Butyrate Conditions Human Dendritic Cells to Prime Type 1 Regulatory T Cells via both Histone Deacetylase Inhibition and G Protein-Coupled Receptor 109A Signaling

Kaisar, Maria M. M.; Pelgrom, Leonard R.; Ham, Alwin J. van der; Yazdanbakhsh, Maria; Everts, Bart

doi:10.3389/fimmu.2017.01429

Cited by 140 publications

(145 citation statements)

References 51 publications

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“…7 Based on the transcriptional profile of butyrate-treated LPS + IFN-c-matured DCs, we here find that butyrate treatment of moDC does not lead to an immunosuppressive phenotype as strong as PCF treatment. 7 Based on the transcriptional profile of butyrate-treated LPS + IFN-c-matured DCs, we here find that butyrate treatment of moDC does not lead to an immunosuppressive phenotype as strong as PCF treatment.…”

Section: Discussionmentioning

confidence: 62%

“…7 Based on the transcriptional profile of butyrate-treated LPS + IFN-c-matured DCs, we here find that butyrate treatment of moDC does not lead to an immunosuppressive phenotype as strong as PCF treatment. 36 However, as the IL-23 subunit IL12B is strongly down-regulated by butyrate, and IL-23 is a cardinal cytokine for Th17 amplification, we conclude that butyratetreated pro-inflammatory moDCs will hold a non-Th17polarizing phenotype, as also supported by Kaisar et al, 7 while promoting an innate based Type 17 environment. Although we identified a strong down-regulation of the IL12B, making it difficult to form the Th17-amplifying cytokine IL-23, other components of a Th17-polarizing phenotype are in play, e.g.…”

Section: Discussionmentioning

confidence: 62%

“…However, it seems that they induce different Treg cell subsets, as butyrate treatment of DCs induces IL-10-producing Type 1 Treg cells, 7 whereas helminth PCF induces inducible CD4 + CD25 hi Foxp3 + Treg cells. However, it seems that they induce different Treg cell subsets, as butyrate treatment of DCs induces IL-10-producing Type 1 Treg cells, 7 whereas helminth PCF induces inducible CD4 + CD25 hi Foxp3 + Treg cells.…”

Section: Discussionmentioning

confidence: 99%

“…TSLP has been reported to influence DCs to promote Th2 responses, 4 and IL-33 seems to further strengthen TSLP-DC-mediated Th2 responses 5 as well as inducing Treg cell immune responses. 7,8 Due to the strong Th2/Treg responses induced by helminths, 9,10 deliberate infection with helminths has been extensively explored as a therapy for various inflammatory disorders. 7,8 Due to the strong Th2/Treg responses induced by helminths, 9,10 deliberate infection with helminths has been extensively explored as a therapy for various inflammatory disorders.…”

Section: Introductionmentioning

confidence: 99%

“…6 Additionally, succinate, an intermediate metabolite of the Krebs cycle, and butyrate, a fiber-derived gut bacterial metabolite, have both been reported to induce immune regulatory mechanisms in PAMP-exposed DCs. 7,8 Due to the strong Th2/Treg responses induced by helminths, 9,10 deliberate infection with helminths has been extensively explored as a therapy for various inflammatory disorders. 11 However, helminth infections per se may not be necessary to exploit helminth-mediated host protection because helminth-derived products themselves have proven effective in relieving pro-inflammatory conditions.…”

Section: Introductionmentioning

confidence: 99%

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Body fluid from the parasitic worm Ascaris suum inhibits broad‐acting pro‐inflammatory programs in dendritic cells

et al. 2019

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Dendritic cells (DCs) are essential for generating T-cell-based immune responses through sensing of potential inflammatory and metabolic cues in the local environment. However, there is still limited insight into the processes defining the resultant DC phenotype, including the type of early transcriptional changes in pro-inflammatory cues towards regulatory or type 2 immune-based cues induced by a variety of exogenous and endogenous molecules. Here we compared the ability of a selected number of molecules to modulate the pro-inflammatory phenotype of lipopolysaccharide (LPS) and interferon-c (IFN-c)-stimulated human monocytederived DCs towards an anti-inflammatory or regulatory phenotype, including Ascaris suum body fluid [helminth pseudocoelomic fluid (PCF)], the metabolites succinate and butyrate, and the type 2 cytokines thymic stromal lymphopoietin and interleukin-25. Our data show that helminth PCF and butyrate treatment suppress the T helper type 1 (Th1)inducing pro-inflammatory DC phenotype through induction of different transcriptional programs in DCs. RNA sequencing indicated that helminth PCF treatment strongly inhibited the Th1 and Th17 polarizing ability of LPS + IFN-c-matured DCs by down-regulating myeloid differentiation primary response gene 88 (MyD88)-dependent and MyD88-independent pathways in Toll-like receptor 4 signaling. By contrast, butyrate treatment had a strong Th1-inhibiting action, and transcripts encoding important gut barrier defending factors such as IL18, IL1B and CXCL8 were up-regulated. Collectively, our results further understanding of how compounds from parasites and gut microbiota-derived butyrate may exert immunomodulatory effects on the host immune system.

