scholarly journals Indoleamine 2, 3-Dioxygenase Promotes Aryl Hydrocarbon Receptor-Dependent Differentiation Of Regulatory B Cells in Lung Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Sultan Tousif ◽  
Yong Wang ◽  
Joshua Jackson ◽  
Kenneth P. Hough ◽  
John G. Strenkowski ◽  
...  
Keyword(s):  
Lung Cancer ◽  
B Cells ◽  
Aryl Hydrocarbon Receptor ◽  
Cell Function ◽  
Metabolic Enzyme ◽  
Dependent Manner ◽  
Regulatory B Cells ◽  
Indoleamine 2 ◽  
Aryl Hydrocarbon ◽  
Syngeneic Mouse Model

Regulatory B cells (Breg) are IL-10 producing subsets of B cells that contribute to immunosuppression in the tumor microenvironment (TME). Breg are elevated in patients with lung cancer; however, the mechanisms underlying Breg development and their function in lung cancer have not been adequately elucidated. Herein, we report a novel role for Indoleamine 2, 3- dioxygenase (IDO), a metabolic enzyme that degrades tryptophan (Trp) and the Trp metabolite L-kynurenine (L-Kyn) in the regulation of Breg differentiation in the lung TME. Using a syngeneic mouse model of lung cancer, we report that Breg frequencies significantly increased during tumor progression in the lung TME and secondary lymphoid organs, while Breg were reduced in tumor-bearing IDO deficient mice (IDO-/-). Trp metabolite L-Kyn promoted Breg differentiation in-vitro in an aryl hydrocarbon receptor (AhR), toll-like receptor-4-myeloid differentiation primary response 88, (TLR4-MyD88) dependent manner. Importantly, using mouse models with conditional deletion of IDO in myeloid-lineage cells, we identified a significant role for immunosuppressive myeloid-derived suppressor cell (MDSC)-associated IDO in modulating in-vivo and ex-vivo differentiation of Breg. Our studies thus identify Trp metabolism as a therapeutic target to modulate regulatory B cell function during lung cancer progression.

scholarly journals Microbiota-Derived Metabolites Suppress Arthritis by Amplifying Aryl-Hydrocarbon Receptor Activation in Regulatory B Cells

2020 ◽  
Vol 31 (4) ◽  
pp. 837-851.e10 ◽  
Author(s):  
Elizabeth C. Rosser ◽  
Christopher J.M. Piper ◽  
Diana E. Matei ◽  
Paul A. Blair ◽  
André F. Rendeiro ◽  
...  
Keyword(s):  
B Cells ◽  
Aryl Hydrocarbon Receptor ◽  
Receptor Activation ◽  
Regulatory B Cells ◽  
Aryl Hydrocarbon

scholarly journals Aryl Hydrocarbon Receptor Contributes to the Transcriptional Program of IL-10-Producing Regulatory B Cells

Cell Reports ◽  
2019 ◽  
Vol 29 (7) ◽  
pp. 1878-1892.e7 ◽  
Author(s):  
Christopher J.M. Piper ◽  
Elizabeth C. Rosser ◽  
Kristine Oleinika ◽  
Kiran Nistala ◽  
Thomas Krausgruber ◽  
...  
Keyword(s):  
B Cells ◽  
Aryl Hydrocarbon Receptor ◽  
Regulatory B Cells ◽  
Transcriptional Program ◽  
Aryl Hydrocarbon

scholarly journals Regulatory B cells (Bregs) inhibit osteoclastogenesis and prevent bone loss in osteoporotic mice model

2021 ◽  
Author(s):  
Leena Sapra ◽  
Asha Bhardwaj ◽  
Pradyumna K. Mishra ◽  
Bhupendra K. Verma ◽  
Rupesh K. Srivastava
Keyword(s):  
B Cells ◽  
Bone Marrow Cells ◽  
Dependent Manner ◽  
Regulatory B Cells ◽  
Mice Model ◽  
Post Menopausal Osteoporosis ◽  
Post Menopausal ◽  
First Time

