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Liu Q, Deng G, Jiang X, Fu Y, Zhang J, Wu X, Li X, Ai J, Liu H, Tan G. Macrophage-mediated activation of the IL4I1/AhR axis is a key player in allergic rhinitis. Int Immunopharmacol 2025; 152:114439. [PMID: 40080924 DOI: 10.1016/j.intimp.2025.114439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 02/22/2025] [Accepted: 03/04/2025] [Indexed: 03/15/2025]
Abstract
BACKGROUND Epidemiological evidence suggests that environmental pollutants precipitate the occurrence of allergic rhinitis (AR). The aryl hydrocarbon receptor (AhR), a receptor or sensor for various contaminants, is closely related to immunomodulation and the polarization of M2 macrophages. However, the mechanisms involving AhR and M2 macrophages in AR remain unclear. METHODS Bioinformatics analysis of GEO datasets (GSE180697 and GSE180697) assessed AhR and IL4I1 expression levels, which were then verified in the nasal mucosa, monocytes and serum of patients with AR using western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence, and enzyme-linked immunosorbent assay (ELISA). Primary human mononuclear cells were isolated from peripheral blood using a magnetic separation technique, and THP-1 cell lines with IL4I1 overexpression or downexpression were established through lentiviral constructs. M2 macrophages were induced with the cytokines CSF, IL4 and IL13 and then treated with the AhR agonist FICZ or inhibitor CH223191. The polarization of M2 macrophages was measured by flow cytometry and western blotting. Furthermore, primary nasal epithelial cells and macrophages were co-cultured to assess the epithelial-mesenchymal transition (EMT) in epithelial cells. The AR murine model was established using ovalbumin (OVA). Inflammation within the nasal mucosa and lung tissue was examined after CH223191 or IL4I1 treatment. RESULTS Nuclear translocation of AhR and upregulation of IL4I1 was observed in peripheral mononuclear cells and nasal mucosal tissue of patients with AR. Through the activation of AhR, IL4I1 promoted M2 macrophage polarization. Furthermore, modulation of the IL4I1/AhR axis regulated the migratory impact of OVA on T-M2 cells. The IL4I1/AhR axis was involved in the regulation of M2 macrophage-associated EMT and contributed to the expression of IL-33 and STAT6 phosphorylation in epithelial cells. In AR mice, increased AhR nuclear translocation and higher expression of IL4I1 and the M2 macrophage marker CD206 in the lungs was observed. The IL4I1/AhR axis exacerbated allergic symptoms in AR mice, fostering allergic inflammation within the nasal mucosa and lungs. CONCLUSIONS The IL4I1/AhR axis is activated within the mononuclear phagocyte system of patients with AR. This activation facilitates the polarization of mononuclear cells into M2 macrophages, which further aggravates EMT in epithelial cells and exacerbates inflammation in AR. This study may provide novel strategies for the precise treatment of AR.
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Affiliation(s)
- Qian Liu
- Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China; Department of Otolaryngology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215123, China
| | - Guohao Deng
- Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Xian Jiang
- Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Yanpeng Fu
- Department of Otorhinolaryngology Head and Neck Surgery, Second Afliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, China
| | - Jian Zhang
- Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Xue Wu
- Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Xinlong Li
- Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Jingang Ai
- Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Honghui Liu
- Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China.
| | - Guolin Tan
- Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China.
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McMahon S, Spector T, Ramana KV. Significance of Macrophage-Mediated Inflammatory Response in Ocular Inflammatory Complications. FRONT BIOSCI-LANDMRK 2025; 30:26698. [PMID: 40152374 DOI: 10.31083/fbl26698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 10/27/2024] [Accepted: 10/30/2024] [Indexed: 03/29/2025]
Abstract
Immune cells such as macrophages play a significant role in ocular inflammation by activating or inhibiting several cellular pathways. Systemic infections and autoimmune diseases could activate macrophages by releasing various pro-inflammatory cytokines, chemokines, and growth factors, which reach the eyes through the blood-retina barrier and cause immune and inflammatory responses. In addition, environmental pollutants, allergens, and eye injuries could also activate macrophages and cause an inflammatory response. Further, the inflammatory response generated by the macrophages could recruit additional immune cells and enhance the inflammatory response. The inflammatory response leads to ocular tissue damage and dysfunction and affects vision. Macrophages are generally implicated in the clearance of pathogens and debris, generate reactive oxygen species, and initiate immune response. However, uncontrolled immune and inflammatory responses could damage the ocular tissues, leading to various ocular inflammatory complications such as uveitis, scleritis, diabetic retinopathy, and retinitis. Recent studies describe the role of individual cytokines in the mediation of specific ocular inflammatory diseases. In this article, we discussed the potential impact of macrophages and their mediated inflammatory response on the development of various ocular inflammatory diseases and possible treatment strategies.
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Affiliation(s)
- Sara McMahon
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, Provo, UT 84045, USA
| | - Tori Spector
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, Provo, UT 84045, USA
| | - Kota V Ramana
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, Provo, UT 84045, USA
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Barreira-Silva P, Lian Y, Kaufmann SHE, Moura-Alves P. The role of the AHR in host-pathogen interactions. Nat Rev Immunol 2025; 25:178-194. [PMID: 39415055 DOI: 10.1038/s41577-024-01088-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/28/2024] [Indexed: 10/18/2024]
Abstract
Host-microorganism encounters take place in many different ways and with different types of outcomes. Three major types of microorganisms need to be distinguished: (1) pathogens that cause harm to the host and must be controlled; (2) environmental microorganisms that can be ignored but must be controlled at higher abundance; and (3) symbiotic microbiota that require support by the host. Recent evidence indicates that the aryl hydrocarbon receptor (AHR) senses and initiates signalling and gene expression in response to a plethora of microorganisms and infectious conditions. It was originally identified as a receptor that binds xenobiotics. However, it was subsequently found to have a critical role in numerous biological processes, including immunity and inflammation and was recently classified as a pattern recognition receptor. Here we review the role of the AHR in host-pathogen interactions, focusing on AHR sensing of different microbial classes, the ligands involved, responses elicited and disease outcomes. Moreover, we explore the therapeutic potential of targeting the AHR in the context of infection.
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Affiliation(s)
- Palmira Barreira-Silva
- IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
- i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Yilong Lian
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | - Stefan H E Kaufmann
- Max Planck Institute for Infection Biology, Berlin, Germany
- Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
- Hagler Institute for Advanced Study, Texas A&M University, College Station, TX, USA
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Pedro Moura-Alves
- IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
- i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
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4
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Xie A, Wang T, Shi W, He F, Sun X, Li P. Unveiling the Immune effects of AHR in tumors: a decade of insights from bibliometric analysis (2010-2023). Discov Oncol 2024; 15:616. [PMID: 39495340 PMCID: PMC11535112 DOI: 10.1007/s12672-024-01480-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 10/22/2024] [Indexed: 11/05/2024] Open
Abstract
BACKGROUND The Aryl Hydrocarbon Receptor (AHR) is a transcription factor that regulates several biological processes. Its potential in anti-tumor immunotherapy is becoming clearer, yet no bibliometric studies on this topic exist. This study aims to understand the current research landscape and identify future directions through a bibliometric analysis of AHR's anti-tumor immunological effects. METHODS We conducted a comprehensive bibliometric analysis of AHR antitumor immunotherapy papers in the Web of Science Core Collection. Various aspects of the publications were analyzed, and research hotspots and future trends were identified using scientific bibliometric tools and statistical methods. RESULTS We collected 592 English papers published between 2010 and 2023, with an almost annual increase. Most publications were from the USA, followed by China, Germany, and Italy. The journal "Frontiers in Immunology" had the most papers, and the most cited paper was Christiane A. Opitz's "An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor." The research is centered around AHR gene expression, with a growing focus on intestinal disease and the development of Programmed cell death ligand 1 (PD-L1) drugs. CONCLUSION This bibliometric study highlights the significance of AHR in immunomodulatory research, outlining the research trends and key contributors. It suggests AHR's immune effects may mediate the process of colitis cancer transformation, providing valuable insights for future anti-tumor immunotherapy strategies based on AHR.
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Affiliation(s)
- Anni Xie
- Anhui University of Traditional Chinese Medicine, Hefei, 230001, China
| | - Ting Wang
- Oncology Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230001, China
| | - Wenjing Shi
- Oncology Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230001, China
| | - Fang He
- Anhui University of Traditional Chinese Medicine, Hefei, 230001, China
| | - Xin Sun
- Oncology Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230001, China.
| | - Ping Li
- Anhui University of Traditional Chinese Medicine, Hefei, 230001, China.
- Oncology Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230001, China.
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Bahman F, Choudhry K, Al-Rashed F, Al-Mulla F, Sindhu S, Ahmad R. Aryl hydrocarbon receptor: current perspectives on key signaling partners and immunoregulatory role in inflammatory diseases. Front Immunol 2024; 15:1421346. [PMID: 39211042 PMCID: PMC11358079 DOI: 10.3389/fimmu.2024.1421346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 07/26/2024] [Indexed: 09/04/2024] Open
Abstract
The aryl hydrocarbon receptor (AhR) is a versatile environmental sensor and transcription factor found throughout the body, responding to a wide range of small molecules originating from the environment, our diets, host microbiomes, and internal metabolic processes. Increasing evidence highlights AhR's role as a critical regulator of numerous biological functions, such as cellular differentiation, immune response, metabolism, and even tumor formation. Typically located in the cytoplasm, AhR moves to the nucleus upon activation by an agonist where it partners with either the aryl hydrocarbon receptor nuclear translocator (ARNT) or hypoxia-inducible factor 1β (HIF-1β). This complex then interacts with xenobiotic response elements (XREs) to control the expression of key genes. AhR is notably present in various crucial immune cells, and recent research underscores its significant impact on both innate and adaptive immunity. This review delves into the latest insights on AhR's structure, activating ligands, and its multifaceted roles. We explore the sophisticated molecular pathways through which AhR influences immune and lymphoid cells, emphasizing its emerging importance in managing inflammatory diseases. Furthermore, we discuss the exciting potential of developing targeted therapies that modulate AhR activity, opening new avenues for medical intervention in immune-related conditions.
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Affiliation(s)
- Fatemah Bahman
- Department of Immunology & Microbiology, Dasman Diabetes Institute, Dasman, Kuwait
| | - Khubaib Choudhry
- Department of Human Biology, University of Toronto, Toronto, ON, Canada
| | - Fatema Al-Rashed
- Department of Immunology & Microbiology, Dasman Diabetes Institute, Dasman, Kuwait
| | - Fahd Al-Mulla
- Department of Translational Research, Dasman Diabetes Institute, Dasman, Kuwait
| | - Sardar Sindhu
- Department of Immunology & Microbiology, Dasman Diabetes Institute, Dasman, Kuwait
- Animal & Imaging Core Facilities, Dasman Diabetes Institute, Dasman, Kuwait
| | - Rasheed Ahmad
- Department of Immunology & Microbiology, Dasman Diabetes Institute, Dasman, Kuwait
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Jiang L, Sun XY, Wang SQ, Liu YL, Lu LJ, Wu WH, Zhi H, Wang ZY, Liu XD, Liu L. Indoxyl sulphate-TNFα axis mediates uremic encephalopathy in rodent acute kidney injury. Acta Pharmacol Sin 2024; 45:1406-1424. [PMID: 38589687 PMCID: PMC11192958 DOI: 10.1038/s41401-024-01251-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 02/26/2024] [Indexed: 04/10/2024]
Abstract
Acute kidney injury (AKI) is often accompanied by uremic encephalopathy resulting from accumulation of uremic toxins in brain possibly due to impaired blood-brain barrier (BBB) function. Anionic uremic toxins are substrates or inhibitors of organic anionic transporters (OATs). In this study we investigated the CNS behaviors and expression/function of BBB OAT3 in AKI rats and mice, which received intraperitoneal injection of cisplatin 8 and 20 mg/kg, respectively. We showed that cisplatin treatment significantly inhibited the expressions of OAT3, synaptophysin and microtubule-associated protein 2 (MAP2), impaired locomotor and exploration activities, and increased accumulation of uremic toxins in the brain of AKI rats and mice. In vitro studies showed that uremic toxins neither alter OAT3 expression in human cerebral microvascular endothelial cells, nor synaptophysin and MAP2 expressions in human neuroblastoma (SH-SY5Y) cells. In contrast, tumour necrosis factor alpha (TNFα) and the conditioned medium (CM) from RAW264.7 cells treated with indoxyl sulfate (IS) significantly impaired OAT3 expression. TNFα and CM from IS-treated BV-2 cells also inhibited synaptophysin and MAP2 expressions in SH-SY5Y cells. The alterations caused by TNFα and CMs in vitro, and by AKI and TNFα in vivo were abolished by infliximab, a monoclonal antibody designed to intercept and neutralize TNFα, suggesting that AKI impaired the expressions of OAT3, synaptophysin and MAP2 in the brain via IS-induced TNFα release from macrophages or microglia (termed as IS-TNFα axis). Treatment of mice with TNFα (0.5 mg·kg-1·d-1, i.p. for 3 days) significantly increased p-p65 expression and reduced the expressions of Nrf2 and HO-1. Inhibiting NF-κB pathway, silencing p65, or activating Nrf2 and HO-1 obviously attenuated TNFα-induced downregulation of OAT3, synaptophysin and MAP2 expressions. Significantly increased p-p65 and decreased Nrf2 and HO-1 protein levels were also detected in brain of AKI mice and rats. We conclude that AKI inhibits the expressions of OAT3, synaptophysin and MAP2 due to IS-induced TNFα release from macrophages or microglia. TNFα impairs the expressions of OAT3, synaptophysin and MAP2 partly via activating NF-κB pathway and inhibiting Nrf2-HO-1 pathway.
