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Chen Y, Wang Y, Fu Y, Yin Y, Xu K. Modulating AHR function offers exciting therapeutic potential in gut immunity and inflammation. Cell Biosci 2023; 13:85. [PMID: 37179416 PMCID: PMC10182712 DOI: 10.1186/s13578-023-01046-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 05/04/2023] [Indexed: 05/15/2023] Open
Abstract
Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a classical exogenous synthetic ligand of AHR that has significant immunotoxic effects. Activation of AHR has beneficial effects on intestinal immune responses, but inactivation or overactivation of AHR can lead to intestinal immune dysregulation and even intestinal diseases. Sustained potent activation of AHR by TCDD results in impairment of the intestinal epithelial barrier. However, currently, AHR research has been more focused on elucidating physiologic AHR function than on dioxin toxicity. The appropriate level of AHR activation plays a role in maintaining gut health and protecting against intestinal inflammation. Therefore, AHR offers a crucial target to modulate intestinal immunity and inflammation. Herein, we summarize our current understanding of the relationship between AHR and intestinal immunity, the ways in which AHR affects intestinal immunity and inflammation, the effects of AHR activity on intestinal immunity and inflammation, and the effect of dietary habits on intestinal health through AHR. Finally, we discuss the therapeutic role of AHR in maintaining gut homeostasis and relieving inflammation.
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Affiliation(s)
- Yue Chen
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, 450000, China
| | - Yadong Wang
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
| | - Yawei Fu
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, 450000, China
| | - Yulong Yin
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, 450000, China
| | - Kang Xu
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China.
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Salminen A. Aryl hydrocarbon receptor (AhR) impairs circadian regulation: impact on the aging process. Ageing Res Rev 2023; 87:101928. [PMID: 37031728 DOI: 10.1016/j.arr.2023.101928] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/23/2023] [Accepted: 04/06/2023] [Indexed: 04/11/2023]
Abstract
Circadian clocks control the internal sleep-wake rhythmicity of 24hours which is synchronized by the solar cycle. Circadian regulation of metabolism evolved about 2.5 billion years ago, i.e., the rhythmicity has been conserved from cyanobacteria and Archaea through to mammals although the mechanisms utilized have developed with evolution. While the aryl hydrocarbon receptor (AhR) is an evolutionarily conserved defence mechanism against environmental threats, it has gained many novel functions during evolution, such as the regulation of cell cycle, proteostasis, and many immune functions. There is robust evidence that AhR signaling impairs circadian rhythmicity, e.g., by interacting with the core BMAL1/CLOCK complex and disturbing the epigenetic regulation of clock genes. The maintenance of circadian rhythms is impaired with aging, disturbing metabolism and many important functions in aged organisms. Interestingly, it is known that AhR signaling promotes an age-related tissue degeneration, e.g., it is able to inhibit autophagy, enhance cellular senescence, and disrupt extracellular matrix. These alterations are rather similar to those induced by a long-term impairment of circadian rhythms. However, it is not known whether AhR signaling enhances the aging process by impairing circadian homeostasis. I will examine the experimental evidence indicating that AhR signaling is able to promote the age-related degeneration via a disruption of circadian rhythmicity.
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Affiliation(s)
- Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
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Rose JR, Akdogan-Ozdilek B, Rahmberg AR, Powell MD, Hicks SL, Scharer CD, Boss JM. Distinct transcriptomic and epigenomic modalities underpin human memory T cell subsets and their activation potential. Commun Biol 2023; 6:363. [PMID: 37012418 PMCID: PMC10070634 DOI: 10.1038/s42003-023-04747-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 03/22/2023] [Indexed: 04/05/2023] Open
Abstract
Human memory T cells (MTC) are poised to rapidly respond to antigen re-exposure. Here, we derived the transcriptional and epigenetic programs of resting and ex vivo activated, circulating CD4+ and CD8+ MTC subsets. A progressive gradient of gene expression from naïve to TCM to TEM is observed, which is accompanied by corresponding changes in chromatin accessibility. Transcriptional changes suggest adaptations of metabolism that are reflected in altered metabolic capacity. Other differences involve regulatory modalities comprised of discrete accessible chromatin patterns, transcription factor binding motif enrichment, and evidence of epigenetic priming. Basic-helix-loop-helix factor motifs for AHR and HIF1A distinguish subsets and predict transcription networks to sense environmental changes. Following stimulation, primed accessible chromatin correlate with an augmentation of MTC gene expression as well as effector transcription factor gene expression. These results identify coordinated epigenetic remodeling, metabolic, and transcriptional changes that enable MTC subsets to ultimately respond to antigen re-encounters more efficiently.
