scholarly journals Butyrate increases IL-23 production by stimulated dendritic cells

2012 ◽  
Vol 303 (12) ◽  
pp. G1384-G1392 ◽  
Author(s):  
Bradford E. Berndt ◽  
Min Zhang ◽  
Stephanie Y. Owyang ◽  
Tyler S. Cole ◽  
Teresa W. Wang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Epigenetic Modification ◽  
Experimental Colitis ◽  
Short Chain Fatty Acids ◽  
Dss Colitis ◽  
Deacetylase Inhibitor ◽  
Mucosal Homeostasis ◽  
Dc Maturation

The gut microbiota is essential for the maintenance of intestinal immune homeostasis and is responsible for breaking down dietary fiber into short-chain fatty acids (SCFAs). Butyrate, the most abundant bioactive SCFA in the gut, is a histone deacetylase inhibitor (HDACi), a class of drug that has potent immunomodulatory properties. This characteristic of butyrate, along with our previous discovery that conventional dendritic cells (DCs) are required for the development of experimental colitis, led us to speculate that butyrate may modulate DC function to regulate gut mucosal homeostasis. We found that butyrate, in addition to suppressing LPS-induced bone marrow-derived DC maturation and inhibiting DC IL-12 production, significantly induced IL-23 expression. The upregulation of mRNA subunit IL-23p19 at the pretranslational level was consistent with the role of HDACi on the epigenetic modification of gene expression. Furthermore, the mechanism of IL-23p19 upregulation was independent of Stat3 and ZBP89. Coculture of splenocytes with LPS-stimulated DCs pretreated with or without butyrate was performed and showed a significant induction of IL-17 and IL-10. We demonstrated further the effect of butyrate in vivo using dextran sulfate sodium (DSS)-induced colitis and found that the addition of butyrate in the drinking water of mice worsened DSS-colitis. This is in contrast to the daily intraperitoneal butyrate injection of DSS-treated mice, which mildly improved disease severity. Our study highlights a novel effect of butyrate in upregulating IL-23 production of activated DCs and demonstrates a difference in the host response to the oral vs. systemic route of butyrate administration.

scholarly journals Oxytocin signalling in dendritic cells regulates immune tolerance in the intestine and alleviates DSS-induced colitis

2021 ◽  
Vol 135 (4) ◽  
pp. 597-611
Author(s):  
Dandan Dou ◽  
Jinghui Liang ◽  
Xiangyu Zhai ◽  
Guosheng Li ◽  
Hongjuan Wang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Ex Vivo ◽  
Experimental Colitis ◽  
Akt Pathway ◽  
T Helper 1 ◽  
Colon Tissue ◽  
Cytokine Modulation ◽  
Inflammatory Bowel ◽  
Dc Maturation

Abstract Background: Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) that is associated with immune dysfunction. Recent studies have indicated that the neurosecretory hormone oxytocin (OXT) has been proven to alleviate experimental colitis. Methods: We investigated the role of OXT/OXT receptor (OXTR) signalling in dendritic cells (DCs) using mice with specific OXTR deletion in CD11c+ cells (OXTRflox/flox×CD11c-cre mice) and a dextran sulfate sodium (DSS)-induced colitis model. Results: The level of OXT was abnormal in the serum or colon tissue of DSS-induced colitis mice or the plasma of UC patients. Both bone marrow-derived DCs (BMDCs) and lamina propria DCs (LPDCs) express OXTR. Knocking out OXTR in DCs exacerbated DSS-induced acute and chronic colitis in mice. In contrast, the injection of OXT-pretreated DCs significantly ameliorated colitis. Mechanistically, OXT prevented DC maturation through the phosphatidylinositol 4,5-bisphosphate 3-kinase (Pi3K)/AKT pathway and promoted phagocytosis, adhesion and cytokine modulation in DCs. Furthermore, OXT pre-treated DCs prevent CD4+ T cells differentiation to T helper 1 (Th1) and Th17. Conclusions: Our results suggest that OXT-induced tolerogenic DCs efficiently protect against experimental colitis via Pi3K/AKT pathway. Our work provides evidence that the nervous system participates in the immune regulation of colitis by modulating DCs. Our findings suggest that generating ex vivo DCs pretreated with OXT opens new therapeutic perspectives for the treatment of UC in humans.