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Affiliation(s)
- Ling Jiang
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Xue-Ying Sun
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Si-Qian Wang
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Yan-Lin Liu
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Ling-Jue Lu
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Wen-Han Wu
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Hao Zhi
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Zhong-Yan Wang
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Xiao-Dong Liu
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Li Liu
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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Malany K, Li X, Vogel CFA, Ehrlich AK. Mechanisms underlying aryl hydrocarbon receptor-driven divergent macrophage function. Toxicol Sci 2024; 200:1-10. [PMID: 38603630 PMCID: PMC11199922 DOI: 10.1093/toxsci/kfae050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/13/2024] Open
Abstract
Macrophages play an essential role in the innate immune system by differentiating into functionally diverse subsets in order to fight infection, repair damaged tissues, and regulate inappropriate immune responses. This functional diversity stems from their ability to adapt and respond to signals in the environment, which is in part mediated through aryl hydrocarbon receptor (AHR)-signaling. AHR, an environmental sensor, can be activated by various ligands, ranging from environmental contaminants to microbially derived tryptophan metabolites. This review discusses what is currently known about how AHR-signaling influences macrophage differentiation, polarization, and function. By discussing studies that are both consistent and divergent, our goal is to highlight the need for future research on the mechanisms by which AHR acts as an immunological switch in macrophages. Ultimately, understanding the contexts in which AHR-signaling promotes and/or inhibits differentiation, proinflammatory functions, and immunoregulatory functions, will help uncover functional predictions of immunotoxicity following exposure to environmental chemicals as well as better design AHR-targeted immunotherapies.
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Affiliation(s)
- Keegan Malany
- Department of Environmental Toxicology, University of California, Davis, California, USA
| | - Xiaohan Li
- Center for Health and the Environment, University of California, Davis, California, USA
| | - Christoph F A Vogel
- Department of Environmental Toxicology, University of California, Davis, California, USA
- Center for Health and the Environment, University of California, Davis, California, USA
| | - Allison K Ehrlich
- Department of Environmental Toxicology, University of California, Davis, California, USA
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Quan S, Huang J, Chen G, Zhang A, Yang Y, Wu Z. Genistein Promotes M2 Macrophage Polarization via Aryl Hydrocarbon Receptor and Alleviates Intestinal Inflammation in Broilers with Necrotic Enteritis. Int J Mol Sci 2024; 25:6656. [PMID: 38928362 PMCID: PMC11203855 DOI: 10.3390/ijms25126656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 06/13/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
The aryl hydrocarbon receptor (AhR) is a transcription factor that regulates the immune system through complicated transcriptional programs. Genistein, an AhR ligand, exhibits anti-inflammatory properties. However, its role in modulating immune responses via the AhR signaling pathway remains unclear. In this study, 360 male Arbor Acre broilers (1-day-old) were fed a basal diet supplemented with 40 or 80 mg/kg genistein and infected with or without Clostridium perfringens (Cp). Our results demonstrated that genistein ameliorated Cp-induced intestinal damage, as reflected by the reduced intestinal lesion scores and improved intestinal morphology and feed-to-gain ratio. Moreover, genistein increased intestinal sIgA, TGF-β, and IL-10, along with elevated serum IgG, IgA, and lysozyme levels. Genistein improved intestinal AhR and cytochrome P450 family 1 subfamily A member 1 (CYP1A1) protein levels and AhR+ cell numbers in Cp-challenged broilers. The increased number of AhR+CD163+ cells in the jejunum suggested a potential association between genistein-induced AhR activation and anti-inflammatory effects mediated through M2 macrophage polarization. In IL-4-treated RAW264.7 cells, genistein increased the levels of AhR, CYP1A1, CD163, and arginase (Arg)-1 proteins, as well as IL-10 mRNA levels. This increase was attenuated by the AhR antagonist CH223191. In summary, genistein activated the AhR signaling pathway in M2 macrophages, which enhanced the secretion of anti-inflammatory cytokines and attenuated intestinal damage in Cp-infected broilers Cp.
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Affiliation(s)
| | | | | | | | - Ying Yang
- College of Animal Science & Technology, China Agricultural University, Beijing 100193, China; (S.Q.); (J.H.); (G.C.); (A.Z.); (Z.W.)
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9
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Peyvandi S, Lan Q, Chabloz A, Prével F, La Torre YH, Ives A, Tacchini-Cottier F. The β-Carboline Harmine Has a Protective Immunomodulatory Role in Nonhealing Cutaneous Leishmaniasis. J Invest Dermatol 2024; 144:862-873.e4. [PMID: 37852357 DOI: 10.1016/j.jid.2023.09.280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 09/15/2023] [Accepted: 09/28/2023] [Indexed: 10/20/2023]
Abstract
Cutaneous leishmaniasis affects 1 million people worldwide annually. Although conventional treatments primarily target the parasite, there is growing interest in host immune modulation. In this study, we investigated the impact of synthetic β-carboline harmine (ACB1801), previously shown to be immunoregulatory in cancer, on the pathology caused by a drug-resistant Leishmania major strain causing persistent cutaneous lesions. Exposure to ACB1801 in vitro had a modest impact on parasite burden within host macrophages. Moreover, it significantly increased major histocompatibility complex II and costimulatory molecule expression on infected dendritic cells, suggesting an enhanced immune response. In vivo, ACB1801 monotherapy led to a substantial reduction in lesion development and parasite burden in infected C57BL/6 mice, comparable with efficacy of amphotericin B. Transcriptomics analysis further supported ACB1801 immunomodulatory effects, revealing an enrichment of TNF-α, IFN-γ, and major histocompatibility complex II antigen presentation signatures in the draining lymph nodes of treated mice. Flow cytometry analysis confirmed an increased frequency (1.5×) of protective CD4+IFN-γ+TNF-α+ T cells and a decreased frequency (2×) in suppressive IL-10+FoxP3- T cells at the site of infection and in draining lymph nodes. In addition, ACB1801 downregulated the aryl hydrocarbon receptor signaling, known to enhance immunosuppressive cytokines. Thus, these results suggest a potential use for ACB1801 alone or in combination therapy for cutaneous leishmaniasis.
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Affiliation(s)
- Sanam Peyvandi
- Department of Immunobiology, Faculty of Biology and Medicine, University of Lausanne, Epalinges, Switzerland
| | - Qiang Lan
- Cell and Tissue Dynamics Research Program, Institute of Biotechnology, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
| | | | - Florence Prével
- Department of Immunobiology, Faculty of Biology and Medicine, University of Lausanne, Epalinges, Switzerland
| | - Yazmin Hauyon La Torre
- Department of Immunobiology, Faculty of Biology and Medicine, University of Lausanne, Epalinges, Switzerland
| | | | - Fabienne Tacchini-Cottier
- Department of Immunobiology, Faculty of Biology and Medicine, University of Lausanne, Epalinges, Switzerland.
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10
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Laabi S, LeMmon C, Vogel C, Chacon M, Jimenez VM. Deciphering psilocybin: Cytotoxicity, anti-inflammatory effects, and mechanistic insights. Int Immunopharmacol 2024; 130:111753. [PMID: 38401463 DOI: 10.1016/j.intimp.2024.111753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 02/13/2024] [Accepted: 02/21/2024] [Indexed: 02/26/2024]
Abstract
A decade of clinical research has indicated psilocybin's effectiveness in treating various neuropsychiatric disorders, such as depression and substance abuse. The correlation between increased pro-inflammatory cytokines and the severity of neuropsychiatric symptoms, along with the known anti-inflammatory potential of some psychedelics, suggests an immunomodulatory role for psilocybin. This study aims to understand the mechanism of action of psilocybin by investigating the cytotoxic and immunomodulatory effects of psilocybin and psilocin on both resting and LPS-activated RAW 264.7 murine macrophages. The study evaluated the cytotoxicity of psilocybin and psilocin using an LDH assay across various doses and assessed their impact on cytokine production in RAW 264.7 cells, measuring cytokine expression via ELISA. Different doses, including those above and below the LC50, were used in both pre-treatment and post-treatment approaches. The LDH assay revealed that psilocybin is almost twice as cytotoxic as psilocin, with an LC50 of 12 ng/ml and 28 ng/ml, respectively. In resting macrophages, both psilocybin and psilocin triggered significant release of TNF- α after 4 h, with the lowest doses inducing higher levels of the cytokine than the highest doses. IL-10 expression in resting cells was only triggered by the highest dose of psilocin in the 4-hour incubation group. In LPS-stimulated cells, psilocin reduced TNF- α levels more than psilocybin in pre-treatment and post-treatment, with no significant effects on IL-10 in pre-treatment. Psilocin, but not psilocybin, induced a significant increase of IL-10 in post-treatment, leading to the conclusion that psilocin, but not psilocybin, exerts anti-inflammatory effects on classically activated macrophages.
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Affiliation(s)
- Salma Laabi
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, 2162 S 180 E, Provo, UT 84606, United States
| | - Claire LeMmon
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, 2162 S 180 E, Provo, UT 84606, United States
| | - Callie Vogel
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, 2162 S 180 E, Provo, UT 84606, United States
| | - Mariana Chacon
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, 2162 S 180 E, Provo, UT 84606, United States
| | - Victor M Jimenez
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, 2162 S 180 E, Provo, UT 84606, United States; Department of Pharmacy, Roseman University of Health Sciences, 10920 S River Front Pkwy, South Jordan, UT 84095, United States.
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11
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Griffith BD, Frankel TL. The Aryl Hydrocarbon Receptor: Impact on the Tumor Immune Microenvironment and Modulation as a Potential Therapy. Cancers (Basel) 2024; 16:472. [PMID: 38339226 PMCID: PMC10854841 DOI: 10.3390/cancers16030472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/18/2024] [Accepted: 01/21/2024] [Indexed: 02/12/2024] Open
Abstract
The aryl hydrocarbon receptor (AhR) is a ubiquitous nuclear receptor with a broad range of functions, both in tumor cells and immune cells within the tumor microenvironment (TME). Activation of AhR has been shown to have a carcinogenic effect in a variety of organs, through induction of cellular proliferation and migration, promotion of epithelial-to-mesenchymal transition, and inhibition of apoptosis, among other functions. However, the impact on immune cell function is more complicated, with both pro- and anti-tumorigenic roles identified. Although targeting AhR in cancer has shown significant promise in pre-clinical studies, there has been limited efficacy in phase III clinical trials to date. With the contrasting roles of AhR activation on immune cell polarization, understanding the impact of AhR activation on the tumor immune microenvironment is necessary to guide therapies targeting the AhR. This review article summarizes the state of knowledge of AhR activation on the TME, limitations of current findings, and the potential for modulation of the AhR as a cancer therapy.
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Affiliation(s)
- Brian D. Griffith
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Timothy L. Frankel
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA;
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
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12
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Shang Z, Ma Z, Wu E, Chen X, Tuo B, Li T, Liu X. Effect of metabolic reprogramming on the immune microenvironment in gastric cancer. Biomed Pharmacother 2024; 170:116030. [PMID: 38128177 DOI: 10.1016/j.biopha.2023.116030] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/03/2023] [Accepted: 12/14/2023] [Indexed: 12/23/2023] Open
Abstract
Gastric cancer (GC) is a malignant tumor of the gastrointestinal tract with a high mortality rate worldwide, a low early detection rate and a poor prognosis. The rise of metabolomics has facilitated the early detection and treatment of GC. Metabolism in the GC tumor microenvironment (TME) mainly includes glucose metabolism, lipid metabolism and amino acid metabolism, which provide energy and nutrients for GC cell proliferation and migration. Abnormal tumor metabolism can influence tumor progression by regulating the functions of immune cells and immune molecules in the TME, thereby contributing to tumor immune escape. Thus, in this review, we summarize the impact of metabolism on the TME during GC progression. We also propose novel strategies to modulate antitumor immune responses by targeting metabolism.
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Affiliation(s)
- Zhengye Shang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Zhiyuan Ma
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Enqin Wu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Xingzhao Chen
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Taolang Li
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Dalian Road 149, Zunyi 563000, China.
| | - Xuemei Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China.