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Affiliation(s)
- James R Rose
- Department of Microbiology and Immunology, and the Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Bagdeser Akdogan-Ozdilek
- Department of Microbiology and Immunology, and the Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Andrew R Rahmberg
- Barrier Immunity Section, Laboratory of Viral Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - Michael D Powell
- Department of Microbiology and Immunology, and the Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Sakeenah L Hicks
- Department of Microbiology and Immunology, and the Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Christopher D Scharer
- Department of Microbiology and Immunology, and the Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Jeremy M Boss
- Department of Microbiology and Immunology, and the Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, 30322, USA.
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Salminen A. Aryl hydrocarbon receptor (AhR) reveals evidence of antagonistic pleiotropy in the regulation of the aging process. Cell Mol Life Sci 2022; 79:489. [PMID: 35987825 PMCID: PMC9392714 DOI: 10.1007/s00018-022-04520-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 07/14/2022] [Accepted: 08/08/2022] [Indexed: 11/24/2022]
Abstract
The antagonistic pleiotropy hypothesis is a well-known evolutionary theory to explain the aging process. It proposes that while a particular gene may possess beneficial effects during development, it can exert deleterious properties in the aging process. The aryl hydrocarbon receptor (AhR) has a significant role during embryogenesis, but later in life, it promotes several age-related degenerative processes. For instance, AhR factor (i) controls the pluripotency of stem cells and the stemness of cancer stem cells, (ii) it enhances the differentiation of embryonal stem cells, especially AhR signaling modulates the differentiation of hematopoietic stem cells and progenitor cells, (iii) it also stimulates the differentiation of immunosuppressive Tregs, Bregs, and M2 macrophages, and finally, (iv) AhR signaling participates in the differentiation of many peripheral tissues. On the other hand, AhR signaling is involved in many processes promoting cellular senescence and pathological processes, e.g., osteoporosis, vascular dysfunction, and the age-related remodeling of the immune system. Moreover, it inhibits autophagy and aggravates extracellular matrix degeneration. AhR signaling also stimulates oxidative stress, promotes excessive sphingolipid synthesis, and disturbs energy metabolism by catabolizing NAD+ degradation. The antagonistic pleiotropy of AhR signaling is based on the complex and diverse connections with major signaling pathways in a context-dependent manner. The major regulatory steps include, (i) a specific ligand-dependent activation, (ii) modulation of both genetic and non-genetic responses, (iii) a competition and crosstalk with several transcription factors, such as ARNT, HIF-1α, E2F1, and NF-κB, and (iv) the epigenetic regulation of target genes with binding partners. Thus, not only mTOR signaling but also the AhR factor demonstrates antagonistic pleiotropy in the regulation of the aging process.
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Affiliation(s)
- Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland.
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Salminen A. Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions. J Mol Med (Berl) 2021; 99:1553-1569. [PMID: 34432073 PMCID: PMC8384586 DOI: 10.1007/s00109-021-02123-w] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 07/21/2021] [Accepted: 07/30/2021] [Indexed: 01/10/2023]
Abstract
The functional competence of the immune system gradually declines with aging, a process called immunosenescence. The age-related remodelling of the immune system affects both adaptive and innate immunity. In particular, a chronic low-grade inflammation, termed inflammaging, is associated with the aging process. Immunosenescence not only is present in inflammaging state, but it also occurs in several pathological conditions in conjunction with chronic inflammation. It is known that persistent inflammation stimulates a counteracting compensatory immunosuppression intended to protect host tissues. Inflammatory mediators enhance myelopoiesis and induce the generation of immature myeloid-derived suppressor cells (MDSC) which in mutual cooperation stimulates the immunosuppressive network. Immunosuppressive cells, especially MDSCs, regulatory T cells (Treg), and M2 macrophages produce immunosuppressive factors, e.g., TGF-β, IL-10, ROS, arginase-1 (ARG1), and indoleamine 2,3-dioxygenase (IDO), which suppress the functions of CD4/CD8T and B cells as well as macrophages, natural killer (NK) cells, and dendritic cells. The immunosuppressive armament (i) inhibits the development and proliferation of immune cells, (ii) decreases the cytotoxic activity of CD8T and NK cells, (iii) prevents antigen presentation and antibody production, and (iv) suppresses responsiveness to inflammatory mediators. These phenotypes are the hallmarks of immunosenescence. Immunosuppressive factors are able to control the chromatin landscape, and thus, it seems that the immunosenescence state is epigenetically regulated.