scholarly journals Gut Microbiota-Derived Propionate Regulates the Expression of Reg3 Mucosal Lectins and Ameliorates Experimental Colitis in Mice

2020 ◽  
Vol 14 (10) ◽  
pp. 1462-1472 ◽  
Author(s):  
Danica Bajic ◽  
Adrian Niemann ◽  
Anna-Katharina Hillmer ◽  
Raquel Mejias-Luque ◽  
Sena Bluemel ◽  
...  
Keyword(s):  
Protective Factor ◽  
Experimental Colitis ◽  
Short Chain Fatty Acids ◽  
Stem Cell Marker ◽  
Knock Out ◽  
Interleukin 22 ◽  
Epithelial Regeneration ◽  
Dss Colitis ◽  
Colitis Model

Abstract Background and Aims Regenerating islet-derived protein type 3 [Reg3] lectins are antimicrobial peptides at mucosal surfaces of the gut, whose expression is regulated by pathogenic gut microbes via interleukin-22- or Toll-like receptor signalling. In addition to antimicrobial effects, tissue protection is hypothesized, but has been poorly investigated in the gut. Methods We applied antibiotic-induced microbiota perturbations, gnotobiotic approaches and a dextran-sodium sulfate [DSS] colitis model to assess microbial Reg3 regulation in the intestines and its role in colitis. We also used an intestinal organoid model to investigate this axis in vitro. Results First, we studied whether gut commensals are involved in Reg3 expression in mice, and found that antibiotic-mediated reduction of Clostridia downregulated intestinal Reg3B. A loss in Clostridia was accompanied by a significant reduction of short-chain fatty acids [SCFAs], and knock-out [KO] mice for SCFA receptors GPR43 and GPR109 expressed less intestinal Reg3B/-G. Propionate was found to induce Reg3 in intestinal organoids and in gnotobiotic mice colonized with a defined, SCFA-producing microbiota. Investigating the role of Reg3B as a protective factor in colitis, we found that Reg3B-KO mice display increased inflammation and less crypt proliferation in the DSS colitis model. Propionate decreased colitis and increased proliferation. Treatment of organoids exposed to DSS with Reg3B or propionate reversed the chemical injury with a loss of expression of the stem-cell marker Lgr5 and Olfm4. Conclusions Our results suggest that Clostridia can regulate Reg3-associated epithelial homeostasis through propionate signalling. We also provide evidence that the Reg3–propionate axis may be an important mediator of gut epithelial regeneration in colitis.

Role of Dendritic Cells in Induction of Tolerance and Immunity in Vivo

1997 ◽  
pp. 255-263 ◽  
Author(s):  
Barbara Fazekas de St. Groth ◽  
Matthew C. Cook ◽  
Adrian L. Smith ◽  
Matthew E. Wikstrom ◽  
Antony Basten
Keyword(s):  
Dendritic Cells ◽  
Induction Of Tolerance

scholarly journals In Vivo Role of Dendritic Cells in a Murine Model of Pulmonary Cryptococcosis

2006 ◽  
Vol 74 (7) ◽  
pp. 3817-3824 ◽  
Author(s):  
Karen L. Wozniak ◽  
Jatin M. Vyas ◽  
Stuart M. Levitz
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Mouse Lung

