Roles of WNT, NOTCH, and Hedgehog signaling in the differentiation and function of innate and innate-like lymphocytes

Kling, Jessica C.; Blumenthal, Antje

doi:10.1189/jlb.1mr0616-272r

Cited by 29 publications

(20 citation statements)

References 196 publications

(291 reference statements)

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“…This is in line with our previous observations showing an anti-inflammatory and anti-proliferative effect following GSK-J4 treatment. Whereas pathways such as Notch signaling and glycolysis have been previously shown to be important for NK cell function ( 48 , 49 ), we observed a strong induction of metallothionein genes; however, the reason for this remains enigmatic at this point. Next, we validated the RNA-seq data by performing qPCR on NK cells treated for 24 h with GSK-J4.…”

Section: Resultscontrasting

confidence: 59%

Inhibition of histone H3K27 demethylases selectively modulates inflammatory phenotypes of natural killer cells

Cribbs

Hookway

Wells

et al. 2018

Journal of Biological Chemistry

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Natural killer (NK) cells are innate lymphocytes, important in immune surveillance and elimination of stressed, transformed, or virus-infected cells. They critically shape the inflammatory cytokine environment to orchestrate interactions of cells of the innate and adaptive immune systems. Some studies have reported that NK cell activation and cytokine secretion are controlled epigenetically but have yielded only limited insight into the mechanisms. Using chemical screening with small-molecule inhibitors of chromatin methylation and acetylation, further validated by knockdown approaches, we here identified Jumonji-type histone H3K27 demethylases as key regulators of cytokine production in human NK cell subsets. The prototypic JMJD3/UTX (Jumonji domain–containing protein 3) H3K27 demethylase inhibitor GSK-J4 increased global levels of the repressive H3K27me3 mark around transcription start sites of effector cytokine genes. Moreover, GSK-J4 reduced IFN-γ, TNFα, granulocyte–macrophage colony-stimulating factor (GM-CSF), and interleukin-10 levels in cytokine-stimulated NK cells while sparing their cytotoxic killing activity against cancer cells. The anti-inflammatory effect of GSK-J4 in NK cell subsets, isolated from peripheral blood or tissue from individuals with rheumatoid arthritis (RA), coupled with an inhibitory effect on formation of bone-resorbing osteoclasts, suggested that histone demethylase inhibition has broad utility for modulating immune and inflammatory responses. Overall, our results indicate that H3K27me3 is a dynamic and important epigenetic modification during NK cell activation and that JMJD3/UTX-driven H3K27 demethylation is critical for NK cell function.

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Section: Resultscontrasting

confidence: 59%

Inhibition of histone H3K27 demethylases selectively modulates inflammatory phenotypes of natural killer cells

Cribbs

Hookway

Wells

et al. 2018

Journal of Biological Chemistry

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“…Their development is regulated by the morphogenic pathways NOTCH and Wnt/β-catenin (reviewed in ref. 40 ); thus, it is important to establish whether there is a role for Hh/Gli signaling in the differentiation and function of this cell type.…”

Section: Resultsmentioning

confidence: 99%

Frontline Science: Shh production and Gli signaling is activated in vivo in lung, enhancing the Th2 response during a murine model of allergic asthma

Standing

Yánez

Ross

et al. 2017

Journal of Leukocyte Biology

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“…Within the hematopoietic system, Notch is critical for promoting T cell development (32). The Notch pathway has also been implicated in regulation of innate lymphocytes and in generation, differentiation, and maturation of ILC2 and other ILCs cells (25,63). However, it has remained unclear to what degree canonical Notch signaling has an impact on conventional NKPs and maturation, because most experiments addressing the impact of Notch were limited to NK cell differentiation in vitro (16,17,25).…”

Section: Discussionmentioning

confidence: 99%

“…The Notch pathway has also been implicated in regulation of innate lymphocytes and in generation, differentiation, and maturation of ILC2 and other ILCs cells (25,63). However, it has remained unclear to what degree canonical Notch signaling has an impact on conventional NKPs and maturation, because most experiments addressing the impact of Notch were limited to NK cell differentiation in vitro (16,17,25). Previous in vivo studies with chimera mice generated after transplantation of Rbpj-deleted BM cells showed no significant alterations in donor-derived conventional NK cell pool in the spleen and no changes in thymic-dependent IL-7R + NK cell population, whereas, as expected, T cells were absent (21, 26).…”

Section: Discussionmentioning

confidence: 99%

Loss of Canonical Notch Signaling Affects Multiple Steps in NK Cell Development in Mice

Chaves

Zriwil

Wittmann

et al. 2018

The Journal of Immunology

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Within the hematopoietic system, the Notch pathway is critical for promoting thymic T cell development and suppressing the B and myeloid lineage fates; however, its impact on NK lymphopoiesis is less understood. To study the role of Notch during NK cell development in vivo, we investigated different NK cell compartments and function in Rbp-Jk fl/fl Vav-Cre tg/+ mice, in which Rbp-Jk, the major transcriptional effector of canonical Notch signaling, was specifically deleted in all hematopoietic cells. Peripheral conventional cytotoxic NK cells in Rbp-Jk-deleted mice were significantly reduced and had an activated phenotype. Furthermore, the pool of early NK cell progenitors in the bone marrow was decreased, whereas immature NK cells were increased, leading to a block in NK cell maturation. These changes were cell intrinsic as the hematopoietic chimeras generated after transplantation of Rbp-Jk-deficient bone marrow cells had the same NK cell phenotype as the Rbp-Jk-deleted donor mice, whereas the wild-type competitors did not. The expression of several crucial NK cell regulatory pathways was significantly altered after Rbp-Jk deletion. Together, these results demonstrate the involvement of canonical Notch signaling in regulation of multiple stages of NK cell development.

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Roles of WNT, NOTCH, and Hedgehog signaling in the differentiation and function of innate and innate-like lymphocytes

Cited by 29 publications

References 196 publications

Inhibition of histone H3K27 demethylases selectively modulates inflammatory phenotypes of natural killer cells

Inhibition of histone H3K27 demethylases selectively modulates inflammatory phenotypes of natural killer cells

Frontline Science: Shh production and Gli signaling is activated in vivo in lung, enhancing the Th2 response during a murine model of allergic asthma

Loss of Canonical Notch Signaling Affects Multiple Steps in NK Cell Development in Mice

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