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13
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Pérez-Stuardo D, Frazão M, Ibaceta V, Brianson B, Sánchez E, Rivas-Pardo JA, Vallejos-Vidal E, Reyes-López FE, Toro-Ascuy D, Vidal EA, Reyes-Cerpa S. KLF17 is an important regulatory component of the transcriptomic response of Atlantic salmon macrophages to Piscirickettsia salmonis infection. Front Immunol 2023; 14:1264599. [PMID: 38162669 PMCID: PMC10755876 DOI: 10.3389/fimmu.2023.1264599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 11/07/2023] [Indexed: 01/03/2024] Open
Abstract
Piscirickettsia salmonis is the most important health problem facing Chilean Aquaculture. Previous reports suggest that P. salmonis can survive in salmonid macrophages by interfering with the host immune response. However, the relevant aspects of the molecular pathogenesis of P. salmonis have been poorly characterized. In this work, we evaluated the transcriptomic changes in macrophage-like cell line SHK-1 infected with P. salmonis at 24- and 48-hours post-infection (hpi) and generated network models of the macrophage response to the infection using co-expression analysis and regulatory transcription factor-target gene information. Transcriptomic analysis showed that 635 genes were differentially expressed after 24- and/or 48-hpi. The pattern of expression of these genes was analyzed by weighted co-expression network analysis (WGCNA), which classified genes into 4 modules of expression, comprising early responses to the bacterium. Induced genes included genes involved in metabolism and cell differentiation, intracellular transportation, and cytoskeleton reorganization, while repressed genes included genes involved in extracellular matrix organization and RNA metabolism. To understand how these expression changes are orchestrated and to pinpoint relevant transcription factors (TFs) controlling the response, we established a curated database of TF-target gene regulatory interactions in Salmo salar, SalSaDB. Using this resource, together with co-expression module data, we generated infection context-specific networks that were analyzed to determine highly connected TF nodes. We found that the most connected TF of the 24- and 48-hpi response networks is KLF17, an ortholog of the KLF4 TF involved in the polarization of macrophages to an M2-phenotype in mammals. Interestingly, while KLF17 is induced by P. salmonis infection, other TFs, such as NOTCH3 and NFATC1, whose orthologs in mammals are related to M1-like macrophages, are repressed. In sum, our results suggest the induction of early regulatory events associated with an M2-like phenotype of macrophages that drives effectors related to the lysosome, RNA metabolism, cytoskeleton organization, and extracellular matrix remodeling. Moreover, the M1-like response seems delayed in generating an effective response, suggesting a polarization towards M2-like macrophages that allows the survival of P. salmonis. This work also contributes to SalSaDB, a curated database of TF-target gene interactions that is freely available for the Atlantic salmon community.
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Affiliation(s)
- Diego Pérez-Stuardo
- Centro de Genómica y Bioinformática, Facultad de Ciencias, Ingeniería y Tecnología, Universidad Mayor, Santiago, Chile
- Programa de Doctorado en Genómica Integrativa, Vicerrectoría de Investigación, Universidad Mayor, Santiago, Chile
| | - Mateus Frazão
- Centro de Genómica y Bioinformática, Facultad de Ciencias, Ingeniería y Tecnología, Universidad Mayor, Santiago, Chile
- Escuela de Biotecnología, Facultad de Ciencias, Ingeniería y Tecnología, Universidad Mayor, Santiago, Chile
| | - Valentina Ibaceta
- Centro de Genómica y Bioinformática, Facultad de Ciencias, Ingeniería y Tecnología, Universidad Mayor, Santiago, Chile
- Escuela de Biotecnología, Facultad de Ciencias, Ingeniería y Tecnología, Universidad Mayor, Santiago, Chile
| | - Bernardo Brianson
- Centro de Genómica y Bioinformática, Facultad de Ciencias, Ingeniería y Tecnología, Universidad Mayor, Santiago, Chile
- Escuela de Biotecnología, Facultad de Ciencias, Ingeniería y Tecnología, Universidad Mayor, Santiago, Chile
| | - Evelyn Sánchez
- Centro de Genómica y Bioinformática, Facultad de Ciencias, Ingeniería y Tecnología, Universidad Mayor, Santiago, Chile
- Programa de Doctorado en Genómica Integrativa, Vicerrectoría de Investigación, Universidad Mayor, Santiago, Chile
- Agencia Nacional de Investigación y Desarrollo (ANID) Millennium Science Initiative Program-Millennium Institute for Integrative Biology (iBio), Santiago, Chile
| | - J. Andrés Rivas-Pardo
- Centro de Genómica y Bioinformática, Facultad de Ciencias, Ingeniería y Tecnología, Universidad Mayor, Santiago, Chile
- Escuela de Biotecnología, Facultad de Ciencias, Ingeniería y Tecnología, Universidad Mayor, Santiago, Chile
| | - Eva Vallejos-Vidal
- Núcleo de Investigaciones Aplicadas en Ciencias Veterinarias y Agronómicas, Facultad de Medicina Veterinaria y Agronomía, Universidad De Las Américas, La Florida, Santiago, Chile
- Centro de Biotecnología Acuícola, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
- Centro de Nanociencia y Nanotecnología (CEDENNA), Universidad de Santiago de Chile, Santiago, Chile
| | - Felipe E. Reyes-López
- Centro de Biotecnología Acuícola, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
| | - Daniela Toro-Ascuy
- Laboratorio de Virología, Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - Elena A. Vidal
- Centro de Genómica y Bioinformática, Facultad de Ciencias, Ingeniería y Tecnología, Universidad Mayor, Santiago, Chile
- Escuela de Biotecnología, Facultad de Ciencias, Ingeniería y Tecnología, Universidad Mayor, Santiago, Chile
- Agencia Nacional de Investigación y Desarrollo (ANID) Millennium Science Initiative Program-Millennium Institute for Integrative Biology (iBio), Santiago, Chile
| | - Sebastián Reyes-Cerpa
- Centro de Genómica y Bioinformática, Facultad de Ciencias, Ingeniería y Tecnología, Universidad Mayor, Santiago, Chile
- Escuela de Biotecnología, Facultad de Ciencias, Ingeniería y Tecnología, Universidad Mayor, Santiago, Chile
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14
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Lkhagva-Yondon E, Seo MS, Oh Y, Jung J, Jeon E, Na K, Yoo HS, Kim WC, Esser C, Song SU, Jeon MS. The aryl hydrocarbon receptor controls mesenchymal stromal cell-mediated immunomodulation via ubiquitination of eukaryotic elongation factor-2 kinase. Cell Death Dis 2023; 14:812. [PMID: 38071243 PMCID: PMC10710493 DOI: 10.1038/s41419-023-06341-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 11/07/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023]
Abstract
Mesenchymal stem cells (MSCs) have great therapeutic advantages due to their immunosuppressive properties. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor whose signaling plays an important role in the immune system. AHR may be involved in the regulation of MSC-associated immunomodulatory functions. However, the mechanisms by which AHR controls the immunosuppressive functions of MSCs are not well understood. Here, we report that Ahr-deficient MSCs show decreased therapeutic efficacy against graft-versus-host disease (GVHD) compared to wild-type (WT)-MSCs. This was probably due to decreased iNOS protein expression, which is a key regulatory enzyme in MSC immunomodulation. The expression of eukaryotic elongation factor 2 kinase (eEF2K), which inhibits the elongation stage of protein synthesis, is significantly increased in the Ahr-deficient MSCs. Inhibition of eEF2K restored iNOS protein expression. AHR is known to act as an E3 ligase together with CUL4B. We observed constitutive binding of AHR to eEF2K. Consequently, ubiquitination and degradation of eEF2K were inhibited in Ahr-deficient MSCs and by the AHR antagonist CH223191 in WT-MSCs. In summary, AHR regulates the immunomodulatory functions of MSCs through ubiquitination of eEF2K, thereby controlling iNOS protein synthesis and its product, nitric oxide levels.
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Affiliation(s)
- Enkhmaa Lkhagva-Yondon
- Translational Research Center, Inha University Hospital, Incheon, 22332, Republic of Korea
- Program in Biomedical Science & Engineering Inha University, Incheon, 22212, Republic of Korea
| | - Myeong Seong Seo
- Translational Research Center, Inha University Hospital, Incheon, 22332, Republic of Korea
- Program in Biomedical Science & Engineering Inha University, Incheon, 22212, Republic of Korea
| | - Yena Oh
- Translational Research Center, Inha University Hospital, Incheon, 22332, Republic of Korea
- Department of Molecular Biomedicine, College of Medicine Inha University, Incheon, 22212, Republic of Korea
| | - Jonghun Jung
- Translational Research Center, Inha University Hospital, Incheon, 22332, Republic of Korea
- Program in Biomedical Science & Engineering Inha University, Incheon, 22212, Republic of Korea
| | - Eunhae Jeon
- Translational Research Center, Inha University Hospital, Incheon, 22332, Republic of Korea
- Department of Molecular Biomedicine, College of Medicine Inha University, Incheon, 22212, Republic of Korea
| | - Kwangmin Na
- Translational Research Center, Inha University Hospital, Incheon, 22332, Republic of Korea
| | - Hyun Seung Yoo
- Translational Research Center, Inha University Hospital, Incheon, 22332, Republic of Korea
- Department of Molecular Biomedicine, College of Medicine Inha University, Incheon, 22212, Republic of Korea
| | - Woo Chul Kim
- Department of Radiation Oncology, Inha University Hospital, Incheon, 22332, Republic of Korea
| | - Charlotte Esser
- IUF-Leibniz Research Institute for Environmental Medicine, Düsseldorf, 40021, Germany
| | - Sun U Song
- Translational Research Center, Inha University Hospital, Incheon, 22332, Republic of Korea
- Department of Molecular Biomedicine, College of Medicine Inha University, Incheon, 22212, Republic of Korea
- SCM Lifescience, Incheon, 21999, Republic of Korea
| | - Myung-Shin Jeon
- Translational Research Center, Inha University Hospital, Incheon, 22332, Republic of Korea.
- Program in Biomedical Science & Engineering Inha University, Incheon, 22212, Republic of Korea.
- Department of Molecular Biomedicine, College of Medicine Inha University, Incheon, 22212, Republic of Korea.
- SCM Lifescience, Incheon, 21999, Republic of Korea.
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15
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Xia T, Fu S, Yang R, Yang K, Lei W, Yang Y, Zhang Q, Zhao Y, Yu J, Yu L, Zhang T. Advances in the study of macrophage polarization in inflammatory immune skin diseases. J Inflamm (Lond) 2023; 20:33. [PMID: 37828492 PMCID: PMC10568804 DOI: 10.1186/s12950-023-00360-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 10/02/2023] [Indexed: 10/14/2023] Open
Abstract
When exposed to various microenvironmental stimuli, macrophages are highly plastic and primarily polarized into the pro-inflammatory M1-type and the anti-inflammatory M2-type, both of which perform almost entirely opposing functions. Due to this characteristic, macrophages perform different functions at different stages of immunity and inflammation. Inflammatory immune skin diseases usually show an imbalance in the M1/M2 macrophage ratio, and altering the macrophage polarization phenotype can either make the symptoms worse or better. Therefore, this review presents the mechanisms of macrophage polarization, inflammation-related signaling pathways (JAK/STAT, NF-κB, and PI3K/Akt), and the role of both in inflammatory immune skin diseases (psoriasis, AD, SLE, BD, etc.) to provide new directions for basic and clinical research of related diseases.
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Affiliation(s)
- Tingting Xia
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
- Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Shengping Fu
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Ruilin Yang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Kang Yang
- Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Wei Lei
- Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Ying Yang
- Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Qian Zhang
- Department of Human Anatomy, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yujie Zhao
- Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Jiang Yu
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Limei Yu
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Tao Zhang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.
- Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.
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16
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Renga G, D'Onofrio F, Pariano M, Galarini R, Barola C, Stincardini C, Bellet MM, Ellemunter H, Lass-Flörl C, Costantini C, Napolioni V, Ehrlich AK, Antognelli C, Fini M, Garaci E, Nunzi E, Romani L. Bridging of host-microbiota tryptophan partitioning by the serotonin pathway in fungal pneumonia. Nat Commun 2023; 14:5753. [PMID: 37717018 PMCID: PMC10505232 DOI: 10.1038/s41467-023-41536-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 09/06/2023] [Indexed: 09/18/2023] Open
Abstract
The aromatic amino acid L-tryptophan (Trp) is essentially metabolized along the host and microbial pathways. While much is known about the role played by downstream metabolites of each pathways in intestinal homeostasis, their role in lung immune homeostasis is underappreciated. Here we have examined the role played by the Trp hydroxylase/5-hydroxytryptamine (5-HT) pathway in calibrating host and microbial Trp metabolism during Aspergillus fumigatus pneumonia. We found that 5-HT produced by mast cells essentially contributed to pathogen clearance and immune homeostasis in infection by promoting the host protective indoleamine-2,3-dioxygenase 1/kynurenine pathway and limiting the microbial activation of the indole/aryl hydrocarbon receptor pathway. This occurred via regulation of lung and intestinal microbiota and signaling pathways. 5-HT was deficient in the sputa of patients with Cystic fibrosis, while 5-HT supplementation restored the dysregulated Trp partitioning in murine disease. These findings suggest that 5-HT, by bridging host-microbiota Trp partitioning, may have clinical effects beyond its mood regulatory function in respiratory pathologies with an inflammatory component.
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Affiliation(s)
- Giorgia Renga
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Fiorella D'Onofrio
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Marilena Pariano
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Roberta Galarini
- Istituto Zooprofilattico Sperimentale dell'Umbria e delle Marche "Togo Rosati,", Perugia, Italy
| | - Carolina Barola
- Istituto Zooprofilattico Sperimentale dell'Umbria e delle Marche "Togo Rosati,", Perugia, Italy
| | | | - Marina M Bellet
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Cornelia Lass-Flörl
- Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria
| | - Claudio Costantini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Valerio Napolioni
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy
| | - Allison K Ehrlich
- Department of Environmental Toxicology, University of California, Davis, CA, USA
| | - Cinzia Antognelli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Massimo Fini
- University San Raffaele and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele, Rome, Italy
| | - Enrico Garaci
- University San Raffaele and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele, Rome, Italy
| | - Emilia Nunzi
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Luigina Romani
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
- University San Raffaele and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele, Rome, Italy.
