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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling by array to investigate how Aryl hydrocarbon receptor governs a transcriptional programme that determines regulatory B cell differentiation and function

ABSTRACT: Regulatory B cells (Breg) play a critical role in the control of autoimmunity and inflammation. Although IL-10 is considered the hallmark for the identification of Bregs, the molecular programme that controls IL-10 production in Bregs is yet to be defined. Here, we demonstrate that aryl hydrocarbon receptor (AhR) controls the differentiation and function of IL-10-producing Bregs. Deficiency of AhR-expressing B cells drastically reduces IL-10 production by B cells. This leads to the unrestrained differentiation of T helper (Th)17 cells and a significant reduction in the percentage of regulatory T cells (Treg), which increases the severity of experimental arthritis when compared to control animals with AhR-sufficient B cells. A combination of chromatin-landscape profiling by ATAC-seq and transcriptome analyses by RNA-seq demonstrated that a loss of AhR expression in B cells not only reduces IL-10 expression by Bregs, defined as CD21hiCD24hi B cells, but also promotes a pro-inflammatory programme in CD21hiCD24hi B cells, even under Breg inducing conditions. Thus, AhR acts as a master transcriptional regulator of Breg differentiation by implementing a molecular programme that controls IL-10 production and represses pro-inflammatory cytokine production.

ORGANISM(S): Mus musculus

SUBMITTER: Ignat Drozdov

PROVIDER: E-MTAB-7375 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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RNASeq: Aryl hydrocarbon receptor governs a transcriptional programme that determines regulatory B cell differentiation and function

Project description:Regulatory B cells (Breg) play a critical role in the control of autoimmunity and inflammation. Although IL-10 is considered the hallmark for the identification of Bregs, the molecular programme that controls IL-10 production in Bregs is yet to be defined. Here, we demonstrate that aryl hydrocarbon receptor (AhR) controls the differentiation and function of IL-10-producing Bregs. Deficiency of AhR-expressing B cells drastically reduces IL-10 production by B cells. This leads to the unrestrained differentiation of T helper (Th)17 cells and a significant reduction in the percentage of regulatory T cells (Treg), which increases the severity of experimental arthritis when compared to control animals with AhR-sufficient B cells. A combination of chromatin-landscape profiling by ATAC-seq and transcriptome analyses by RNA-seq demonstrated that a loss of AhR expression in B cells not only reduces IL-10 expression by Bregs, defined as CD21hiCD24hi B cells, but also promotes a pro-inflammatory programme in CD21hiCD24hi B cells, even under Breg inducing conditions. Thus, AhR acts as a master transcriptional regulator of Breg differentiation by implementing a molecular programme that controls IL-10 production and represses pro-inflammatory cytokine production.

2019-10-15 | E-MTAB-7345 | biostudies-arrayexpress

ATAC-seq: Aryl hydrocarbon receptor governs a transcriptional programme that determines regulatory B cell differentiation and function

2019-10-15 | E-MTAB-7525 | biostudies-arrayexpress

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Project description:Regulatory B cells (Bregs) are immune cells that constrain the immune response and restrict inflammation via their expression of interleukin (IL)-10. However, the molecular mechanisms underlying Breg differentiation and IL-10 secretion remain unclear. Previous data suggest that cellular metabolism determines both the fate and function of these cells. Here, we suggest an essential role for mitochondrial oxidative phosphorylation (OXPHOS) in the regulation of IL-10 in these Bregs. We found that IL-10+ B cells from IL-10-green fluorescent protein-expressing mice had higher oxygen consumption rate than IL-10- B cells. In addition, inhibition of OXPHOS decreased the expression of IL-10 in B cells. Further, suppression of OXPHOS diminished the expression of surface markers for Bregs and impaired their therapeutic effects in dextran sulfate sodium-induced colitis. Mechanistically, mitochondrial OXPHOS was found to regulate the transcription factor HIF-1α through the extracellular signal-related kinase pathway. Taken together, this study reveals a strong correlation between mitochondrial OXPHOS and Breg phenotype/function, indicating OXPHOS as a therapeutic target in autoimmune diseases driven by Breg dysfunction.

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Schistosoma mansoni egg-derived thioredoxin and Sm14 drive the development of IL-10 producing regulatory B cells

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2023-10-24 | PXD031333 | Pride

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2018-01-25 | E-MTAB-6381 | biostudies-arrayexpress

A regulatory CD9+ B cell subset controls HDM-induced allergic airway inflammation

Project description:Background: A specific subset of regulatory IL-10 producing B cells has been extensively studied in autoimmune and inflammatory pathologies. These cells are able to constrain exacerbated inflammation by inhibiting T cell mediated responses and maturation of antigen presenting cells. In allergic diseases, observations that increase of regulatory B cells is necessary for allergen tolerance suggest that development of allergic asthma would be associated with a defect in the regulatory B cells compartment. Objective: We sought to (i) characterize regulatory IL-10+ regulatory B cell subset in Balb/c mice by microarray and flow cytometry and (ii) investigate their regulatory capacity in vivo in a house dust mite model of allergic asthma. Results: We identified an IL-10 producing B cells subset able to control T cell proliferation in vitro in both control and asthmatic mice. This subset is decreased in allergic mice. IL-10+ Breg cells express high levels of CD9 and upregulate CD70 and CD73 after activation. Expression of CD9 allows identifying more than 50% of Bregs. Interestingly CD9+ B cells inhibit TH2-TH17 allergic airway inflammation in vivo after adoptive transfer in an IL-10 dependent manner. Conclusions: Herein, we demonstrate that induction of allergic asthma dampens the generation of Bregs contributing to exacerbated airway inflammation. We identified a distinct CD9+ Breg-cell population decreased in lung of HDM mice and able to control asthma and allergic airway inflammation by producing IL-10 after adoptive transfer. This study points B cells as an interesting therapeutic target in allergic asthma. IL-10+ B cells (n=3) and 3 IL-10- B cells (n=3) in control mice + IL-10+ B cells (n=3) and 3 IL-10- B cells (n=3) from asthmatic allergic (HDM) mice

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A regulatory CD9+ B cell subset controls HDM-induced allergic airway inflammation

2015-03-01 | GSE57772 | GEO

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Project description:single cell RNA-sequencing (scRNA-seq) was performed to delineate the phenotype of Bregs-TLR and Bregs-CpG cells and potentially identify gene signatures characteristic of each Breg subset.

2022-09-29 | GSE208527 | GEO

Aryl hydrocarbon receptor activity downstream of IL-10 signaling is required to promote regulatory functions in human dendritic cells [RNA_in_vitro_DC10_iDC_DC10CH]

Project description:Peripheral immune tolerance is a key physiological mechanism sustained by the activity of regulatory cells that impedes immune reaction to self and non-dangerous antigens. Interleukin 10 (IL-10) plays a key immunosuppressive role in this system by inhibiting effector cells and instructing regulatory cells. While the molecular mechanisms and gene expression patterns defining identity and function of T regulatory cells have been deeply studied, the molecular pattern driving tolerogenicity in myeloid antigen presenting cells remain less defined. We have investigated the molecular mechanisms underlying IL-10 tolerogenic activity in human myeloid cells. By performing chromatin and transcriptomic studies in IL-10-induced monocyte-derived DC, we have found that IL-10 imprinted a pattern of accessible enhancers, which were exploited by Aryl Hydrocarbon Receptor (AHR) to promote the expression of a set of core genes. Functional studies demonstrated that AHR activation and core gene expression were necessary for IL-10-mediated induction of tolerogenic functions in in vitro differentiated DC. AHR exerted its role down-stream to IL-10 inducing tolerogenic and repressing inflammatory genes. Analyses of naturally occurring tolerogenic DC from peripheral blood showed that the IL-10-induced AHR module was active also in vivo in healthy conditions. In multiple sclerosis patients, instead, we observed significant alterations in the IL-10-induced AHR module that correlated with functional defects and reduced frequencies of in vitro differentiated and in vivo occurring IL-10-induced tolerogenic DC, respectively. This study unveiled a previously undescribed IL-10-induced molecular mechanism required for establishing tolerogenic functions in human myeloid cells.

2023-03-04 | GSE180761 | GEO

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