AbstractIncreasing evidences in recent years have suggested that regulatory B cells (Bregs) are crucial modulator in various inflammatory disease conditions. However, the role of Bregs in case of postmenopausal osteoporosis remains unknown. Also, no study till date have ever investigated the significance of Bregs in modulating osteoclastogenesis. In the present study, we for the first time examined the anti-osteoclastogenic potential of Bregs under in vitro conditions and we observed that Bregs suppressed RANKL mediated osteoclastogenesis in bone marrow cells in a dose dependent manner. We further elucidated the mechanism behind the suppression of osteoclasts differentiation by Bregs and found that Bregs inhibit osteoclastogenesis via IL-10 production. To further confirm the bone health modulating potential of Bregs we employed post-menopausal osteoporotic mice model. Remarkably, our in vivo data clearly suggest a significant reduction (p < 0.01) in both CD19+IL-10+ and CD19+CD1dhiCD5+IL-10+ B10 Bregs in case of osteoporotic mice model. Moreover, our serum cytokine data further confirms the significant reduction of IL-10 levels in osteoporotic mice. Taken together, the present study for the first time unravels and establish the unexplored role of regulatory B cells in case of osteoporosis and provide new insight into Bregs biology in the context of post-menopausal osteoporosis.

scholarly journals Lymphocyte-Specific Protein Tyrosine Kinase (LCK) is Involved in the Aryl Hydrocarbon Receptor-Mediated Impairment of Immunoglobulin Secretion in Human Primary B Cells

2018 ◽  
Vol 165 (2) ◽  
pp. 322-334
Author(s):  
Jiajun Zhou ◽  
Qiang Zhang ◽  
Joseph E Henriquez ◽  
Robert B Crawford ◽  
Norbert E Kaminski
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
Aryl Hydrocarbon Receptor ◽  
Protein Tyrosine Kinase ◽  
Specific Protein ◽  
Immunoglobulin M ◽  
Protein Tyrosine ◽  
Immunoglobulin Secretion ◽  
Aryl Hydrocarbon

AbstractThe aryl hydrocarbon receptor (AHR) is a cytosolic ligand-activated transcription factor involved in xenobiotic sensing, cell cycle regulation, and cell development. In humans, the activation of AHR by 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a high affinity AHR-ligand, impairs the secretion of immunoglobulin M (IgM) to suppress humoral immunity. However, the mechanisms bridging the activation of AHR and the impairment of IgM secretion by human primary B cells remain poorly understood. Recent transcriptomic analysis revealed upregulation of lymphocyte-specific protein tyrosine kinase (LCK) in AHR-activated human primary B cells. LCK is a well-characterized tyrosine kinase that phosphorylates critical signaling proteins involved in activation and cytokine production in T cells. Conversely, the role of LCK in human primary B cells is not well understood. In the current studies, we have verified the transcriptomic finding by detecting AHR-mediated upregulation of LCK protein in human primary B cells. We also confirmed the role of AHR in the upregulation of LCK by using a specific AHR antagonist, which abolished the AHR-mediated increase of LCK. Furthermore, we have confirmed the role of LCK in the AHR-mediated suppression of IgM by using LCK specific inhibitors, which restored the IgM secretion by human B cells in the presence of TCDD. Collectively, the current studies demonstrate a novel role of LCK in IgM response and provide new insights into the mechanism for AHR-mediated impairment of immunoglobulin secretion by human primary B cells.

scholarly journals Activated CD4+CD25+ T cells selectively kill B lymphocytes

Blood ◽  
2006 ◽  
Vol 107 (10) ◽  
pp. 3925-3932 ◽  
Author(s):  
Dong-Mei Zhao ◽  
Angela M. Thornton ◽  
Richard J. DiPaolo ◽  
Ethan M. Shevach
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Cell Death ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Fas Ligand ◽  
Cell Function ◽  
Cell Contact ◽  
Dependent Manner