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“…7 Based on the transcriptional profile of butyrate-treated LPS + IFN-c-matured DCs, we here find that butyrate treatment of moDC does not lead to an immunosuppressive phenotype as strong as PCF treatment. 7 Based on the transcriptional profile of butyrate-treated LPS + IFN-c-matured DCs, we here find that butyrate treatment of moDC does not lead to an immunosuppressive phenotype as strong as PCF treatment.…”

Section: Discussionmentioning

confidence: 62%

“…7 Based on the transcriptional profile of butyrate-treated LPS + IFN-c-matured DCs, we here find that butyrate treatment of moDC does not lead to an immunosuppressive phenotype as strong as PCF treatment. 36 However, as the IL-23 subunit IL12B is strongly down-regulated by butyrate, and IL-23 is a cardinal cytokine for Th17 amplification, we conclude that butyratetreated pro-inflammatory moDCs will hold a non-Th17polarizing phenotype, as also supported by Kaisar et al, 7 while promoting an innate based Type 17 environment. Although we identified a strong down-regulation of the IL12B, making it difficult to form the Th17-amplifying cytokine IL-23, other components of a Th17-polarizing phenotype are in play, e.g.…”

Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Body fluid from the parasitic worm Ascaris suum inhibits broad‐acting pro‐inflammatory programs in dendritic cells

et al. 2019

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A murine model of tuberculosis/type 2 diabetes comorbidity for investigating the microbiome, metabolome and associated immune parameters

Sathkumara

Eaton

Field

et al. 2021

Anim Models and Exp Med

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Tuberculosis (TB) is one of the deadliest infectious diseases in the world. The metabolic disease type 2 diabetes (T2D) significantly increases the risk of developing active TB. Effective new TB vaccine candidates and novel therapeutic interventions are required to meet the challenges of global TB eradication. Recent evidence suggests that the microbiota plays a significant role in how the host responds to infection, injury and neoplastic changes. Animal models that closely reflect human physiology are crucial in assessing new treatments and to decipher the underlying immunological defects responsible for increased TB susceptibility in comorbid patients. In this study, using a diet‐induced murine T2D model that reflects the etiopathogenesis of clinical T2D and increased TB susceptibility, we investigated how the intestinal microbiota may impact the development of T2D, and how the gut microbial composition changes following a very low‐dose aerosol infection with Mycobacterium tuberculosis (Mtb). Our data revealed a substantial intestinal microbiota dysbiosis in T2D mice compared to non‐diabetic animals. The observed differences were comparable to previous clinical reports in TB patients, in which it was shown that Mtb infection causes rapid loss of microbial diversity. Furthermore, diversity index and principle component analyses demonstrated distinct clustering of Mtb‐infected non‐diabetic mice vs. Mtb‐infected T2D mice. Our findings support a broad applicability of T2D mice as a tractable small animal model for studying distinct immune parameters, microbiota and the immune‐metabolome of TB/T2D comorbidity. This model may also enable answers to be found to critical outstanding questions about targeted interventions of the gut microbiota and the gut‐lung axis.

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Human milk oligosaccharides promote immune tolerance via direct interactions with human dendritic cells

et al. 2019

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Human milk oligosaccharides (HMOS) are a complex mixture of bioactive components supporting the immune development of breastfed‐infants. Dendritic cells (DCs) play a central role in the regulation of immune responses, being specialized in antigen presentation and driving T‐cell priming as well as differentiation. However, little is known about the direct effects of HMOS on human DC phenotypes and functions. Here, we report that HMOS mixture isolated from pooled human milk, induced semi‐maturation of human monocytes‐derived DCs (moDCs), and elevated levels of IL‐10, IL‐27 and IL‐6 but not IL‐12p70 and TNF‐α. Consistently, HMOS‐conditioned human moDCs promoted Treg generation from naïve CD4+ T cells. Interestingly, HMOS limited LPS‐induced maturation of human moDCs, while maintained IL‐10 and IL‐27 secretion and reduced LPS‐induced production of IL‐12p70, IL‐6 and TNF‐α. Furthermore, HMOS+LPS‐stimulated DCs induced a higher frequency of Tregs and increased IL‐10 production, while a reduction in Tbet+Th1 frequency and IFN‐γ production was detected as compared to LPS‐DCs. The regulatory effects of HMOS seemed to be mediated by interactions of HMOS with receptors, including but not limited to TLR4 and DC‐SIGN on human moDCs. In conclusion, HMOS contain tolerogenic factors influencing human moDCs and thereby modulating the development of the neonatal immune system.

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Butyrate Conditions Human Dendritic Cells to Prime Type 1 Regulatory T Cells via both Histone Deacetylase Inhibition and G Protein-Coupled Receptor 109A Signaling

Cited by 140 publications

References 51 publications

Body fluid from the parasitic worm Ascaris suum inhibits broad‐acting pro‐inflammatory programs in dendritic cells

Body fluid from the parasitic worm Ascaris suum inhibits broad‐acting pro‐inflammatory programs in dendritic cells

A murine model of tuberculosis/type 2 diabetes comorbidity for investigating the microbiome, metabolome and associated immune parameters

Human milk oligosaccharides promote immune tolerance via direct interactions with human dendritic cells

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