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17
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Huang J, Wang YN, Zhou Y. Constitutive aryl hydrocarbon receptor facilitates the regenerative potential of mouse bone marrow mesenchymal stromal cells. World J Stem Cells 2023; 15:807-820. [PMID: 37700822 PMCID: PMC10494570 DOI: 10.4252/wjsc.v15.i8.807] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/29/2023] [Accepted: 07/14/2023] [Indexed: 08/25/2023] Open
Abstract
BACKGROUND Bone marrow mesenchymal stromal cells (BMSCs) are the commonly used seed cells in tissue engineering. Aryl hydrocarbon receptor (AhR) is a transcription factor involved in various cellular processes. However, the function of constitutive AhR in BMSCs remains unclear. AIM To investigate the role of AhR in the osteogenic and macrophage-modulating potential of mouse BMSCs (mBMSCs) and the underlying mechanism. METHODS Immunochemistry and immunofluorescent staining were used to observe the expression of AhR in mouse bone marrow tissue and mBMSCs. The overexpression or knockdown of AhR was achieved by lentivirus-mediated plasmid. The osteogenic potential was observed by alkaline phosphatase and alizarin red staining. The mRNA and protein levels of osteogenic markers were detected by quantitative polymerase chain reaction (qPCR) and western blot. After coculture with different mBMSCs, the cluster of differentiation (CD) 86 and CD206 expressions levels in RAW 264.7 cells were analyzed by flow cytometry. To explore the underlying molecular mechanism, the interaction of AhR with signal transducer and activator of transcription 3 (STAT3) was observed by co-immunoprecipitation and phosphorylation of STAT3 was detected by western blot. RESULTS AhR expressions in mouse bone marrow tissue and isolated mBMSCs were detected. AhR overexpression enhanced the osteogenic potential of mBMSCs while AhR knockdown suppressed it. The ratio of CD86+ RAW 264.7 cells cocultured with AhR-overexpressed mBMSCs was reduced and that of CD206+ cells was increased. AhR directly interacted with STAT3. AhR overexpression increased the phosphorylation of STAT3. After inhibition of STAT3 via stattic, the promotive effects of AhR overexpression on the osteogenic differentiation and macrophage-modulating were partially counteracted. CONCLUSION AhR plays a beneficial role in the regenerative potential of mBMSCs partially by increasing phosphorylation of STAT3.
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Affiliation(s)
- Jing Huang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, Hubei Province, China
| | - Yi-Ning Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, Hubei Province, China
| | - Yi Zhou
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, Hubei Province, China.
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18
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Yang D, Ding M, Song Y, Hu Y, Xiu W, Yuwen L, Xie Y, Song Y, Shao J, Song X, Dong H. Nanotherapeutics with immunoregulatory functions for the treatment of bacterial infection. Biomater Res 2023; 27:73. [PMID: 37481650 PMCID: PMC10363325 DOI: 10.1186/s40824-023-00405-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 06/05/2023] [Indexed: 07/24/2023] Open
Abstract
The advent of drug-resistant pathogens results in the occurrence of stubborn bacterial infections that cannot be treated with traditional antibiotics. Antibacterial immunotherapy by reviving or activating the body's immune system to eliminate pathogenic bacteria has confirmed promising therapeutic strategies in controlling bacterial infections. Subsequent studies found that antimicrobial immunotherapy has its own benefits and limitations, such as avoiding recurrence of infection and autoimmunity-induced side effects. Current studies indicate that the various antibacterial therapeutic strategies inducing immune regulation can achieve superior therapeutic efficacy compared with monotherapy alone. Therefore, summarizing the recent advances in nanomedicine with immunomodulatory functions for combating bacterial infections is necessary. Herein, we briefly introduce the crisis caused by drug-resistant bacteria and the opportunity for antibacterial immunotherapy. Then, immune-involved multimodal antibacterial therapy for the treatment of infectious diseases was systematically summarized. Finally, the prospects and challenges of immune-involved combinational therapy are discussed.
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Affiliation(s)
- Dongliang Yang
- Key Laboratory of Flexible Electronics (KLOFE) and Institute of Advanced Materials (IAM), School of Physical and Mathematical Sciences, Nanjing Tech University (NanjingTech), Nanjing, 211816, China
| | - Meng Ding
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Yanni Song
- Key Laboratory of Flexible Electronics (KLOFE) and Institute of Advanced Materials (IAM), School of Physical and Mathematical Sciences, Nanjing Tech University (NanjingTech), Nanjing, 211816, China.
| | - Yanling Hu
- State Key Laboratory of Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), Nanjing University of Posts & Telecommunications, 9 Wenyuan Road, Nanjing, 210023, China
| | - Weijun Xiu
- State Key Laboratory of Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), Nanjing University of Posts & Telecommunications, 9 Wenyuan Road, Nanjing, 210023, China
| | - Lihui Yuwen
- State Key Laboratory of Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), Nanjing University of Posts & Telecommunications, 9 Wenyuan Road, Nanjing, 210023, China
| | - Yannan Xie
- State Key Laboratory of Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), Nanjing University of Posts & Telecommunications, 9 Wenyuan Road, Nanjing, 210023, China.
| | - Yingnan Song
- Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550025, China.
| | - Jinjun Shao
- Key Laboratory of Flexible Electronics (KLOFE) and Institute of Advanced Materials (IAM), School of Physical and Mathematical Sciences, Nanjing Tech University (NanjingTech), Nanjing, 211816, China
| | - Xuejiao Song
- Key Laboratory of Flexible Electronics (KLOFE) and Institute of Advanced Materials (IAM), School of Physical and Mathematical Sciences, Nanjing Tech University (NanjingTech), Nanjing, 211816, China
| | - Heng Dong
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
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19
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Huang W, Rui K, Wang X, Peng N, Zhou W, Shi X, Lu L, Hu D, Tian J. The aryl hydrocarbon receptor in immune regulation and autoimmune pathogenesis. J Autoimmun 2023; 138:103049. [PMID: 37229809 DOI: 10.1016/j.jaut.2023.103049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/10/2023] [Accepted: 04/18/2023] [Indexed: 05/27/2023]
Abstract
As a ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR) is activated by structurally diverse ligands derived from the environment, diet, microorganisms, and metabolic activity. Recent studies have demonstrated that AhR plays a key role in modulating both innate and adaptive immune responses. Moreover, AhR regulates innate immune and lymphoid cell differentiation and function, which is involved in autoimmune pathogenesis. In this review, we discuss recent advances in understanding the mechanism of activation of AhR and its mediated functional regulation in various innate immune and lymphoid cell populations, as well as the immune-regulatory effect of AhR in the development of autoimmune diseases. In addition, we highlight the identification of AhR agonists and antagonists that may serve as potential therapeutic targets for the treatment of autoimmune disorders.
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Affiliation(s)
- Wei Huang
- Institute of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China; Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Ke Rui
- Institute of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China; Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
| | - Xiaomeng Wang
- Institute of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China; Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Na Peng
- Department of Rheumatology and Nephrology, The Second People's Hospital, China Three Gorges University, Yichang, China
| | - Wenhao Zhou
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Xiaofei Shi
- Department of Rheumatology and Immunology, The First Affiliated Hospital and School of Medicine, Henan University of Science and Technology, Luoyang, China
| | - Liwei Lu
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Chongqing International Institute for Immunology, China
| | - Dajun Hu
- Department of Rheumatology and Nephrology, The Second People's Hospital, China Three Gorges University, Yichang, China.
| | - Jie Tian
- Institute of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China; Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China.
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Yang L, Zheng C, Xia YF, Dai Y, Wei ZF. 3, 3'-diindolylmethane enhances macrophage efferocytosis and subsequently relieves visceral pain via the AhR/Nrf2/Arg-1-mediated arginine metabolism pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 116:154874. [PMID: 37216760 DOI: 10.1016/j.phymed.2023.154874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 04/28/2023] [Accepted: 05/09/2023] [Indexed: 05/24/2023]
Abstract
BACKGROUND 3, 3'-diindolylmethane (DIM), a classical aryl hydrocarbon receptor (AhR) agonist, has been shown to relieve neuropathic pain, but few studies have reported the efficacy of DIM in visceral pain under colitis condition. PURPOSE This study aimed to investigate the effect and mechanism of DIM on visceral pain under colitis condition. METHODS Cytotoxicity was performed using the MTT assay. RT-qPCR and ELISA assays were applied to determine the expression and release of algogenic substance P (SP), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Flow cytometry was used to examine the apoptosis and efferocytosis. The expression of Arg-1-arginine metabolism-related enzymes was detected using western blotting assays. ChIP assays were used to examine the binding of Nrf2 to Arg-1. Mouse models of dextran sulfate sodium (DSS) were established to illustrate the effect of DIM and validate the mechanism in vivo. RESULTS DIM did not directly affect expressions and release of algogenic SP, NGF and BDNF in enteric glial cells (EGCs). However, when co-cultured with DIM-pre-treated RAW264.7 cells, the release of SP and NGF was decreased in lipopolysaccharides-stimulated EGCs. Furthermore, DIM increased the number of PKH67+ F4/80+ cells in the co-culture system of EGCs and RAW264.7 cells in vitro and alleviated visceral pain under colitis condition by regulating levels of SP and NGF as well as values of electromyogram (EMG), abdominal withdrawal reflex (AWR) and tail-flick latency (TFL) in vivo, which was significantly inhibited by efferocytosis inhibitor. Subsequently, DIM was found to down-regulate levels of intracellular arginine, up-regulate levels of ornithine, putrescine and Arg-1 but not extracellular arginine or other metabolic enzymes, and polyamine scavengers reversed the effect of DIM on efferocytosis and release of SP and NGF. Moving forward, Nrf2 transcription and the binding of Nrf2 to Arg-1-0.7 kb was enhanced by DIM, AhR antagonist CH223191 abolished the promotion of DIM on Arg-1 and efferocytosis. Finally, nor-NOHA validated the importance of Arg-1-dependent arginine metabolism in DIM-alleviated visceral pain. CONCLUSION DIM enhances macrophage efferocytosis in an arginine metabolism-dependent manner via "AhR-Nrf2/Arg-1" signals and inhibits the release of SP and NGF to relieve visceral pain under colitis condition. These findings provide a potential therapeutic strategy for the treatment of visceral pain in patients with colitis.
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Affiliation(s)
- Ling Yang
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Chen Zheng
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Yu-Feng Xia
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Yue Dai
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
| | - Zhi-Feng Wei
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
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Riaz F, Pan F, Wei P. Aryl hydrocarbon receptor: The master regulator of immune responses in allergic diseases. Front Immunol 2022; 13:1057555. [PMID: 36601108 PMCID: PMC9806217 DOI: 10.3389/fimmu.2022.1057555] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 12/02/2022] [Indexed: 12/23/2022] Open
Abstract
The aryl hydrocarbon receptor (AhR) is a widely studied ligand-activated cytosolic transcriptional factor that has been associated with the initiation and progression of various diseases, including autoimmune diseases, cancers, metabolic syndromes, and allergies. Generally, AhR responds and binds to environmental toxins/ligands, dietary ligands, and allergens to regulate toxicological, biological, cellular responses. In a canonical signaling manner, activation of AhR is responsible for the increase in cytochrome P450 enzymes which help individuals to degrade and metabolize these environmental toxins and ligands. However, canonical signaling cannot be applied to all the effects mediated by AhR. Recent findings indicate that activation of AhR signaling also interacts with some non-canonical factors like Kruppel-like-factor-6 (KLF6) or estrogen-receptor-alpha (Erα) to affect the expression of downstream genes. Meanwhile, enormous research has been conducted to evaluate the effect of AhR signaling on innate and adaptive immunity. It has been shown that AhR exerts numerous effects on mast cells, B cells, macrophages, antigen-presenting cells (APCs), Th1/Th2 cell balance, Th17, and regulatory T cells, thus, playing a significant role in allergens-induced diseases. This review discussed how AhR mediates immune responses in allergic diseases. Meanwhile, we believe that understanding the role of AhR in immune responses will enhance our knowledge of AhR-mediated immune regulation in allergic diseases. Also, it will help researchers to understand the role of AhR in regulating immune responses in autoimmune diseases, cancers, metabolic syndromes, and infectious diseases.