The suppressive capacity of naturally occurring mouse CD4+CD25+ T cells on T-cell activation has been well documented. The present study is focused on the interaction of CD4+CD25+ T cells and B cells. By coculturing preactivated CD4+CD25+ T cells with B cells in the presence of polyclonal B-cell activators, we found that B-cell proliferation was significantly suppressed. The suppression of B-cell proliferation was due to increased cell death caused by the CD4+CD25+ T cells in a cell-contact–dependent manner. The induction of B-cell death is not mediated by Fas–Fas ligand pathway, but surprisingly, depends on the up-regulation of perforin and granzymes in the CD4+CD25+ T cells. Furthermore, activated CD4+CD25+ T cells preferentially killed antigen-presenting but not bystander B cells. Our results demonstrate that CD4+CD25+ T cells can act directly on B cells and suggest that the prevention of autoimmunity by CD4+CD25+ T cells can be explained, at least in part, by the direct regulation of B-cell function.

scholarly journals Galactomyces fermentation filtrate prevents T helper 2‐mediated reduction of filaggrin in an aryl hydrocarbon receptor‐dependent manner

2015 ◽  
Vol 40 (7) ◽  
pp. 786-793 ◽  
Author(s):  
K. Takei ◽  
C. Mitoma ◽  
A. Hashimoto‐Hachiya ◽  
M. Takahara ◽  
G. Tsuji ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Dependent Manner ◽  
T Helper ◽  
T Helper 2 ◽  
Aryl Hydrocarbon ◽  
Mediated Reduction

Up-regulation of osteopontin expression by aryl hydrocarbon receptor via both ligand-dependent and ligand-independent pathways in lung cancer

Gene ◽  
2012 ◽  
Vol 492 (1) ◽  
pp. 262-269 ◽  
Author(s):  
Cheng-Yen Chuang ◽  
Han Chang ◽  
Pinpin Lin ◽  
Shih-Jung Sun ◽  
Po-Hung Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Aryl Hydrocarbon Receptor ◽  
Osteopontin Expression ◽  
Aryl Hydrocarbon

scholarly journals The Role of the Aryl Hydrocarbon Receptor (AHR) in Immune and Inflammatory Diseases

2018 ◽  
Vol 19 (12) ◽  
pp. 3851 ◽  
Author(s):  
Drew Neavin ◽  
Duan Liu ◽  
Balmiki Ray ◽  
Richard Weinshilboum
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Nuclear Receptor ◽  
Binding Sites ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Dependent Manner ◽  
Nucleotide Polymorphisms ◽  
Aryl Hydrocarbon ◽  
Inflammatory Processes ◽  
Targeted Gene Expression

The aryl hydrocarbon receptor (AHR) is a nuclear receptor that modulates the response to environmental stimuli. It was recognized historically for its role in toxicology but, in recent decades, it has been increasingly recognized as an important modulator of disease—especially for its role in modulating immune and inflammatory responses. AHR has been implicated in many diseases that are driven by immune/inflammatory processes, including major depressive disorder, multiple sclerosis, rheumatoid arthritis, asthma, and allergic responses, among others. The mechanisms by which AHR has been suggested to impact immune/inflammatory diseases include targeted gene expression and altered immune differentiation. It has been suggested that single nucleotide polymorphisms (SNPs) that are near AHR-regulated genes may contribute to AHR-dependent disease mechanisms/pathways. Further, we have found that SNPs that are outside of nuclear receptor binding sites (i.e., outside of AHR response elements (AHREs)) may contribute to AHR-dependent gene regulation in a SNP- and ligand-dependent manner. This review will discuss the evidence and mechanisms of AHR contributions to immune/inflammatory diseases and will consider the possibility that SNPs that are outside of AHR binding sites might contribute to AHR ligand-dependent inter-individual variation in disease pathophysiology and response to pharmacotherapeutics.

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