ABSTRACT Dendritic cells (DC) have been shown to phagocytose and kill Cryptococcus neoformans in vitro and are believed to be important for inducing protective immunity against this organism. Exposure to C. neoformans occurs mainly by inhalation, and in this study we examined the in vivo interactions of C. neoformans with DC in the lung. Fluorescently labeled live C. neoformans and heat-killed C. neoformans were administered intranasally to C57BL/6 mice. At specific times postinoculation, mice were sacrificed, and lungs were removed. Single-cell suspensions of lung cells were prepared, stained, and analyzed by microscopy and flow cytometry. Within 2 h postinoculation, fluorescently labeled C. neoformans had been internalized by DC, macrophages, and neutrophils in the mouse lung. Additionally, lung DC from mice infected for 7 days showed increased expression of the maturation markers CD80, CD86, and major histocompatibility complex class II. Finally, ex vivo incubation of lung DC from infected mice with Cryptococcus-specific T cells resulted in increased interleukin-2 production compared to the production by DC from naïve mice, suggesting that there was antigen-specific T-cell activation. This study demonstrated that DC in the lung are capable of phagocytosing Cryptococcus in vivo and presenting antigen to C. neoformans-specific T cells ex vivo, suggesting that these cells have roles in innate and adaptive pulmonary defenses against cryptococcosis.

scholarly journals Dendritic cells mediate the induction of polyfunctional human IL17-producing cells (Th17-1 cells) enriched in the bone marrow of patients with myeloma

Blood ◽  
2008 ◽  
Vol 112 (7) ◽  
pp. 2878-2885 ◽  
Author(s):  
Kavita M. Dhodapkar ◽  
Scott Barbuto ◽  
Phillip Matthews ◽  
Anjli Kukreja ◽  
Amitabha Mazumder ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Th17 Cells ◽  
T Helper ◽  
Tumor Bed ◽  
Distinct Lineage ◽  
Human Dendritic Cells ◽  
Antigen Presenting ◽  
Dc Maturation

Abstract IL17-producing (Th17) cells are a distinct lineage of T helper cells that regulate immunity and inflammation. The role of antigen-presenting cells in the induction of Th17 cells in humans remains to be fully defined. Here, we show that human dendritic cells (DCs) are efficient inducers of Th17 cells in culture, including antigen-specific Th17 cells. Although most freshly isolated circulating human Th17 cells secrete IL17 alone or with IL2, those induced by DCs are polyfunctional and coexpress IL17 and IFNγ (Th17-1 cells). The capacity of DCs to expand Th17-1 cells is enhanced upon DC maturation, and mature DCs are superior to monocytes for the expansion of autologous Th17 cells. In myeloma, where tumors are infiltrated by DCs, Th17 cells are enriched in the bone marrow relative to circulation. Bone marrow from patients with myeloma contains a higher proportion of Th17-1 cells compared with the marrow in preneoplastic gammopathy (monoclonal gammopathy of undetermined significance [MGUS]). Uptake of apoptotic but not necrotic myeloma tumor cells by DCs leads to enhanced induction of Th17-1 cells. These data demonstrate the capacity of DCs to induce expansion of polyfunctional IL17-producing T cells in humans, and suggest a role for DCs in the enrichment of Th17-1 cells in the tumor bed.

scholarly journals P075 Muc5ac expression protects the colonic barrier in experimental colitis

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S173-S173
Author(s):  
L O’Connell ◽  
K Olli ◽  
C Rapp ◽  
C Collins ◽  
E McNamee ◽  
...  
Keyword(s):  
Antibiotic Treatment ◽  
Functional Role ◽  
Intestinal Barrier ◽  
Experimental Colitis ◽  
Intestinal Helminth ◽  
Mesenteric Lymph Nodes ◽  
Murine Colitis ◽  
Dss Colitis ◽  
Mucus Gel