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Affiliation(s)
- Farooq Riaz
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen, China
| | - Fan Pan
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen, China,*Correspondence: Ping Wei, ; Fan Pan,
| | - Ping Wei
- Department of Otolaryngology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing, China,*Correspondence: Ping Wei, ; Fan Pan,
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Wu J, Pang T, Lin Z, Zhao M, Jin H. The key player in the pathogenesis of environmental influence of systemic lupus erythematosus: Aryl hydrocarbon receptor. Front Immunol 2022; 13:965941. [PMID: 36110860 PMCID: PMC9468923 DOI: 10.3389/fimmu.2022.965941] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 08/01/2022] [Indexed: 11/28/2022] Open
Abstract
The aryl hydrocarbon receptor was previously known as an environmental receptor that modulates the cellular response to external environmental changes. In essence, the aryl hydrocarbon receptor is a cytoplasmic receptor and transcription factor that is activated by binding to the corresponding ligands, and they transmit relevant information by binding to DNA, thereby activating the transcription of various genes. Therefore, we can understand the development of certain diseases and discover new therapeutic targets by studying the regulation and function of AhR. Several autoimmune diseases, including systemic lupus erythematosus (SLE), have been connected to AhR in previous studies. SLE is a classic autoimmune disease characterized by multi-organ damage and disruption of immune tolerance. We discuss here the homeostatic regulation of AhR and its ligands among various types of immune cells, pathophysiological roles, in addition to the roles of various related cytokines and signaling pathways in the occurrence and development of SLE.
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Dental Pulp-Derived Stem Cells Reduce Inflammation, Accelerate Wound Healing and Mediate M2 Polarization of Myeloid Cells. Biomedicines 2022; 10:biomedicines10081999. [PMID: 36009546 PMCID: PMC9624276 DOI: 10.3390/biomedicines10081999] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/11/2022] [Accepted: 08/15/2022] [Indexed: 01/09/2023] Open
Abstract
This work aimed to validate the potential use of dental pulp-derived stem cells (DPSCs) for the treatment of inflammation by defining their mechanisms of action. We planned to investigate whether priming of DPSC with proinflammatory molecules had any impact on their behavior and function. In the first step of our validation in vitro, we showed that priming of DPSCs with the bioactive agents LPS, TNF-α, or IFN-γ altered DPSCs’ immunologic properties by increasing their expression levels of IL-10, HGF, IDO, and IL-4 and by decreasing their mitochondrial functions. Moreover, DPSCs induced accelerated wound healing irrespective of priming, as determined by using a gut epithelial cell line in a scratch wound assay. Wound healing of gut epithelial cells was mediated by regulating the expressions of AKT, NF-κB, and ERK1/2 proteins compared to the control epithelial cells. In addition, primed DPSCs altered monocyte polarization toward an immuno-suppressive phenotype (M2), where monocytes expressed higher levels of IL-4R, IL-6, Arg1, and YM-1 compared to monocytes cultured with control DPSCs. In silico analysis revealed that this was accomplished in part by the interaction between kynurenine and PPARγ, which regulated the expression of M2 differentiation-related genes. Collectively, these data provided evidence that the DPSCs reduced inflammation, induced M2 polarization of myeloid cells, and healed damaged gut epithelial cells through inactivation of inflammation and modulating constitutively active signaling pathways.
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Huang J, Wang Y, Zhou Y. Beneficial roles of the AhR ligand FICZ on the regenerative potentials of BMSCs and primed cartilage templates. RSC Adv 2022; 12:11505-11516. [PMID: 35425032 PMCID: PMC9007154 DOI: 10.1039/d2ra00622g] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 03/30/2022] [Indexed: 12/14/2022] Open
Abstract
Bone marrow-derived mesenchymal stem cells (BMSCs) are commonly used seed cells, and BMSC-derived primed cartilage templates have been shown to achieve bone regeneration in bone tissue engineering. Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in various cellular processes such as osteogenesis and immune regulation. This study investigated the effects of the AhR endogenous ligand 6-formyl (3,2-b) carbazole (FICZ) on the behavior of BMSCs and cartilage templates as well as the possible underlying molecular mechanisms. AhR expressions in rat bone marrow and isolated BMSCs were detected via immunohistochemistry (IHC) and immunofluorescent staining. Alkaline phosphatase staining and alizarin red staining showed that FICZ treatment enhanced the osteogenic potential of BMSCs without influencing their proliferation. FICZ was shown to alleviate the LPS-induced inflammatory cytokines IL-1β, 6 and TNF-α via the quantitative polymerase chain reaction (qPCR). In the chondrogenic process from BMSCs to primed cartilage templates, the expressions of AhR and its target gene cytochrome P450 subfamily B member 1 (CYP1B1) were inhibited. However, IHC staining demonstrated that AhR was still involved in the subcutaneous ossification of cartilage templates. Then, the effects of FICZ on cartilage templates were investigated. The osteogenic markers were upregulated by FICZ administration. The RAW 264.7 treated by condition medium of FICZ-treated cartilage templates exhibited an anti-inflammatory phenotype. Finally, high-throughput sequencing was applied to analyze the differentially expressed genes (DEGs) in the FICZ-treated cartilage templates. The upregulation of cytochrome P450 subfamily A member 1 (CYP1A1) and sphingomyelin phosphodiesterase 3 (Smpd3) were verified by qPCR, which might be the downstream targets of AhR in the cartilage templates promoting osteogenesis and macrophage polarization. These data implied a beneficial role of FICZ in the regenerative potentials of both BMSCs and primed cartilage templates. The FICZ/AhR axis might be a practical target to achieve optimal bone regeneration.
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Affiliation(s)
- Jing Huang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST), Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University 237 Luoyu Road Wuhan 430079 China +86 27 87873260 +86 27 87686318
| | - Yining Wang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST), Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University 237 Luoyu Road Wuhan 430079 China +86 27 87873260 +86 27 87686318
- Department of Prosthodontics, Hospital of Stomatology, Wuhan University Wuhan 430079 China
| | - Yi Zhou
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST), Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University 237 Luoyu Road Wuhan 430079 China +86 27 87873260 +86 27 87686318
- Department of Prosthodontics, Hospital of Stomatology, Wuhan University Wuhan 430079 China
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Dean JW, Zhou L. Cell-intrinsic view of the aryl hydrocarbon receptor in tumor immunity. Trends Immunol 2022; 43:245-258. [PMID: 35131180 PMCID: PMC8882133 DOI: 10.1016/j.it.2022.01.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/06/2022] [Accepted: 01/07/2022] [Indexed: 12/15/2022]
Abstract
Emerging insights into aryl hydrocarbon receptor (Ahr) biology have revealed its key role in regulating mammalian host immunity and tissue homeostasis. Depending on the context, immune cells can play either a pro- or antitumor role in cancer. Ahr has classically been viewed as protumorigenic; however, given recent advances in our understanding of Ahr functions, especially in the immune system, this view requires reassessment. Moreover, given its cell type-specific activity, therapeutic exploitation of the Ahr pathway should be cautiously considered. We describe the function of Ahr in different immune cells, and connect with their roles in cancer immunology. In addition, we discuss clinical perspectives of how recent advances in our understanding of Ahr biology might be therapeutically applied to improve cancer outcomes.
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Affiliation(s)
- Joseph W. Dean
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Liang Zhou
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA.
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Rannug A. 6-Formylindolo[3,2-b]carbazole, a Potent Ligand for the Aryl Hydrocarbon Receptor Produced Both Endogenously and by Microorganisms, can Either Promote or Restrain Inflammatory Responses. FRONTIERS IN TOXICOLOGY 2022; 4:775010. [PMID: 35295226 PMCID: PMC8915874 DOI: 10.3389/ftox.2022.775010] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 01/11/2022] [Indexed: 12/13/2022] Open
Abstract
The aryl hydrocarbon receptor (AHR) binds major physiological modifiers of the immune system. The endogenous 6-formylindolo[3,2-b]carbazole (FICZ), which binds with higher affinity than any other compound yet tested, including TCDD, plays a well-documented role in maintaining the homeostasis of the intestines and skin. The effects of transient activation of AHR by FICZ differ from those associated with continuous stimulation and, depending on the dose, include either differentiation into T helper 17 cells that express proinflammatory cytokines or into regulatory T cells or macrophages with anti-inflammatory properties. Moreover, in experimental models of human diseases high doses stimulate the production of immunosuppressive cytokines and suppress pathogenic autoimmunity. In our earlier studies we characterized the formation of FICZ from tryptophan via the precursor molecules indole-3-pyruvate and indole-3-acetaldehyde. In the gut formation of these precursor molecules is catalyzed by microbial aromatic-amino-acid transaminase ArAT. Interestingly, tryptophan can also be converted into indole-3-pyruvate by the amino-acid catabolizing enzyme interleukin-4 induced gene 1 (IL4I1), which is secreted by host immune cells. By thus generating derivatives of tryptophan that activate AHR, IL4I1 may have a role to play in anti-inflammatory responses, as well as in a tumor escape mechanism that reduces survival in cancer patients. The realization that FICZ can be produced from tryptophan by sunlight, by enzymes expressed in our cells (IL4I1), and by microorganisms as well makes it highly likely that this compound is ubiquitous in humans. A diurnal oscillation in the level of FICZ that depends on the production by the fluctuating number of microbes might influence not only intestinal and dermal immunity locally, but also systemic immunity.
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Fernández-Gallego N, Sánchez-Madrid F, Cibrian D. Role of AHR Ligands in Skin Homeostasis and Cutaneous Inflammation. Cells 2021; 10:cells10113176. [PMID: 34831399 PMCID: PMC8622815 DOI: 10.3390/cells10113176] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/09/2021] [Accepted: 11/12/2021] [Indexed: 02/07/2023] Open
Abstract
Aryl hydrocarbon receptor (AHR) is an important regulator of skin barrier function. It also controls immune-mediated skin responses. The AHR modulates various physiological functions by acting as a sensor that mediates environment–cell interactions, particularly during immune and inflammatory responses. Diverse experimental systems have been used to assess the AHR’s role in skin inflammation, including in vitro assays of keratinocyte stimulation and murine models of psoriasis and atopic dermatitis. Similar approaches have addressed the role of AHR ligands, e.g., TCDD, FICZ, and microbiota-derived metabolites, in skin homeostasis and pathology. Tapinarof is a novel AHR-modulating agent that inhibits skin inflammation and enhances skin barrier function. The topical application of tapinarof is being evaluated in clinical trials to treat psoriasis and atopic dermatitis. In the present review, we summarize the effects of natural and synthetic AHR ligands in keratinocytes and inflammatory cells, and their relevance in normal skin homeostasis and cutaneous inflammatory diseases.
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Affiliation(s)
- Nieves Fernández-Gallego
- Immunology Service, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa (IIS-IP), 28006 Madrid, Spain;
- Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - Francisco Sánchez-Madrid
- Immunology Service, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa (IIS-IP), 28006 Madrid, Spain;
- Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
- CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence: (F.S.-M.); (D.C.)
| | - Danay Cibrian
- Immunology Service, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa (IIS-IP), 28006 Madrid, Spain;
- Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
- CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence: (F.S.-M.); (D.C.)
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Jayaraman A, Arianas M, Jayaraman S. Epigenetic modulation of selected immune response genes and altered functions of T lymphocytes and macrophages collectively contribute to autoimmune diabetes protection. BBA ADVANCES 2021; 1:100031. [PMID: 37082012 PMCID: PMC10074972 DOI: 10.1016/j.bbadva.2021.100031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
We have previously demonstrated that weekly treatment of female prediabetic NOD mice with a low dose of the histone deacetylase inhibitor Trichostatin A (TSA) bestowed long-lasting, irreversible protection against autoimmune diabetes. Herein we show that drug treatment diminished the infiltration of the pancreas with CD4+, CD8+ T cells, and Ly-6C+ monocytes. Significantly, TSA administration selectively repressed the expression of a set of genes exaggerated during diabetes and constitutively expressed primarily in the spleen and rarely in the pancreas. These genes encode lymphokines, macrophage-associated determinants, and transcription factors. Although the copy numbers of many histone deacetylases increased during diabetes in the spleen and pancreas, only those upregulated in the spleen were rendered sensitive to repression by TSA treatment. Mitogen-activated T lymphocytes derived from drug-treated donors displayed diminished diabetogenic potential following transfer into immunodeficient NOD.scid mice. In the immunocompromised recipients, diabetes caused by the transfer of activated T lymphocytes from untreated diabetic mice was hampered by the co-transfer of highly purified splenic CD11b+Ly-6C+ macrophages from drug-treated mice. However, the transfer of CD11b+Ly-6C+ macrophages from drug-treated mice failed to block ongoing diabetes in wild-type NOD mice. These data demonstrate that the modified gene expression and functional alteration of T lymphocytes and macrophages collectively contribute to diabetes protection afforded by the histone modifier in female NOD mice.
