Uremic toxin indoxyl 3-sulfate regulates the differentiation of Th2 but not of Th1 cells to lessen allergic asthma

Hwang, You-Jung; Yun, Mi-Ok; Jeong, Kyu-Tae; Park, Joo-Hung

doi:10.1016/j.toxlet.2013.11.027

Cited by 24 publications

(16 citation statements)

References 60 publications

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“…17,20 In addition, 3-IS was described to directly regulate T-cell differentiation by stimulating Th2 responses, which may also contribute to GVHD protection. 21 Second, the association of Lachnospiraceae with high 3-IS-levels is of major interest. This does not imply that the identified OTUs all produce and release indole; they may just grow better in the presence of indole and some of its derivatives, which have proved capable of slowing the growth of other bacteria such as gram-negative enteric bacilli.…”

Section: Discussionmentioning

confidence: 99%

Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome

Weber

Oefner

Hiergeist

et al. 2015

Blood

175

158

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Key Points• Urinary 3-IS levels predict outcome after ASCT and are associated with antibiotics and NOD2/CARD15 variants.Indole, which is produced from L-tryptophan by commensal bacteria expressing tryptophanase, not only is an important intercellular signal in microbial communities, but also modulates mucosal barrier function and expression of pro-and anti-inflammatory genes by intestinal epithelial cells. Here, we hypothesized that decreased urinary excretion of 3-indoxyl sulfate (3-IS), the major conjugate of indole found in humans, may be a marker of gut microbiota disruption and increased risk of developing gastrointestinal (GI) graftversus-host-disease. Using liquid chromatography/tandem mass spectrometry, 3-IS was determined in urine specimens collected weekly within the first 28 days after allogeneic stem cell transplantation (ASCT) in 131 patients. Low 3-IS levels within the first 10 days after ASCT were associated with significantly higher transplant-related mortality (P 5 .017) and worse overall survival (P 5 .05) 1 year after ASCT. Least absolute shrinkage and selection operator regression models trained on lognormalized counts of 763 operational taxonomic units derived from next-generation sequencing of the hypervariable V3 region of the 16S ribosomal RNA gene showed members of the families of Lachnospiraceae and Ruminococcaceae of the class of Clostridia to be associated with high urinary 3-IS levels, whereas members of the class of Bacilli were associated with low 3-IS levels. Risk factors of early suppression of 3-IS levels were the type of GI decontamination (P 5 .01), early onset of antibiotic treatment (P 5 .001), and recipient NOD2/ CARD15 genotype (P 5 .04). In conclusion, our findings underscore the relevance of microbiota-derived indole and metabolites thereof in mucosal integrity and protection from inflammation. (Blood. 2015;126(14):1723-1728) IntroductionAllogeneic stem cell transplantation (ASCT) constitutes a potential curative therapy for various hematologic malignancies, bone marrow failure, and immune deficiency syndromes. However, this treatment is still associated with a high risk of mortality because of infectious complications and acute graft-versus-host disease (GVHD). A significant part of these severe complications originates from the gastrointestinal (GI) tract. 1The introduction of 16S ribosomal RNA (rRNA) sequencing has provided novel insights into the diversity and complexity of the gut ecosystem.2 Loss of a diverse composition of the microbiome has been associated with a variety of diseases including inflammatory bowel and autoimmune diseases. At least in part this may be because of the increasingly recognized role that commensal bacteria play in maintaining immunologic homeostasis and epithelial integrity and in exerting anti-inflammatory effects and intestinal tolerance by inducing regulatory T cells. 3,4 Recent studies have demonstrated an association between intestinal bacterial diversity in both mouse models and humans and outcome of ASCT.5-7 A significantly higher ...

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Section: Discussionmentioning

confidence: 99%

Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome

Weber

Oefner

Hiergeist

et al. 2015

Blood

175

158

View full text Add to dashboard Cite

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“…In the study, activation of STAT1, but not of STAT3, was regulated by AhR activation ( 50 ). In other studies, indoxyl 3-sulfate and 6-formylindolo(3,2-b)carbazole (FICZ) inhibited the phosphorylation of STAT5 and STAT6 and of STAT6 during Th2 differentiation, respectively ( 51 52 ). In contrast, indoxyl 3-sulfate stimulated the phosphorylation of STAT3 during Th17 differentiation ( 42 ).…”