Abstract Background The mucus gel layer (MGL) lining the colon is integral to exclusion of bacteria and maintaining intestinal homeostasis in health and disease. MGL defects allowing bacteria to directly contact the colonic surface are commonly observed in ulcerative colitis (UC). The major macromolecular component of the colonic MGL is the secreted gel-forming mucin, MUC2, whose expression is essential for homeostasis in health. In UC, another gel-forming mucin, MUC5AC is induced. In mice, Muc5ac is protective during intestinal helminth infection. Here, we tested the expression and functional role of MUC5AC/Muc5ac in colitis patient biopsies and murine colitis. Methods We measured MUC5AC/Muc5ac expression in UC patient biopsies and during acute dextran sulphate sodium (DSS) colitis. We performed DSS-colitis in mice deficient in Muc5ac (Muc5ac−/−) to model the potential functional role of Muc5ac in colitis. To assess MGL integrity, we quantified bacterial–epithelial interaction and translocation to mesenteric lymph nodes (MLNs). Antibiotic treatment was performed to directly investigate the role of colonic bacteria in our murine colitis studies. Results Colonic MUC5AC/Muc5ac mRNA expression increased significantly in active UC and murine colitis. Muc5ac−/− mice experienced worsened injury and inflammation in DSS-colitis compared with controls. This was associated with increased bacterial–epithelial contact and translocation to the MLN. Antibiotic treatment normalised colitis severity in Muc5ac−/− mice to that of antibiotic treated controls. Conclusion We demonstrate for the first time that MUC5AC/Muc5ac induction in acute colitis controls injury by reducing bacterial breach of the MGL. Therefore, developing strategies to induce MUC5AC expression may protect the intestinal barrier in UC.

scholarly journals The gut microbial metabolite trimethylamine N-oxide aggravates GVHD by inducing M1 macrophage polarization in mice

Blood ◽  
2020 ◽  
Vol 136 (4) ◽  
pp. 501-515 ◽  
Author(s):  
Kunpeng Wu ◽  
Yan Yuan ◽  
Huihui Yu ◽  
Xin Dai ◽  
Shu Wang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Macrophage Polarization ◽  
Short Chain Fatty Acids ◽  
Inflammasome Activation ◽  
Microbial Metabolites ◽  
M1 Macrophage ◽  
The Impact

Abstract The diversity of the human microbiome heralds the difference of the impact that gut microbial metabolites exert on allogenic graft-versus-host (GVH) disease (GVHD), even though short-chain fatty acids and indole were demonstrated to reduce its severity. In this study, we dissected the role of choline-metabolized trimethylamine N-oxide (TMAO) in the GVHD process. Either TMAO or a high-choline diet enhanced the allogenic GVH reaction, whereas the analog of choline, 3,3-dimethyl-1-butanol reversed TMAO-induced GVHD severity. Interestingly, TMAO-induced alloreactive T-cell proliferation and differentiation into T-helper (Th) subtypes was seen in GVHD mice but not in in vitro cultures. We thus investigated the role of macrophage polarization, which was absent from the in vitro culture system. F4/80+CD11b+CD16/32+ M1 macrophage and signature genes, IL-1β, IL-6, TNF-α, CXCL9, and CXCL10, were increased in TMAO-induced GVHD tissues and in TMAO-cultured bone marrow–derived macrophages (BMDMs). Inhibition of the NLRP3 inflammasome reversed TMAO-stimulated M1 features, indicating that NLRP3 is the key proteolytic activator involved in the macrophage’s response to TMAO stimulation. Consistently, mitochondrial reactive oxygen species and enhanced NF-κB nuclear relocalization were investigated in TMAO-stimulated BMDMs. In vivo depletion of NLRP3 in GVHD recipients not only blocked M1 polarization but also reversed GVHD severity in the presence of TMAO treatment. In conclusion, our data revealed that TMAO-induced GVHD progression resulted from Th1 and Th17 differentiation, which is mediated by the polarized M1 macrophage requiring NLRP3 inflammasome activation. It provides the link among the host choline diet, microbial metabolites, and GVH reaction, shedding light on alleviating GVHD by controlling choline intake.