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Affiliation(s)
- Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland.
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Zablocki-Thomas L, Menzies SA, Lehner PJ, Manel N, Benaroch P. A genome-wide CRISPR screen identifies regulation factors of the TLR3 signalling pathway. Innate Immun 2020; 26:459-472. [PMID: 32248720 PMCID: PMC7491238 DOI: 10.1177/1753425920915507] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
A subset of TLRs is specialised in the detection of incoming pathogens by sampling endosomes for nucleic acid contents. Among them, TLR3 senses the abnormal presence of double-stranded RNA in the endosomes and initiates a potent innate immune response via activation of NF-κB and IRF3. Nevertheless, mechanisms governing TLR3 regulation remain poorly defined. To identify new molecular players involved in the TLR3 pathway, we performed a genome-wide screen using CRISPR/Cas9 technology. We generated TLR3+ reporter cells carrying a NF-κB-responsive promoter that controls GFP expression. Cells were next transduced with a single-guide RNA (sgRNA) library, subjected to sequential rounds of stimulation with poly(I:C) and sorting of the GFP-negative cells. Enrichments in sgRNA estimated by deep sequencing identified genes required for TLR3-induced activation of NF-κB. Among the hits, five genes known to be critically involved in the TLR3 pathway, including TLR3 itself and the chaperone UNC93B1, were identified by the screen, thus validating our strategy. We further studied the top 40 hits and focused on the transcription factor aryl hydrocarbon receptor (AhR). Depletion of AhR had a dual effect on the TLR3 response, abrogating IL-8 production and enhancing IP-10 release. Moreover, in primary human macrophages exposed to poly(I:C), AhR activation enhanced IL-8 and diminished IP-10 release. Overall, these results reveal AhR plays a role in the TLR3 cellular innate immune response.
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Affiliation(s)
| | - Sam A Menzies
- Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, UK
| | - Paul J Lehner
- Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, UK
| | - Nicolas Manel
- Institut Curie, PSL Research University, INSERM U932, France
| | - Philippe Benaroch
- Institut Curie, PSL Research University, INSERM U932, France,Philippe Benaroch, Institut Curie, PSL Research University, INSERM U932, France. Nicolas Manel, Institut Curie, PSL Research University, INSERM U932, France.
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Wang XS, Cao F, Zhang Y, Pan HF. Therapeutic potential of aryl hydrocarbon receptor in autoimmunity. Inflammopharmacology 2019; 28:63-81. [PMID: 31617124 DOI: 10.1007/s10787-019-00651-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 09/30/2019] [Indexed: 12/11/2022]
Abstract
Aryl hydrocarbon receptor (AhR), a type of transcriptional factor, is widely expressed in immune cells. The activation of AhR signaling pathway depends on its ligands, which exist in environment and can also be produced by metabolism. Normal expressions of AhR and AhR-mediated signaling may be essential for immune responses, and effects of AhR signaling on the development and function of innate and adaptive immune cells have also been revealed in previous studies. Recent studies also indicate that aberrant AhR signaling may be related to autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), autoimmune uveitis (AU), autoimmune diabetes, Behcet's disease (BD) and myasthenia gravis (MG). Moreover, administration of AhR ligands or drugs has been proven effective for improving pathological outcomes in some autoimmune diseases or models. In this review, we summarize the effects of AhR on several innate and adaptive immune cells associated with autoimmunity, and the mechanism on how AhR participates in autoimmune diseases. In addition, we also discuss therapeutic potential and application prospect of AhR in autoimmune diseases, so as to provide valuable information for exploring novel and effective approaches to autoimmune disease treatments.
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Affiliation(s)
- Xiao-Song Wang
- The First Affiliated Hospital of Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.,Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China
| | - Fan Cao
- Department of Clinical Medicine, The Second School of Clinical Medicine, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Yi Zhang
- Reproductive Medicine Center, Anhui Women and Child Health Care Hospital, 15 Yimin Street, Hefei, Anhui, 230011, China
| | - Hai-Feng Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China. .,Anhui Province Key Laboratory of Major Autoimmune Diseases, 81 Meishan Road, Hefei, Anhui, China.
