Loss of Nrf2 in bone marrow-derived macrophages impairs antigen-driven CD8+ T cell function by limiting GSH and Cys availability

Sha, Lisa K.; Sha, Weixiao; Kuchler, Laura; Daiber, Andreas; Giegerich, Annika K.; Weigert, Andreas; Knape, Tilo; Snodgrass, Ryan G.; Schröder, Katrin; Brandes, Ralf P.; Brüne, Bernhard; Knethen, Andreas von

doi:10.1016/j.freeradbiomed.2015.02.004

Cited by 40 publications

(32 citation statements)

References 51 publications

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“…Previous studies demonstrated that Nrf2 -deficient macrophages had an impaired antigen-presenting function and an impaired antigen-induced T cell function with altered cytokine production30. To evaluate whether similar changes occurred in the mouse genotypes investigated in this study, the mRNA levels of a number of inflammatory factors in macrophages were measured, and the results showed that Csf3 expression increased significantly in the B6.Nrf2 −/− lpr / lpr mice (Fig.…”

Section: Resultsmentioning

confidence: 60%

Nuclear Factor Erythroid 2-related Factor 2 Deficiency Exacerbates Lupus Nephritis in B6/lpr mice by Regulating Th17 Cell Function

Zhao

Chen

Ding

et al. 2016

Sci Rep

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Lupus nephritis (LN) is the major clinical manifestation of systemic lupus erythematosus. LN is promoted by T helper 17 (Th17) cells, which are the major pro-inflammatory T cell subset contributing to autoimmunity regulation. Nuclear factor erythroid 2-related factor 2 (NRF2) is critical for suppressing reactive oxygen species (ROS) and relieving oxidant stress by regulating antioxidant gene expression. Previous studies have demonstrated that Nrf2 deficiency promotes drug-induced or spontaneous LN. However, whether NRF2 regulates Th17 function during LN development is still unclear. In this study, we introduced Nrf2 deficiency into a well-known LN model, the B6/lpr mouse strain, and found that it promoted early-stage LN with altered Th17 activation. Th17 cells and their relevant cytokines were dramatically increased in these double-mutant mice. We also demonstrated that naïve T cells from the double-mutant mice showed significantly increased differentiation into Th17 cells in vitro, with decreased expression of the Th17 differentiation suppressor Socs3 and increased phosphorylation of STAT3. Our results demonstrated that Nrf2 deficiency promoted Th17 differentiation and function during LN development. Moreover, our results suggested that the regulation of Th17 differentiation via NRF2 could be a therapeutic target for the treatment of subclinical LN patients.

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Section: Resultsmentioning

confidence: 60%

Nuclear Factor Erythroid 2-related Factor 2 Deficiency Exacerbates Lupus Nephritis in B6/lpr mice by Regulating Th17 Cell Function

Zhao

Chen

Ding

et al. 2016

Sci Rep

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“…NRF2 also induces an anti-inflammatory phenotype that modulates the functions of CD8 + T cells (Sha et al, 2015) as well as in macrophages and microglia ( Rojo et al, 2010( Rojo et al, , 2014aBrune et al, 2013). This is because NRF2 increases cysteine and GSH levels in macrophages through regulation of the cystine/glutamate transporter and the GSH-synthesizing enzyme g-glutamyl cysteine ligase modulator and catalytic subunits [g-glutamyl cysteine ligase modulator subunit (GCLM) and g-glutamyl cysteine ligase catalytic subunit (GCLC)].…”

Section: A Key Role Of Nuclear Factor (Erythroid-derived 2)-like 2 Imentioning

confidence: 99%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

Self Cite

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“…46,47 Antitumor immunity is largely dependent on CD8 + T cells and macrophages, 48 and a study has shown that NRF2 activation in macrophages is necessary for CD8 + T cell function. 49 Regardless of the cause of tumor initiation (environmental exposure, replication-associated mutations, inheritance of susceptibility genes), inhibition of NRF2 seems to be a very promising strategy to slow down tumor growth or to sensitize tumors to chemo or radiation therapies. NRF2 is very frequently upregulated in cancer and NRF2 target genes are involved in processes related to the hallmarks of cancer 50…”

Section: Nrf2 Modulation In Chemical and Genetic Lung Cancer Modelsmentioning

confidence: 99%

The effects of NRF2 modulation on the initiation and progression of chemically and genetically induced lung cancer

Tao

Vega

Chapman

et al. 2017

Molecular Carcinogenesis

103

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Targeting the transcription factor NRF2 has been recognized as a feasible strategy for cancer prevention and treatment, but many of the mechanistic details underlying its role in cancer development and progression are lacking. Therefore, careful mechanistic studies of the NRF2 pathway in cancer initiation and progression are needed to identify which therapeutic avenue-activation or inhibition-is appropriate in a given context. Moreover, while numerous reports confirm the protective effect of NRF2 activation against chemical carcinogenesis little is known of its role in cancer arising from spontaneous mutations. Here, we tested the effects of NRF2 modulation (activation by sulforaphane or inhibition by brusatol) in lung carcinogenesis using a chemical (vinyl carbamate) model in A/J mice and a genetic (conditional Kras oncogene expression, to simulate spontaneous oncogene mutation) model in C57BL/6J mice. Mice were treated with NRF2 modulators before carcinogen exposure or Kras expression to test the role of NRF2 in cancer initiation, or treated after tumor development to test the role of NRF2 in cancer progression. Lung tissues were analyzed to determine tumor burden, as well as status of NRF2 and KRAS pathways. Additionally, proliferation, apoptosis, and oxidative DNA damage were assessed. Overall, NRF2 activation prevents initiation of chemically induced cancer, but promotes progression of pre-existing tumors regardless of chemical or genetic etiology. Once tumors are initiated, NRF2 inhibition is effective against the progression of chemically and spontaneously induced tumors. These results have important implications for NRF2-targeted cancer prevention and intervention strategies.

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Loss of Nrf2 in bone marrow-derived macrophages impairs antigen-driven CD8+ T cell function by limiting GSH and Cys availability

Cited by 40 publications

References 51 publications

Nuclear Factor Erythroid 2-related Factor 2 Deficiency Exacerbates Lupus Nephritis in B6/lpr mice by Regulating Th17 Cell Function

Nuclear Factor Erythroid 2-related Factor 2 Deficiency Exacerbates Lupus Nephritis in B6/lpr mice by Regulating Th17 Cell Function

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

The effects of NRF2 modulation on the initiation and progression of chemically and genetically induced lung cancer

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