scholarly journals Glyceraldehyde-3-phosphate dehydrogenase from Eimeria acervulina modulates the functions of chicken dendritic cells to boost Th1 type immune response and stimulates autologous CD4+ T cells differentiation in-vitro

2020 ◽  
Vol 51 (1) ◽  
Author(s):  
Shakeel Ahmed Lakho ◽  
Muhammad Haseeb ◽  
Jianmei Huang ◽  
Zhang Yang ◽  
Muhammad Waqqas Hasan ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immunoblot Analysis ◽  
Eimeria Acervulina ◽  
Ifn Γ ◽  
Negative Controls ◽  
Th1 Polarization ◽  
Dc Maturation

AbstractDendritic cells (DCs) play a pivotal role to amplify antigen-specific immune responses. Antigens that sensitize T cells via antigen-presentation by DCs could enhance the capacity of host immunity to fight infections. In this study, we tested the immunogenic profiles of chicken DCs towards Glyceraldehyde-3-phosphate dehydrogenase from Eimeria acervulina (EaGAPDH). Immunoblot analysis showed that recombinant EaGAPDH (rEaGAPDH) protein was successfully recognized by rat sera generated against rEaGAPDH. Interaction and internalisation of rEaGAPDH by chicken splenic-derived DCs (chSPDCs) was confirmed by immunofluorescence analysis. Flow cytometry revealed that chSPDCs upregulated MHCII, CD1.1, CD11c, CD80, and CD86 cell-surface markers. Moreover, mRNA expressions of DC maturation biomarkers (CCL5, CCR7, and CD83) and TLR signalling genes (TLR15 and MyD88) were also upregulated whereas those of Wnt signalling were non-significant compared to negative controls. rEaGAPDH treatment induced IL-12 and IFN-γ secretion in chSPDCs but had no effect on IL-10 and TGF-β. Likewise, DC-T cell co-culture promoted IFN-γ secretion and the level of IL-4 was unaffected. Proliferation of T cells and their differentiation into CD3+/CD4+ T cells were triggered in chSPDCs-T cells co-culture system. Taken together, rEaGAPDH could promote Th1 polarization by activating both host DCs and T cells and sheds new light on the role of this important molecule which might contribute to the development of new DCs-based immunotherapeutic strategies against coccidiosis.

Maturation of dendritic cells leads to up-regulation of cellular FLICE-inhibitory protein and concomitant down-regulation of death ligand–mediated apoptosis

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2628-2631 ◽  
Author(s):  
Martin Leverkus ◽  
Henning Walczak ◽  
Alex McLellan ◽  
Hans-Werner Fries ◽  
Gabi Terbeck ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Tumor Necrosis ◽  
Caspase 8 ◽  
Inhibitory Protein ◽  
Cd95 Ligand ◽  
Induction Of Apoptosis ◽  
Low Levels ◽  
Necrosis Factor ◽  
Dc Maturation

Dendritic cells (DCs) disappear from lymph nodes 1 to 2 days after antigen presentation, presumably by apoptosis. To evaluate the role of death ligands in elimination of DCs, we analyzed the sensitivity of human DCs to CD95 ligand (CD95L) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We found mature DCs to be resistant to killing via CD95L or TRAIL, whereas only immature DCs were partially sensitive. However, all DC populations expressed CD95, TRAIL-R2, and TRAIL-R3 at comparable levels, suggesting that sensitivity to death ligand-induced DC apoptosis is not regulated at the receptor level. Interestingly, mature DCs highly expressed the caspase 8 inhibitory protein cFLIP, whereas only low levels were detected in immature DCs. Thus, death ligand sensitivity proved to be dependent on DC maturation and inversely correlated with expression levels of cFLIP. Induction of apoptosis by TRAIL or CD95L does not seem to play a role in the elimination of mature DCs, but instead might serve to regulate immature DC populations.

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