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Csaba G. Aromatic hydrocarbon receptors in the immune system: Review and hypotheses. Acta Microbiol Immunol Hung 2019; 66:273-287. [PMID: 30803253 DOI: 10.1556/030.66.2019.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ah-receptors (AhRs) recognize and bind foreign environmental molecules as well as some target hormones of other nuclear receptors. As ligands activate transcription factors, they transmit the information on the presence of these molecules by binding to the DNA, which in turn activate xenobiotic metabolism genes. Cross talk with other nuclear receptors or some non-nuclear receptors also activates or inhibits endocrine processes. Immune cells have AhRs by which they are activated for physiological (immunity) or non-physiological (allergy and autoimmunity) processes. They can be imprinted by hormonal or pseudo-hormonal (environmental) factors, which could provoke pathological alterations for life (by faulty perinatal hormonal imprinting). The variety and amount of human-made new environmental molecules (endocrine disruptors) are enormously growing, so the importance of AhR functions is also expanding.
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Affiliation(s)
- György Csaba
- 1 Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary
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Li Y, Xie HQ, Zhang W, Wei Y, Sha R, Xu L, Zhang J, Jiang Y, Guo TL, Zhao B. Type 3 innate lymphoid cells are altered in colons of C57BL/6 mice with dioxin exposure. THE SCIENCE OF THE TOTAL ENVIRONMENT 2019; 662:639-645. [PMID: 30703721 DOI: 10.1016/j.scitotenv.2019.01.139] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 01/10/2019] [Accepted: 01/12/2019] [Indexed: 06/09/2023]
Abstract
Type 3 innate lymphoid cells (ILC3s) are distributed in the gut and regulate inflammation by secreting cytokines, including interferon (IFN)-γ and interleukin (IL)-17. The maintenance and function of ILC3s involve the activity of aryl hydrocarbon receptor (AhR), a potent ligand of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), one of the most toxic dioxin congeners. Thus, TCDD exposure might affect ILC3s. To obtain in vivo evidence supporting this notion, we exposed female C57BL/6 mice orally to TCDD (low/high doses: 0.1/10 μg/kg body weight) during pregnancy and lactation periods, and after the exposure, evaluated the mothers and offspring for alterations in ILC3 differentiation and function in the colon. ILC3 frequency among colonic lamina propria lymphocytes was preferentially diminished in the offspring, and, in parallel, the median fluorescence intensity (MFI) of retinoic acid receptor-related orphan receptor (ROR)γt, which is associated with ILC3 differentiation, was also decreased in ILC3s. Conversely, the percentages of two subsets of the cells, one positive for natural cytotoxicity receptor NKp46 and the other for IL-17a, were increased in TCDD-exposed mothers and offspring. Moreover, the percentage of IFN-γ+ ILC3s was increased specifically in the mothers, but this was in conjunction with a significant decrease in the MFI of IFN-γ, which suggests that the IFN-γ+ ILC3 subset was functionally altered. In conclusion, maternal exposure to TCDD suppresses ILC3 differentiation in the offspring and influences ILC3 function in distinct manners in the mother and offspring. Our study provides new insights into the intergenerational interference of dioxins in colonic ILC3s.
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Affiliation(s)
- Yunping Li
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Heidi Qunhui Xie
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wanglong Zhang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yunbo Wei
- Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250014, China
| | - Rui Sha
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Li Xu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jianqing Zhang
- Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China
| | - Yousheng Jiang
- Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China
| | - Tai L Guo
- Department of Veterinary Biosciences and Diagnostic Imaging, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA
| | - Bin Zhao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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Sasaki-Kudoh E, Kudo I, Kakizaki Y, Hosaka M, Ikeda SI, Uemura S, Grave E, Togashi S, Sugawara T, Shimizu H, Itoh H. Cisplatin Inhibits AhR Activation. ACTA ACUST UNITED AC 2018. [DOI: 10.4236/ajmb.2018.81006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Jurado-Manzano BB, Zavala-Reyes D, Turrubiartes-Martínez EA, Portales-Pérez DP, González-Amaro R, Layseca-Espinosa E. FICZ generates human tDCs that induce CD4 + CD25 high Foxp3 + Treg-like cell differentiation. Immunol Lett 2017; 190:84-92. [PMID: 28765071 DOI: 10.1016/j.imlet.2017.07.013] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 07/21/2017] [Accepted: 07/25/2017] [Indexed: 02/01/2023]
Abstract
Dendritic cells (DCs) play a central role in the maintenance of immune homeostasis, their participation as professional antigen presenting cells is essential to the initiation of the adaptive immune response as well as to the induction of tolerance. The recently described role of the aryl hydrocarbon receptor (AhR) in the immune system, particularly in the modulation of the adaptive immune response has attracted the attention as a potential player in the induction of immune tolerance. However, the effects of AhR activation through endogenous ligands on human DCs have been poorly evaluated. In this study, we investigated the effect of FICZ, a natural AhR ligand, on monocyte-derived dendritic cells (Mo-DCs) from healthy subjects. We found that the activation of AhR through FICZ during DCs differentiation and maturation processes resulted in a decreased expression of CD83, an increased expression of the enzyme IDO and a reduced production of the pro-inflammatory cytokines IL-6 and TNF-α. More importantly, FICZ-treated DCs were able to induce the differentiation of naive T lymphocytes into CD4+ CD25high Foxp3+ T reg-like cells. Our results show that the activation of the AhR on human DCs induces a tolerogenic phenotype with potential implications in immunotherapy.