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Affiliation(s)
- Arathi Jayaraman
- Dept. of Surgery, the University of Illinois at Chicago, Chicago, IL 60612
| | - Maria Arianas
- Dept. of Surgery, the University of Illinois at Chicago, Chicago, IL 60612
| | - Sundararajan Jayaraman
- Dept. of Surgery, the University of Illinois at Chicago, Chicago, IL 60612
- Dept. of Surgery, University of Illinois College of Medicine at Peoria, IL 61603
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Segner H, Bailey C, Tafalla C, Bo J. Immunotoxicity of Xenobiotics in Fish: A Role for the Aryl Hydrocarbon Receptor (AhR)? Int J Mol Sci 2021; 22:ijms22179460. [PMID: 34502366 PMCID: PMC8430475 DOI: 10.3390/ijms22179460] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/25/2021] [Accepted: 08/27/2021] [Indexed: 02/07/2023] Open
Abstract
The impact of anthropogenic contaminants on the immune system of fishes is an issue of growing concern. An important xenobiotic receptor that mediates effects of chemicals, such as halogenated aromatic hydrocarbons (HAHs) and polyaromatic hydrocarbons (PAHs), is the aryl hydrocarbon receptor (AhR). Fish toxicological research has focused on the role of this receptor in xenobiotic biotransformation as well as in causing developmental, cardiac, and reproductive toxicity. However, biomedical research has unraveled an important physiological role of the AhR in the immune system, what suggests that this receptor could be involved in immunotoxic effects of environmental contaminants. The aims of the present review are to critically discuss the available knowledge on (i) the expression and possible function of the AhR in the immune systems of teleost fishes; and (ii) the impact of AhR-activating xenobiotics on the immune systems of fish at the levels of immune gene expression, immune cell proliferation and immune cell function, immune pathology, and resistance to infectious disease. The existing information indicates that the AhR is expressed in the fish immune system, but currently, we have little understanding of its physiological role. Exposure to AhR-activating contaminants results in the modulation of numerous immune structural and functional parameters of fish. Despite the diversity of fish species studied and the experimental conditions investigated, the published findings rather uniformly point to immunosuppressive actions of xenobiotic AhR ligands in fish. These effects are often associated with increased disease susceptibility. The fact that fish populations from HAH- and PAH-contaminated environments suffer immune disturbances and elevated disease susceptibility highlights that the immunotoxic effects of AhR-activating xenobiotics bear environmental relevance.
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Affiliation(s)
- Helmut Segner
- Centre for Fish and Wildlife Health, Department of Pathobiology and Infectious Diseases, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
| | | | | | - Jun Bo
- Laboratory of Marine Biology and Ecology, Third Institute of Oceanography, Xiamen 361005, China
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A Combination of GM-CSF and Released Factors from Gamma-Irradiated Tumor Cells Enhances the Differentiation of Macrophages from Bone Marrow Cells and Their Antigen-Presenting Function and Polarization to Type 1. MEDICINES 2021; 8:medicines8070035. [PMID: 34357151 PMCID: PMC8305403 DOI: 10.3390/medicines8070035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 06/29/2021] [Accepted: 06/30/2021] [Indexed: 11/20/2022]
Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes dendritic cell differentiation from precursors, and consequently, enhances the antigen presentation process and adaptive immune responses. With such functions, GM-CSF has been used as immunotherapy in combination with radiotherapy for cancer treatment to augment the survival and activity of immune cells. However, an immune-suppressive tumor microenvironment may cause anergy of T cells. It has also been reported that GM-CSF contributes to the development of myeloid-derived suppressor cells from the precursors. In this study, to analyze the combined effect of GM-CSF and released factors from cancer cells after gamma-ray irradiation on bone marrow cell differentiation and dynamics, we established an in vitro culture system using mouse bone marrow cells, GM-CSF, and conditioned medium from gamma ray irradiated mouse melanoma B16 cells at 24 Gy. We analyzed the gene expression changes of the bone marrow-derived cells on day 6. The results showed that GM-CSF dose-dependently enhanced the differentiation of macrophages from bone marrow cells, their antigen-presenting function and polarization to type I. The results implied the induced macrophages from the bone marrow may potentially contribute to tumor immune responses in a systemic manner when GM-CSF is boosted during photon-beam radiation therapy.
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Metabolomics in Bone Research. Metabolites 2021; 11:metabo11070434. [PMID: 34357328 PMCID: PMC8303949 DOI: 10.3390/metabo11070434] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/18/2021] [Accepted: 06/28/2021] [Indexed: 12/12/2022] Open
Abstract
Identifying the changes in endogenous metabolites in response to intrinsic and extrinsic factors has excellent potential to obtain an understanding of cells, biofluids, tissues, or organisms' functions and interactions with the environment. The advantages provided by the metabolomics strategy have promoted studies in bone research fields, including an understanding of bone cell behaviors, diagnosis and prognosis of diseases, and the development of treatment methods such as implanted biomaterials. This review article summarizes the metabolism changes during osteogenesis, osteoclastogenesis, and immunoregulation in hard tissue. The second section of this review is dedicated to describing and discussing metabolite changes in the most relevant bone diseases: osteoporosis, bone injuries, rheumatoid arthritis, and osteosarcoma. We consolidated the most recent finding of the metabolites and metabolite pathways affected by various bone disorders. This collection can serve as a basis for future metabolomics-driven bone research studies to select the most relevant metabolites and metabolic pathways. Additionally, we summarize recent metabolic studies on metabolomics for the development of bone disease treatment including biomaterials for bone engineering. With this article, we aim to provide a comprehensive summary of metabolomics in bone research, which can be helpful for interdisciplinary researchers, including material engineers, biologists, and clinicians.
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Vellozo NS, Rigoni TS, Lopes MF. New Therapeutic Tools to Shape Monocyte Functional Phenotypes in Leishmaniasis. Front Immunol 2021; 12:704429. [PMID: 34249011 PMCID: PMC8267810 DOI: 10.3389/fimmu.2021.704429] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 06/14/2021] [Indexed: 01/25/2023] Open
Abstract
In the innate immunity to Leishmania infection tissue-resident macrophages and inflammatory monocytes accumulate host-cell, effector, and efferocytosis functions. In addition, neutrophils, as host, effector, and apoptotic cells, as well as tissue-resident and monocyte-derived dendritic cells (DCs) imprint innate and adaptive immunity to Leishmania parasites. Macrophages develop phenotypes ranging from antimicrobial M1 to parasite-permissive M2, depending on mouse strain, Leishmania species, and T-cell cytokines. The Th1 (IFN-γ) and Th2 (IL-4) cytokines, which induce classically-activated (M1) or alternatively-activated (M2) macrophages, underlie resistance versus susceptibility to leishmaniasis. While macrophage phenotypes have been well discussed, new developments addressed the monocyte functional phenotypes in Leishmania infection. Here, we will emphasize the role of inflammatory monocytes to access how potential host-directed therapies for leishmaniasis, such as all-trans-retinoic acid (ATRA) and the ligand of Receptor Activator of Nuclear Factor-Kappa B (RANKL) might modulate immunity to Leishmania infection, by directly targeting monocytes to develop M1 or M2 phenotypes.
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Affiliation(s)
- Natália S Vellozo
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Thaís S Rigoni
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcela F Lopes
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Valéria Amorim L, de Lima Moreira D, Muálem de Moraes Alves M, Jessé Ramos Y, Pereira Costa Sobrinho E, Arcanjo DDR, Rodrigues de Araújo A, de Souza de Almeida Leite JR, das Chagas Pereira de Andrade F, Mendes AN, Aécio de Amorim Carvalho F. Anti-Leishmania activity of extracts from Piper cabralanum C.DC. (Piperaceae). ACTA ACUST UNITED AC 2021; 76:229-241. [PMID: 33660490 DOI: 10.1515/znc-2020-0284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 02/06/2021] [Indexed: 11/15/2022]
Abstract
Species of Piperaceae are known by biological properties, including antiparasitic such as leishmanicidal, antimalarial and in the treatment of schistosomiasis. The aim of this work was to evaluate the antileishmania activity, cytotoxic effect, and macrophage activation patterns of the methanol (MeOH), hexane (HEX), dichloromethane (DCM) and ethyl acetate (EtOAc) extract fractions from the leaves of Piper cabralanum C.DC. The MeOH, HEX and DCM fractions inhibited Leishmanina amazonensis promastigote-like forms growth with a half maximal inhibitory concentration (IC50) of 144.54, 59.92, and 64.87 μg/mL, respectively. The EtOAc fraction did not show any relevant activity. The half maximal cytotoxic concentration (CC50) for macrophages were determined as 370.70, 83.99, 113.68 and 607 μg/mL for the MeOH, HEX and DCM fractions, respectively. The macrophage infectivity was concentration-dependent, especially for HEX and DCM. MeOH, HEX and DCM fractions showed activity against L. amazonensis with low cytotoxicity to murine macrophages and lowering infectivity by the parasite. Our results provide support for in vivo studies related to a potential application of P. cabralanum extract and fractions as a promising natural resource in the treatment of leishmaniasis.
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Affiliation(s)
- Layane Valéria Amorim
- Antileishmania Activity Laboratory, Federal University of Piauí, Teresina, Piauí, Brazil
| | - Davyson de Lima Moreira
- Natural Products Laboratory, Institute of Pharmaceutical Tecnologies, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro-RJ, Brazil
| | | | - Ygor Jessé Ramos
- Natural Products Laboratory, Institute of Pharmaceutical Tecnologies, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro-RJ, Brazil
| | | | - Daniel Dias Rufino Arcanjo
- Department of Biophysics and Physiology, Laboratory of Funcional and Molecular Studies in Physiopharmacology, Federal University of Piauí, Teresina, Piauí, Brazil
| | - Alyne Rodrigues de Araújo
- Research Center on Biodiversity and Biotechnology, BIOTEC, Federal University of Delta of Parnaíba, UFDPar, Parnaíba, Piauí, Brazil
| | | | | | - Anderson Nogueira Mendes
- Department of Biophysics and Physiology, Laboratory of Innovation on Science and Technology, Federal University of Piauí, Teresina, Piauí, Brazil
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Potential role of polycyclic aromatic hydrocarbons in air pollution-induced non-malignant respiratory diseases. Respir Res 2020; 21:299. [PMID: 33187512 PMCID: PMC7666487 DOI: 10.1186/s12931-020-01563-1] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 11/01/2020] [Indexed: 12/12/2022] Open
Abstract
Epidemiological studies have found strong associations between air pollution and respiratory effects including development and/or exacerbation of asthma and chronic obstructive pulmonary disease (COPD) as well as increased occurrence of respiratory infections and lung cancer. It has become increasingly clear that also polycyclic aromatic hydrocarbons (PAHs) may affect processes linked to non-malignant diseases in the airways. The aim of the present paper was to review epidemiological studies on associations between gas phase and particle-bound PAHs in ambient air and non-malignant respiratory diseases or closely related physiological processes, to assess whether PAH-exposure may explain some of the effects associated with air pollution. Based on experimental in vivo and in vitro studies, we also explore possible mechanisms for how different PAHs may contribute to such events. Epidemiological studies show strongest evidence for an association between PAHs and asthma development and respiratory function in children. This is supported by studies on prenatal and postnatal exposure. Exposure to PAHs in adults seems to be linked to respiratory functions, exacerbation of asthma and increased morbidity/mortality of obstructive lung diseases. However, available studies are few and weak. Notably, the PAHs measured in plasma/urine also represent other exposure routes than inhalation. Furthermore, the role of PAHs measured in air is difficult to disentangle from that of other air pollution components originating from combustion processes. Experimental studies show that PAHs may trigger various processes linked to non-malignant respiratory diseases. Physiological- and pathological responses include redox imbalance, oxidative stress, inflammation both from the innate and adaptive immune systems, smooth muscle constriction, epithelial- and endothelial dysfunction and dysregulated lung development. Such biological responses may at the molecular level be initiated by PAH-binding to the aryl hydrocarbon receptor (AhR), but possibly also through interactions with beta-adrenergic receptors. In addition, reactive PAH metabolites or reactive oxygen species (ROS) may interfere directly with ion transporters and enzymes involved in signal transduction. Overall, the reviewed literature shows that respiratory effects of PAH-exposure in ambient air may extend beyond lung cancer. The relative importance of the specific PAHs ability to induce disease may differ between the biological endpoint in question.
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Yang X, Liu H, Ye T, Duan C, Lv P, Wu X, Liu J, Jiang K, Lu H, Yang H, Xia D, Peng E, Chen Z, Tang K, Ye Z. AhR activation attenuates calcium oxalate nephrocalcinosis by diminishing M1 macrophage polarization and promoting M2 macrophage polarization. Am J Cancer Res 2020; 10:12011-12025. [PMID: 33204326 PMCID: PMC7667681 DOI: 10.7150/thno.51144] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 10/04/2020] [Indexed: 02/06/2023] Open
Abstract
Calcium oxalate (CaOx) crystal can trigger kidney injury, which contributes to the pathogenesis of nephrocalcinosis. The phenotypes of infiltrating macrophage may impact CaOx-mediated kidney inflammatory injury as well as crystal deposition. How aryl hydrocarbon receptor (AhR) regulates inflammation and macrophage polarization is well understood; however, how it modulates CaOx nephrocalcinosis remains unclear. Methods: Mice were intraperitoneally injected with glyoxylate to establish CaOx nephrocalcinosis model with or without the treatment of AhR activator 6-formylindolo(3,2-b)carbazole (FICZ). Positron emission tomography computed tomography (PET-CT) imaging, Periodic acid-Schiff (PAS) staining, and polarized light optical microscopy were used to evaluate kidney injury and crystal deposition in mice kidney. Western blotting, immunofluorescence, chromatin immunoprecipitation, microRNA-fluorescence in situ hybridization, and luciferase reporter assays were applied to analyze polarization state and regulation mechanism of macrophage. Results: AhR expression was significantly upregulated and negatively correlated with interferon-regulatory factor 1 (IRF1) and hypoxia inducible factor 1-alpha (HIF-1α) levels in a murine CaOx nephrocalcinosis model following administration of FICZ. Moreover, AhR activation suppressed IRF1 and HIF-1α levels and decreased M1 macrophage polarization in vitro. In terms of the mechanism, bioinformatics analysis and chromatin immunoprecipitation assay confirmed that AhR could bind to miR-142a promoter to transcriptionally activate miR-142a. In addition, luciferase reporter assays validated that miR-142a inhibited IRF1 and HIF-1α expression by directly targeting their 3'-untranslated regions. Conclusions: Our results indicated that AhR activation could diminish M1 macrophage polarization and promote M2 macrophage polarization to suppress CaOx nephrocalcinosis via the AhR-miR-142a-IRF1/HIF-1α pathway.
