, IL-22, granzyme B, granzyme A, perforin) in response to IL-12/IL-15. Butyrate restricted NK cell function by downregulation of mTORC1 activity, c-Myc mRNA expression and metabolism. Using a shotgun proteomic approach, we confirmed the effect of butyrate on NK cell cytokine signaling and metabolism and identified BRD2, MAT2A and EHD1 as downstream mediators of these effects. This insight into the immunomodulatory activity of butyrate on human NK cell function might help to develop new ways to limit NK cell function during chronic inflammation.

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Section: Discussionmentioning

confidence: 99%

Butyrate limits human natural killer cell effector function

Zaiatz-Bittencourt

Jones

Tosetto

et al. 2023

Sci Rep

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“…In addition, silencing of BET proteins by small interfering RNA reduced TNF-α expression in HC and RA monocytesderived macrophages [59]. Cribbs et al have also showed that monocytes reduced TNF-α production upon co-culture with NK cells stimulated with BET inhibitor JQ1 [60]. Similarly, the immune complex-mediated activation of monocytes was reduced by JQ1 in the lupus model with MRL-lpr mice [61].…”

Section: Role Of Histone Modificationmentioning

confidence: 98%

Tuning Monocytes and Macrophages for Personalized Therapy and Diagnostic Challenge in Rheumatoid Arthritis

Roszkowski

Ciechomska

2021

Cells

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Monocytes/macrophages play a central role in chronic inflammatory disorders, including rheumatoid arthritis (RA). Activation of these cells results in the production of various mediators responsible for inflammation and RA pathogenesis. On the other hand, the depletion of macrophages using specific antibodies or chemical agents can prevent their synovial tissue infiltration and subsequently attenuates inflammation. Their plasticity is a major feature that helps the switch from a pro-inflammatory phenotype (M1) to an anti-inflammatory state (M2). Therefore, understanding the precise strategy targeting pro-inflammatory monocytes/macrophages should be a powerful way of inhibiting chronic inflammation and bone erosion. In this review, we demonstrate potential consequences of different epigenetic regulations on inflammatory cytokines production by monocytes. In addition, we present unique profiles of monocytes/macrophages contributing to identification of new biomarkers of disease activity or predicting treatment response in RA. We also outline novel approaches of tuning monocytes/macrophages by biologic drugs, small molecules or by other therapeutic modalities to reduce arthritis. Finally, the importance of cellular heterogeneity of monocytes/macrophages is highlighted by single-cell technologies, which leads to the design of cell-specific therapeutic protocols for personalized medicine in RA in the future.

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“…IL7R encodes a receptor for interleukin 7 (IL7) and IL‐7 signaling is critical for the development and maintenance of the entire lymphoid compartment 47 . BRD2 controls inflammatory cytokine secretion in NK cells 48 . IRF‐2 was involved in the production and maturation of NK cells 49 .…”

Section: Resultsmentioning

confidence: 99%

Single‐cell RNA‐seq reveals a microenvironment and an exhaustion state of T/NK cells in acute myeloid leukemia

Zhang,

Deng,

Zhu

et al. 2023

Cancer Science

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Acute myeloid leukemia (AML) is a heterogeneous blood cancer. Effective immunotherapies for AML are hindered by a lack of understanding of the tumor microenvironment (TME). Here, we retrieved published single‐cell RNA sequencing data for 128,688 cells derived from 29 bone marrow aspirates, including 21 AML patients and eight healthy donors. We established a global tumor ecosystem including nine main cell types. Myeloid, T, and NK cells were further re‐clustered and annotated. Developmental trajectory analysis indicated that exhausted CD8+ T cells might develop via tissue residual memory T cells (TRM) in the AML TME. Significantly higher expression levels of exhaustion molecules in AML TRM cells suggested that these cells were influenced by the TME and entered an exhausted state. Meanwhile, the upregulation of checkpoint molecules and downregulation of granzyme were also observed in AML NK cells, suggesting an exhaustion state. In conclusion, our comprehensive profiling of T/NK subpopulations provides deeper insights into the AML immunosuppressive ecosystem, which is critical for immunotherapies.

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Dissecting the Role of BET Bromodomain Proteins BRD2 and BRD4 in Human NK Cell Function

Cited by 17 publications

References 61 publications

Butyrate limits human natural killer cell effector function

Butyrate limits human natural killer cell effector function

Tuning Monocytes and Macrophages for Personalized Therapy and Diagnostic Challenge in Rheumatoid Arthritis

Single‐cell RNA‐seq reveals a microenvironment and an exhaustion state of T/NK cells in acute myeloid leukemia

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