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Affiliation(s)
- Brenda B Jurado-Manzano
- Department of Immunology, School of Medicine, Universidad Autónoma de San Luis Potosí, San Luis Potosí, S.L.P., Mexico
| | - Daniel Zavala-Reyes
- Department of Immunology, School of Medicine, Universidad Autónoma de San Luis Potosí, San Luis Potosí, S.L.P., Mexico; Research Center of Health Sciences and Biomedicine (CICSaB), Universidad Autónoma de San Luis Potosí, San Luis Potosí, S.L.P., Mexico
| | - Edgar A Turrubiartes-Martínez
- Laboratory of Genetics and Molecular Diagnostic, Faculty of Chemical Science, Universidad Autónoma de San Luis Potosí, San Luis Potosí, S.L.P., Mexico
| | - Diana P Portales-Pérez
- Laboratory of Immunology and Cellular and Molecular Biology, Faculty of Chemical Science, Universidad Autónoma de San Luis Potosí, San Luis Potosí, S.L.P., Mexico; Research Center of Health Sciences and Biomedicine (CICSaB), Universidad Autónoma de San Luis Potosí, San Luis Potosí, S.L.P., Mexico
| | - Roberto González-Amaro
- Department of Immunology, School of Medicine, Universidad Autónoma de San Luis Potosí, San Luis Potosí, S.L.P., Mexico; Research Center of Health Sciences and Biomedicine (CICSaB), Universidad Autónoma de San Luis Potosí, San Luis Potosí, S.L.P., Mexico
| | - Esther Layseca-Espinosa
- Department of Immunology, School of Medicine, Universidad Autónoma de San Luis Potosí, San Luis Potosí, S.L.P., Mexico; Research Center of Health Sciences and Biomedicine (CICSaB), Universidad Autónoma de San Luis Potosí, San Luis Potosí, S.L.P., Mexico.
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Megna BW, Carney PR, Kennedy GD. Intestinal inflammation and the diet: Is food friend or foe? World J Gastrointest Surg 2016; 8:115-123. [PMID: 26981185 PMCID: PMC4770165 DOI: 10.4240/wjgs.v8.i2.115] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 11/15/2015] [Accepted: 12/11/2015] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic intestinal illness of autoimmune origin affecting millions across the globe. The most common subtypes include ulcerative colitis (UC) and Crohn’s disease. While many medical treatments for IBD exist, none come without the risk of significant immunosuppression and in general do not have benign side effect profiles. Surgical intervention exists only as radical resection for medically refractory UC. There exists a dire need for novel treatments that target the inherent pathophysiologic disturbances of IBD, rather than global immune suppression. One avenue of investigation that could provide such an agent is the interaction between certain dietary elements and the aryl hydrocarbon receptor (AHR). The AHR is a cytosolic transcription factor with a rich history in environmental toxicant handling, however, recently a role has emerged for the AHR as a modulator of the gastrointestinal immune system. Studies have come to elucidate these effects to include the enhancement of Th cell subset differentiation, interactions between enteric flora and the luminal wall, and modulation of inflammatory interleukin and cytokine signaling. This review highlights advancements in our understanding of AHR activity in the digestive tract and how this stimulation may be wrought by certain dietary “micronutriceuticals”, namely indole-3-carbinol (I3C) and its derivatives. Greater clarity surrounding these dynamics could lead to a novel diet-derived agonist of the AHR which is not only non-toxic, but also efficacious in the amelioration of clinical IBD.
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