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Liu C, Sun J. Modulation of the secretion of mesenchymal stem cell immunoregulatory factors by hydrolyzed fish collagen. Exp Ther Med 2020; 20:375-384. [PMID: 32509014 PMCID: PMC7271731 DOI: 10.3892/etm.2020.8674] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 03/26/2020] [Indexed: 12/14/2022] Open
Abstract
The aim of the present study was to investigate the possible immunomodulatory effects of osteogenically differentiated bone marrow mesenchymal stem cells induced by hydrolyzed fish collagen. Marine biomaterials have attracted significant attention for their environmental friendliness and renewability. Hydrolyzed fish collagen (HFC) has been discovered to induce the osteoblastic differentiation of stem cells, which underlies the foundation for its application in tissue engineering. Stem cells and their biomaterial carriers face acute immune rejection mediated by host macrophages. A potential strategy for combatting rejection in stem cell therapy is to modify the polarization of macrophages. However, whether HFC-induced mesenchymal stem cells maintain their immunomodulatory ability remains to be determined. To understand this phenomenon, a co-culture model of direct contact was established between bone marrow mesenchymal stem cells (BMSCs) and RAW264.7 macrophages, where the secretion of nitrous oxide from macrophages was measured using Griess colorimetric assay. ELISAs were performed to measure the secretion of interleukin (IL)-1β, IL-6, transforming growth factor (TGF)-β and IL-10, whilst reverse transcription-quantitative PCR was used to assess the expression levels of IL-1β, IL-6, CD206, resistin-like molecule α (FIZZ1) and prostaglandin E2 receptor 4 (EP4). In addition, the expression levels of relevant proteins in the phosphorylated-cyclic AMP-responsive element-binding protein-CCAAT/enhancer-binding protein β (EBPβ) pathway were investigated using western blotting. HFC-induced BMSCs were found to suppress the expression levels of IL-1β and IL-6, whilst increasing the expression levels of CD206 and FIZZ1 in RAW264.7 macrophages. HFC-induced BMSCs also inhibited the secretion of IL-1β and IL-6, whilst promoting the secretion of TGF-β and IL-10 secretion from RAW264.7 macrophages. Mechanistic studies using western blotting discovered that HFC stimulated the secretion of prostaglandin E2 from BMSCs, which subsequently increased the expression of EP4 on the macrophages. EP4 then increased the expression levels of C/EBPβ and arginase 1 further. In conclusion, results from the present study suggested that following induction with HFC, BMSCs maintain their immunomodulatory activity.
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Affiliation(s)
- Chao Liu
- Shanghai Biomaterials Research and Testing Center, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200023, P.R. China
| | - Jiao Sun
- Shanghai Biomaterials Research and Testing Center, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200023, P.R. China
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Matsumoto K, Kinoshita K, Yoshimizu A, Kurauchi Y, Hisatsune A, Seki T, Katsuki H. Laquinimod and 3,3'-diindolylemethane alleviate neuropathological events and neurological deficits in a mouse model of intracerebral hemorrhage. J Neuroimmunol 2020; 342:577195. [PMID: 32120083 DOI: 10.1016/j.jneuroim.2020.577195] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 02/03/2020] [Accepted: 02/18/2020] [Indexed: 01/02/2023]
Abstract
We examined the effects of compounds shown to activate aryl hydrocarbon receptor (AhR) signaling on a mouse model of intracerebral hemorrhage (ICH). Daily oral administration of laquinimod (25 mg/kg) or 3,3'-diindolylmethane (250 mg/kg) from 3 h after ICH induction improved motor functions, prevented the decrease of neurons within the hematoma, and attenuated activation of microglia/macrophages and astrocytes in the perihematomal region as well as infiltration of neutrophils into the hematoma. Elevated expression of AhR was detected in microglia and neutrophils, and both drugs inhibited upregulation of interleukin-6 and CXCL1. These results propose AhR as a therapeutic target for ICH.
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Affiliation(s)
- Kosei Matsumoto
- Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences and School of Pharmacy, Kumamoto University, Kumamoto 862-0973, Japan
| | - Keita Kinoshita
- Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences and School of Pharmacy, Kumamoto University, Kumamoto 862-0973, Japan
| | - Ayaka Yoshimizu
- Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences and School of Pharmacy, Kumamoto University, Kumamoto 862-0973, Japan
| | - Yuki Kurauchi
- Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences and School of Pharmacy, Kumamoto University, Kumamoto 862-0973, Japan
| | - Akinori Hisatsune
- Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto 860-8555, Japan; Program for Leading Graduate Schools "HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University, Kumamoto 862-0973, Japan
| | - Takahiro Seki
- Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences and School of Pharmacy, Kumamoto University, Kumamoto 862-0973, Japan
| | - Hiroshi Katsuki
- Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences and School of Pharmacy, Kumamoto University, Kumamoto 862-0973, Japan.
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Münck NA, Roth J, Sunderkötter C, Ehrchen J. Aryl Hydrocarbon Receptor-Signaling Regulates Early Leishmania major-Induced Cytokine Expression. Front Immunol 2019; 10:2442. [PMID: 31749794 PMCID: PMC6843081 DOI: 10.3389/fimmu.2019.02442] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 10/01/2019] [Indexed: 02/05/2023] Open
Abstract
The early inflammatory skin micromilieu affects resistance in experimental infection with Leishmania major. We pursue the concept that macrophages, which take up parasites during early infection, exert decisive influence on the inflammatory micromilieu after infection. In order to analyze their distinctive potential, we identified differentially regulated genes of murine granuloma macrophages (GMΦ) from resistant and susceptible mice after their infection with metacyclic Leishmania major. We found induction of several cytokines in GMΦ from both strains and a stronger upregulation of the transcription factor aryl hydrocarbon receptor (AhR) in GMΦ from resistant mice. Using both an AhR agonist and antagonist we demonstrated that AhR is involved in Leishmania-induced production of TNF in macrophages. In vivo, single local injection of an AhR agonist in early lesions of susceptible mice caused an increased induction of Tnf and other cytokines in the skin. Importantly, local agonist treatment led to a reduction of disease severity, reduced parasite loads and a weaker Th2 response. Our results demonstrate that local activation of AhR has a beneficial effect in experimental leishmaniasis.
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Affiliation(s)
- Niels-Arne Münck
- Institute of Immunology, University of Münster, Münster, Germany.,Department of Translational Dermatoinfectiology, University of Münster, Münster, Germany
| | - Johannes Roth
- Institute of Immunology, University of Münster, Münster, Germany
| | - Cord Sunderkötter
- Department of Translational Dermatoinfectiology, University of Münster, Münster, Germany.,Department of Dermatology, University of Münster, Münster, Germany.,Department of Dermatology and Venereology, Martin Luther University of Halle-Wittenberg, Halle, Germany
| | - Jan Ehrchen
- Department of Dermatology, University of Münster, Münster, Germany
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39
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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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Bravo-Ferrer I, Cuartero MI, Medina V, Ahedo-Quero D, Peña-Martínez C, Pérez-Ruíz A, Fernández-Valle ME, Hernández-Sánchez C, Fernández-Salguero PM, Lizasoain I, Moro MA. Lack of the aryl hydrocarbon receptor accelerates aging in mice. FASEB J 2019; 33:12644-12654. [PMID: 31483997 DOI: 10.1096/fj.201901333r] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, largely known for its role in xenobiotic metabolism and detoxification as well as its crucial role as a regulator of inflammation. Here, we have compared a cohort wild-type and AhR-null mice along aging to study the relationship between this receptor and age-associated inflammation, termed as "inflammaging," both at a systemic and the CNS level. Our results show that AhR deficiency is associated with a premature aged phenotype, characterized by early inflammaging, as shown by an increase in plasma cytokines levels. The absence of AhR also promotes the appearance of brain aging anatomic features, such as the loss of the white matter integrity. In addition, AhR-/- mice present an earlier spatial memory impairment and an enhanced astrogliosis in the hippocampus when compared with their age-matched AhR+/+ controls. Importantly, we have found that AhR protein levels decrease with age in this brain structure, strongly suggesting a link between AhR and aging.-Bravo-Ferrer, I., Cuartero, M. I., Medina, V., Ahedo-Quero, D., Peña-Martínez, C., Pérez-Ruíz, A., Fernández-Valle, M. E., Hernández-Sánchez, C., Fernández-Salguero, P. M., Lizasoain, I., Moro, M. A. Lack of the aryl hydrocarbon receptor accelerates aging in mice.
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Affiliation(s)
- Isabel Bravo-Ferrer
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Madrid, Spain.,Instituto Universitario de Investigación en Neuroquímica (IUIN), Madrid, Spain.,Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain
| | - María I Cuartero
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Madrid, Spain.,Instituto Universitario de Investigación en Neuroquímica (IUIN), Madrid, Spain.,Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain
| | - Violeta Medina
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Madrid, Spain.,Instituto Universitario de Investigación en Neuroquímica (IUIN), Madrid, Spain.,Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain
| | - Dalia Ahedo-Quero
- Escuela Superior de Medicina del Instituto Politécnico Nacional, Ciudad de México, México
| | - Carolina Peña-Martínez
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Madrid, Spain.,Instituto Universitario de Investigación en Neuroquímica (IUIN), Madrid, Spain.,Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain
| | - Alberto Pérez-Ruíz
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Madrid, Spain.,Instituto Universitario de Investigación en Neuroquímica (IUIN), Madrid, Spain.,Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain
| | - M Encarnación Fernández-Valle
- Unidad de Resonancia Magnética Nuclear (RMN), Centro de Apoyo a la Investigación (CAI) de Bioimagen, Universidad Complutense de Madrid (UCM), Madrid, Spain
| | - Catalina Hernández-Sánchez
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Pedro M Fernández-Salguero
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, Badajoz, Badajoz, Spain
| | - Ignacio Lizasoain
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Madrid, Spain.,Instituto Universitario de Investigación en Neuroquímica (IUIN), Madrid, Spain.,Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain
| | - María A Moro
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Madrid, Spain.,Instituto Universitario de Investigación en Neuroquímica (IUIN), Madrid, Spain.,Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain
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Gabriely G, Quintana FJ. Role of AHR in the control of GBM-associated myeloid cells. Semin Cancer Biol 2019; 64:13-18. [PMID: 31128300 DOI: 10.1016/j.semcancer.2019.05.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 05/21/2019] [Accepted: 05/21/2019] [Indexed: 12/16/2022]
Abstract
Glioblastoma (GBM) is an aggressive and incurable brain tumor; its malignancy has been associated with the activity of tumor infiltrating myeloid cells. Myeloid cells play important roles in the tumor control by the immune response, but also in tumor progression. Indeed, GBM exploits multiple mechanisms to recruit and modulate myeloid cells. The Aryl Hydrocarbon Receptor (AHR) is a ligand activated transcription factor implicated in the regulation of myeloid cells. In this review, we will summarize current knowledge on the AHR role in the control of myeloid cells and its impact on GBM pathogenesis.
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Affiliation(s)
- Galina Gabriely
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Francisco J Quintana
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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42
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Wang C, Petriello MC, Zhu B, Hennig B. PCB 126 induces monocyte/macrophage polarization and inflammation through AhR and NF-κB pathways. Toxicol Appl Pharmacol 2019; 367:71-81. [PMID: 30768972 DOI: 10.1016/j.taap.2019.02.006] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 01/25/2019] [Accepted: 02/11/2019] [Indexed: 02/07/2023]
Abstract
Polychlorinated biphenyls (PCBs) are persistent organic pollutants that contribute to inflammatory diseases such as atherosclerosis, and macrophages play a key role in the overall inflammatory response. Depending on specific environmental stimuli, macrophages can be polarized either to pro-inflammatory (e.g., M1) or anti-inflammatory (e.g., M2) phenotypes. We hypothesize that dioxin-like PCBs can contribute to macrophage polarization associated with inflammation. To test this hypothesis, human monocytes (THP-1) were differentiated to macrophages and subsequently exposed to PCB 126. Exposure to PCB 126, but not to PCB 153 or 118, significantly induced the expression of inflammatory cytokines, including TNFα and IL-1β, suggesting polarization to the pro-inflammatory M1 phenotype. Additionally, monocyte chemoattractant protein-1 (MCP-1) was increased in PCB 126-activated macrophages, suggesting induction of chemokines which regulate immune cell recruitment and infiltration of monocytes/macrophages into vascular tissues. In addition, oxidative stress sensitive markers including nuclear factor (erythroid-derived 2)-like 2 (NFE2L2; Nrf2) and down-stream genes, such as heme oxygenase 1 (HMOX1) and NAD(P)H quinone oxidoreductase 1 (NQO1), were induced following PCB 126 exposure. Since dioxin-like PCBs may elicit inflammatory cascades through multiple mechanisms, we then pretreated macrophages with both aryl hydrocarbon receptor (AhR) and NF-κB antagonists prior to PCB treatment. The NF-κB antagonist BMS-345541 significantly decreased mRNA and protein levels of multiple cytokines by approximately 50% compared to PCB treatment alone, but the AhR antagonist CH-223191 was protective to a lesser degree. Our data demonstrate the involvement of PCB 126 in macrophage polarization and inflammation, indicating another important role of dioxin-like PCBs in the pathology of atherosclerosis.
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Affiliation(s)
- Chunyan Wang
- University of Kentucky Superfund Research Center, University of Kentucky, Lexington, KY, USA
| | - Michael C Petriello
- University of Kentucky Superfund Research Center, University of Kentucky, Lexington, KY, USA; Cardiovascular Medicine, University of Kentucky, Lexington, KY, USA
| | - Beibei Zhu
- Department of Internal Medicine, Division of Endocrinology, Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, USA
| | - Bernhard Hennig
- University of Kentucky Superfund Research Center, University of Kentucky, Lexington, KY, USA; Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, USA.
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43
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Riemschneider S, Kohlschmidt J, Fueldner C, Esser C, Hauschildt S, Lehmann J. Aryl hydrocarbon receptor activation by benzo(a)pyrene inhibits proliferation of myeloid precursor cells and alters the differentiation state as well as the functional phenotype of murine bone marrow-derived macrophages. Toxicol Lett 2018; 296:106-113. [DOI: 10.1016/j.toxlet.2018.07.050] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 07/13/2018] [Accepted: 07/26/2018] [Indexed: 12/17/2022]
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Zhu J, Luo L, Tian L, Yin S, Ma X, Cheng S, Tang W, Yu J, Ma W, Zhou X, Fan X, Yang X, Yan J, Xu X, Lv C, Liang H. Aryl Hydrocarbon Receptor Promotes IL-10 Expression in Inflammatory Macrophages Through Src-STAT3 Signaling Pathway. Front Immunol 2018; 9:2033. [PMID: 30283437 PMCID: PMC6156150 DOI: 10.3389/fimmu.2018.02033] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 08/17/2018] [Indexed: 12/16/2022] Open
Abstract
The aryl hydrocarbon receptor (AhR) is an important immune regulator with a role in inflammatory response. However, the role of AhR in IL-10 production by inflammatory macrophages is currently unknown. In this study, we investigated LPS-induced IL-10 expression in macrophages from AhR-KO mice and AhR-overexpressing RAW264.7 cells. AhR was highly expressed after LPS stimulation through NF-κB pathway. Loss of AhR resulted in reduced IL-10 expression in LPS-induced macrophages. Moreover, the IL-10 expression was elevated in LPS-induced AhR-overexpressing RAW264.7 cells. Maximal IL-10 expression was dependent on an AhR non-genomic pathway closely related to Src and STAT3. Furthermore, AhR-associated Src activity was responsible for tyrosine phosphorylation of STAT3 and IL-10 expression by inflammatory macrophages. Adoptive transfer of AhR-expressing macrophages protected mice against LPS-induced peritonitis associated with high IL-10 production. In conclusion, we identified the AhR-Src-STAT3-IL-10 signaling pathway as a critical pathway in the immune regulation of inflammatory macrophages, It suggests that AhR may be a potential therapeutic target in immune response.
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Affiliation(s)
- Junyu Zhu
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Li Luo
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Lixing Tian
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Shangqi Yin
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Xiaoyuan Ma
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.,Emergency and Trauma College of Hainan Medical University, Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Shaowen Cheng
- Trauma Center, First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Wanqi Tang
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Jing Yu
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Wei Ma
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Xiaoying Zhou
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Xia Fan
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Xue Yang
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Jun Yan
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Xiang Xu
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Chuanzhu Lv
- Emergency and Trauma College of Hainan Medical University, Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Huaping Liang
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
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Mohammadi S, Memarian A, Sedighi S, Behnampour N, Yazdani Y. Immunoregulatory effects of indole-3-carbinol on monocyte-derived macrophages in systemic lupus erythematosus: A crucial role for aryl hydrocarbon receptor. Autoimmunity 2018; 51:199-209. [PMID: 30289282 DOI: 10.1080/08916934.2018.1494161] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Macrophages are versatile phagocytic cells in immune system with immunoregulatory functions. However, the removal of apoptotic cells by macrophages is disturbed in systemic lupus erythematosus (SLE). Aryl hydrocarbon receptor (AhR) is a ligand-activated cytoplasmic receptor and transcription factor with diverse effects on immune response. Indole-3-carbinol (I3C) is an AhR agonist which has been implicated as a beneficial factor in regulating inflammation and cytokine expression in murine models of SLE. However, the molecular mechanisms are not thoroughly studied. Here, we aimed to investigate the ex vivo effects of I3C on polarization of monocyte-derived macrophages (MDMs) in SLE patients and the expression of regulatory cytokines upon AhR activation. MDMs from 15 newly diagnosed SLE patients and 10 normal subjects were induced by Jurkat apoptotic bodies (JABs) and treated with I3C. I3C enhanced the nuclear accumulation of AhR among MDMs of SLE patients and altered the expression of AhR target genes including CYP1A1, IL1- β, IDO-1 and MRC-1. The imbalanced expression of pro- and anti- inflammatory cytokines (IL-10, IL-12, TGFβ1, TNFα, IL-23, IL-6 and IFN-γ) was compensated in response to I3C. AhR activation was also associated with the overexpression of M2 markers (CD163) and downregulation of M1 markers (CD86). Thus, macrophages are activated alternatively in response to I3C. The obtained data indicate that I3C-mediated AhR activation possess immunoregulatory effects on macrophages of SLE patients by exerting an obvious downregulation in the expression of pro-inflammatory and overexpression of anti-inflammatory cytokines. Therefore, AhR could be targeted and further investigated as a choice of anti-inflammatory therapies for autoimmune disorders such as SLE.
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Affiliation(s)
- Saeed Mohammadi
- a Stem Cell Research Center , Golestan University of Medical Sciences , Gorgan , Iran
| | - Ali Memarian
- b Golestan Research Center of Gastroenterology and Hepatology , Golestan University of Medical Sciences , Gorgan , Iran
| | - Sima Sedighi
- c Joint, Bone and Connective tissue Research Center (JBCRC) , Golestan University of Medical Sciences , Gorgan , Iran
| | - Nasser Behnampour
- d Department of Biostatistics, Faculty of Health , Golestan University of Medical Sciences , Gorgan , Iran
| | - Yaghoub Yazdani
- e Infectious Diseases Research Center and Laboratory Science Research Center , Golestan University of Medical Sciences , Gorgan , Iran
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Chemopreventive Effects of Phytochemicals and Medicines on M1/M2 Polarized Macrophage Role in Inflammation-Related Diseases. Int J Mol Sci 2018; 19:ijms19082208. [PMID: 30060570 PMCID: PMC6121620 DOI: 10.3390/ijms19082208] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 07/16/2018] [Accepted: 07/23/2018] [Indexed: 12/31/2022] Open
Abstract
Macrophages can polarize into two different states (M1 and M2), which play contrasting roles during pathogenesis or tissue damage. M1 polarized macrophages produce pro-inflammatory cytokines and mediators resulting in inflammation, while M2 macrophages have an anti-inflammatory effect. Secretion of appropriate cytokines and chemokines from macrophages can lead to the modification of the microenvironment for bridging innate and adaptive immune responses. Increasing evidence suggests that polarized macrophages are pivotal for disease progression, and the regulation of macrophage polarization may provide a new approach in therapeutic treatment of inflammation-related diseases, including cancer, obesity and metabolic diseases, fibrosis in organs, brain damage and neuron injuries, and colorectal disease. Polarized macrophages affect the microenvironment by secreting cytokines and chemokines while cytokines or mediators that are produced by resident cells or tissues may also influence macrophages behavior. The interplay of macrophages and other cells can affect disease progression, and therefore, understanding the activation of macrophages and the interaction between polarized macrophages and disease progression is imperative prior to taking therapeutic or preventive actions. Manipulation of macrophages can be an entry point for disease improvement, but the mechanism and potential must be understood. In this review, some advanced studies regarding the role of macrophages in different diseases, potential mechanisms involved, and intervention of drugs or phytochemicals, which are effective on macrophage polarization, will be discussed.
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Domínguez-Acosta O, Vega L, Estrada-Muñiz E, Rodríguez MS, Gonzalez FJ, Elizondo G. Activation of aryl hydrocarbon receptor regulates the LPS/IFNγ-induced inflammatory response by inducing ubiquitin-proteosomal and lysosomal degradation of RelA/p65. Biochem Pharmacol 2018; 155:141-149. [PMID: 29935959 DOI: 10.1016/j.bcp.2018.06.016] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 06/19/2018] [Indexed: 01/20/2023]
Abstract
Several studies have identified the aryl hydrocarbon receptor (AhR) as a negative regulator of the innate and adaptive immune responses. However, the molecular mechanisms by which this transcription factor exerts such modulatory effects are not well understood. Interaction between AhR and RelA/p65 has previously been reported. RelA/p65 is the major NFκB subunit that plays a critical role in immune responses to infection. The aim of the present study was to determine whether the activation of AhR disrupted RelA/p65 signaling in mouse peritoneal macrophages by decreasing its half-life. The data demonstrate that the activation of AhR by TCDD and β-naphthoflavone (β-NF) decreased protein levels of the pro-inflammatory cytokines TNF-α, IL-6 and IL-12 after macrophage activation with LPS/IFNγ. In an AhR-dependent manner, TCDD treatment induces RelA/p65 ubiquitination and proteosomal degradation, an effect dependent on AhR transcriptional activity. Activation of AhR also induced lysosome-like membrane structure formation in mouse peritoneal macrophages and RelA/p65 lysosome-dependent degradation. In conclusion, these results demonstrate that AhR activation promotes RelA/p65 protein degradation through the ubiquitin proteasome system, as well as through the lysosomes, resulting in decreased pro-inflammatory cytokine levels in mouse peritoneal macrophages.
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Affiliation(s)
- O Domínguez-Acosta
- Departamento de Biología Celular, CINVESTAV-IPN, Zacatenco, México D. F., Av. IPN 2508, C.P. 07360, Mexico
| | - L Vega
- Departamento de Toxicología, CINVESTAV-IPN, Zacatenco, México D. F., Av. IPN 2508, C.P. 07360, Mexico
| | - E Estrada-Muñiz
- Departamento de Toxicología, CINVESTAV-IPN, Zacatenco, México D. F., Av. IPN 2508, C.P. 07360, Mexico
| | - M S Rodríguez
- Institut des Technologies Avancées en Sciences du Vivant (ITAV) CNRS-USR3505, Institut de Pharmacologie et de Biologie Structurale (IPBS) CNRS UMR8601, Université de Toulouse, 31106 Toulouse, France
| | - F J Gonzalez
- Laboratory of Metabolism, NCI, National Institutes of Health, Bethesda, MD 20892, USA
| | - G Elizondo
- Departamento de Biología Celular, CINVESTAV-IPN, Zacatenco, México D. F., Av. IPN 2508, C.P. 07360, Mexico.
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Mu X, Shi W, Xu Y, Xu C, Zhao T, Geng B, Yang J, Pan J, Hu S, Zhang C, Zhang J, Wang C, Shen J, Che Y, Liu Z, Lv Y, Wen H, You Q. Tumor-derived lactate induces M2 macrophage polarization via the activation of the ERK/STAT3 signaling pathway in breast cancer. Cell Cycle 2018; 17:428-438. [PMID: 29468929 PMCID: PMC5927648 DOI: 10.1080/15384101.2018.1444305] [Citation(s) in RCA: 315] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 02/13/2018] [Accepted: 02/17/2018] [Indexed: 01/14/2023] Open
Abstract
Tumor-associated macrophages (TAM) are prominent components of tumor microenvironment (TME) and capable of promoting cancer progression. However, the mechanisms for the formation of M2-like TAMs remain enigmatic. Here, we show that lactate is a pivotal oncometabolite in the TME that drives macrophage M2-polarization to promote breast cancer proliferation, migration, and angiogenesis. In addition, we identified that the activation of ERK/STAT3, major signaling molecules in the lactate signaling pathway, deepens our molecular understanding of how lactate educates TAMs. Moreover, suppression of ERK/STAT3 signaling diminished tumor growth and angiogenesis by abolishing lactate-induced M2 macrophage polarization. Finally, research data of the natural compound withanolide D provide evidence for ERK/STAT3 signaling as a potential therapeutic strategy for the prevention and treatment of breast cancer. These findings suggest that the lactate-ERK/STAT3 signaling pathway is a driver of breast cancer progression by stimulating macrophage M2-like polarization and reveal potential new therapeutic targets for breast cancer treatment.
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Affiliation(s)
- Xianmin Mu
- Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Wei Shi
- Department of Drug Screening and Evaluation, Chia Tai Tianqing Pharmaceutical Group Co., Ltd, Nanjing, Jiangsu 210023, China
| | - Yue Xu
- Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Che Xu
- Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Ting Zhao
- Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Biao Geng
- Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Jing Yang
- