Aryl hydrocarbon receptor is required for optimal B‐cell proliferation

Villa, Matteo; Gialitakis, Manolis; Tolaini, Mauro; Ahlfors, Helena; Henderson, Colin J.; Wolf, C. Roland; Brink, Robert; Stockinger, Brigitta

doi:10.15252/embj.201695027

Cited by 79 publications

(63 citation statements)

References 32 publications

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“…Emerging evidence indicates that AHR could also be activated by endogenous ligand FICZ (29). FICZ stimulates B-cell proliferation through AHR activation (48). In accordance, FICZ induces the expression of c-Jun and accelerates VSMC proliferation.…”

Section: Discussionmentioning

confidence: 94%

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2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin promotes injury‐induced vascular neointima formation in mice

et al. 2019

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ABSTRACT2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin (TCDD) is an environmental pollutant that causes cardiovascular toxicity. The phenotypic transformation of vascular smooth muscle cells (VSMCs) from the contractile to the synthetic phenotype is a hallmark of vascular response to injury. However, the precise role and molecular mechanism of TCDD in vascular remodeling remains unknown. In the present study, we found that TCDD treatment promoted VSMC phenotypic transition from contractile to synthetic phenotype and exaggerated vascular neointimal hyperplasia after wire injury in mice. TCDD treatment enhanced VSMC entry into cell cycle from G0/G1 phase to S and G2/M phase. The expression of cyclin D1, cyclin‐dependent kinase 4 (CDK4), and its phosphorylation were coordinately increased in response to TCDD treatment. Knocking down of aryl hydrocarbon receptor (AHR) inhibited VSMC phenotypic transition induced by TCDD and promoted S/G2 phase cell cycle arrest. TCDD treatment markedly increased oncogenic c‐Jun gene expression in VSMCs. ChIP assay revealed the direct binding of AHR on the promoter of c‐Jun to up‐regulate the mRNA expression of c‐Jun. Silencing of c‐Jun gene enhanced the expression of p53 and p21, whereas attenuated the expression of CDK4 and cyclin D1 leading to the decrease in the TCDD‐stimulated VSMC proliferation and synthetic phenotype transition in vitro. In vivo study showed that genetic ablation of c‐Jun in VSMCs restricted injury‐induced neointimal hyperplasia in TCDD‐treated mice. Thus, TCDD exposure exaggerated injury‐induced vascular remodeling by the activation of AHR and up‐regulation of the expression of its target gene c‐Jun, indicating that inhibition of AHR may be a promising prevention strategy for TCDD‐associated cardiovascular diseases.—Guo, S., Zhang, R., Liu, Q., Wan, Q., Wang, Y., Yu, Y., Liu, G., Shen, Y., Yu, Y., Zhang, J. 2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin promotes injury‐induced vascular neointima formation in mice. FASEB J. 33, 10207–10217 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 94%

“…Cells were seeded into 96-well plates and serum starved for 24 h before TCDD treatment. Cell proliferation was examined at different timepoints (24,48,72, and 96 h). Cell counting kit-8 (CCK-8) assay was performed using a CCK-8 kit (Dojindo, Kumamoto, Japan) according to the manufacturer's instructions.…”

Section: Cell Counting Kit-8 Assaymentioning

confidence: 99%

2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin promotes injury‐induced vascular neointima formation in mice

et al. 2019

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“…This difference in results might be due to the type of ligand and animal species used and the disease type examined. In addition, Villa et al (2017) demonstrated that intervention with 6-formylindolo[3,2-b]carbazole (FICZ), a natural agonist, increased AhR expression during B cell differentiation and the amount of AhR localized to the nucleus and significantly upregulated the expression of the downstream target gene CYP1A1 on B cells. These results imply that the AhR is involved in B cell proliferation and function.…”

Section: Discussionmentioning

confidence: 99%

Human Umbilical Mesenchymal Stem Cells Display Therapeutic Potential in Rheumatoid Arthritis by Regulating Interactions Between Immunity and Gut Microbiota via the Aryl Hydrocarbon Receptor

Lü

Fan

et al. 2020

Front. Cell Dev. Biol.

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Background: Rheumatoid arthritis (RA) is an autoimmune disease that may be associated with gut microbiota via the aryl hydrocarbon receptor (AhR). Human umbilical mesenchymal stem cells (HUMSCs) have therapeutic potential against RA, but the underlying mechanism has not been fully elucidated. The purpose of this study was to explore the mechanism of action of HUMSCs in rats with collagen-induced arthritis (CIA). Method: HUMSCs (1 × 10 6) were transplanted into each rat with CIA. The tissue localization of HUMSCs and the therapeutic effects in the ankles were assessed. The immune status and expression of immune-related genes and proteins in related lymphoid tissues were subsequently tested. Furthermore, the levels of immune-related factors in serum and the changes in gut microbiota in the ileum were detected, and the levels of indole and their derivatives in plasma and the levels of AhR in the ileum were evaluated. Results: HUMSCs homed to the popliteal lymph node (PLN), mesenteric lymph node (MLN), ankle cartilage, and ileum mucosa in rats with CIA. The transplantation of HUMSCs reduced the pathology scores and the degree of bone damage in the ankles. The immune status of T regulatory cells (Tregs) and T helper (Th)17 cells and the gene expression levels of interleukin (IL)-10, transforming growth factor (TGF)-β1, and IL-17A were altered in the PLN, which is the lymph tissue closest to the nidus, and the MLN, which is one of the gut-associated lymphoid tissues (GALTs). The proportion and function of B cells, Tregs, and Th17 cells were regulated in other GALTs, namely,

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“…Upon ligand binding, AhR is translocated into the nucleus, where AhR forms a heterodimer with AhR nuclear translocator (Arnt) and binds to dioxin response elements to induce transcription of genes involved in xenobiotic metabolism, including Cyp1a1 7 . In addition to its xenobiotic function, AhR also has endobiotic physiological functions in cell proliferation, differentiation, immune suppression, and male infertility 9 – 11 . AhR was recently also shown to play an important role in hepatic lipid metabolism 12 .…”

Section: Introductionmentioning

confidence: 99%

AhR and SHP regulate phosphatidylcholine and S-adenosylmethionine levels in the one-carbon cycle

et al. 2018

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Phosphatidylcholines (PC) and S-adenosylmethionine (SAM) are critical determinants of hepatic lipid levels, but how their levels are regulated is unclear. Here, we show that Pemt and Gnmt, key one-carbon cycle genes regulating PC/SAM levels, are downregulated after feeding, leading to decreased PC and increased SAM levels, but these effects are blunted in small heterodimer partner (SHP)-null or FGF15-null mice. Further, aryl hydrocarbon receptor (AhR) is translocated into the nucleus by insulin/PKB signaling in the early fed state and induces Pemt and Gnmt expression. This induction is blocked by FGF15 signaling-activated SHP in the late fed state. Adenoviral-mediated expression of AhR in obese mice increases PC levels and exacerbates steatosis, effects that are blunted by SHP co-expression or Pemt downregulation. PEMT, AHR, and PC levels are elevated in simple steatosis patients, but PC levels are robustly reduced in steatohepatitis-fibrosis patients. This study identifies AhR and SHP as new physiological regulators of PC/SAM levels.

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Aryl hydrocarbon receptor is required for optimal B‐cell proliferation

Cited by 79 publications

References 32 publications

2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin promotes injury‐induced vascular neointima formation in mice

2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin promotes injury‐induced vascular neointima formation in mice

Human Umbilical Mesenchymal Stem Cells Display Therapeutic Potential in Rheumatoid Arthritis by Regulating Interactions Between Immunity and Gut Microbiota via the Aryl Hydrocarbon Receptor

AhR and SHP regulate phosphatidylcholine and S-adenosylmethionine levels in the one-carbon cycle

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