Section: Discussionmentioning

confidence: 96%

3,3'-Diindolylmethane Inhibits Flt3L/GM-CSF-induced-bone Marrow-derived CD103⁺Dendritic Cell Differentiation Regulating Phosphorylation of STAT3 and STAT5

et al. 2015

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The intestinal immune system maintains oral tolerance to harmless antigens or nutrients. One mechanism of oral tolerance is mediated by regulatory T cell (Treg)s, of which differentiation is regulated by a subset of dendritic cell (DC)s, primarily CD103+ DCs. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, plays an important role in regulating immunity. The intestines are exposed to various AhR ligands, including endogenous metabolites and phytochemicals. It was previously reported that AhR activation induced tolerogenic DCs in mice or in cultures of bone marrow-derived DCs. However, given the variety of tolerogenic DCs, which type of tolerogenic DCs is regulated by AhR remains unknown. In this study, we found that AhR ligand 3,3'-diindolylmethane (DIM) inhibited the development of CD103+ DCs from mouse bone marrow cells stimulated with Flt3L and GM-CSF. DIM interfered with phosphorylation of STAT3 and STAT5 inhibiting the expression of genes, including Id2, E2-2, IDO-1, and Aldh1a2, which are associated with DC differentiation and functions. Finally, DIM suppressed the ability of CD103+ DCs to induce Foxp3+ Tregs.

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“…In an oral tolerance model to ovalbumin, oral tolerance was determined by the level of serum antibodies to ovalbumin ( 43 ). In studies related to effects of AhR on CD4 T cell differentiation, activation of AhR by I3S promotes Th17 differentiation, while inhibiting Th2 differentiation and having little effect on Th1 differentiation, suggesting that AhR functions in a lineage-specific manner ( 52 53 ). AhR can bind and be activated or inhibited by a wide variety of structurally dissimilar compounds via its ligand binding domain (LBD) ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Ligands Indoxyl 3-sulfate and Indole-3-carbinol Inhibit FMS-like Tyrosine Kinase 3 Ligand-induced Bone Marrow-derived plasmacytoid Dendritic Cell Differentiation

Hwang

Kim

et al. 2018

Immune Netw

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Aryl hydrocarbon receptor (AhR) regulates both innate and adaptive immune responses by sensing a variety of small synthetic and natural chemicals, which act as its ligands. AhR, which is expressed in dendritic cells (DCs), regulates the differentiation of DCs. However, effects of AhR on the differentiation of DCs are variable due to the heterogeneity of DCs in cell surface marker expression, anatomical location, and functional responses. The plasmacytoid DCs (pDCs), one of DC subsets, not only induce innate as well as adaptive immune responses by secreting type I interferons and pro-inflammatory cytokines, but also induce IL-10 producing regulatory T cell or anergy or deletion of antigen-specific T cells. We showed here that AhR ligands indoxyl 3-sulfate (I3S) and indole-3-carbinol (I3C) inhibited the development of pDCs derived from bone marrow (BM) precursors induced by FMS-like tyrosine kinase 3 ligand (Flt3L). I3S and I3C downregulated the expression of signal transducer and activator of transcription 3 (STAT3) and E2-2 (Tcf4). In mice orally treated with I3S and I3C, oral tolerance to dinitrofluorobenzene was impaired and the proportion of CD11c+B220+ cells in mesenteric lymph nodes was reduced. These data demonstrate that AhR negatively regulates the development of pDCs from BM precursors induced by Flt3L, probably via repressing the expression of STAT3.

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Uremic toxin indoxyl 3-sulfate regulates the differentiation of Th2 but not of Th1 cells to lessen allergic asthma

Cited by 24 publications

References 60 publications

Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome

Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome

3,3'-Diindolylmethane Inhibits Flt3L/GM-CSF-induced-bone Marrow-derived CD103⁺Dendritic Cell Differentiation Regulating Phosphorylation of STAT3 and STAT5

Aryl Hydrocarbon Receptor Ligands Indoxyl 3-sulfate and Indole-3-carbinol Inhibit FMS-like Tyrosine Kinase 3 Ligand-induced Bone Marrow-derived plasmacytoid Dendritic Cell Differentiation

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Uremic toxin indoxyl 3-sulfate regulates the differentiation of Th2 but not of Th1 cells to lessen allergic asthma

Cited by 24 publications

References 60 publications

Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome

Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome

3,3'-Diindolylmethane Inhibits Flt3L/GM-CSF-induced-bone Marrow-derived CD103+Dendritic Cell Differentiation Regulating Phosphorylation of STAT3 and STAT5

Aryl Hydrocarbon Receptor Ligands Indoxyl 3-sulfate and Indole-3-carbinol Inhibit FMS-like Tyrosine Kinase 3 Ligand-induced Bone Marrow-derived plasmacytoid Dendritic Cell Differentiation

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3,3'-Diindolylmethane Inhibits Flt3L/GM-CSF-induced-bone Marrow-derived CD103⁺Dendritic Cell Differentiation Regulating Phosphorylation of STAT3 and STAT5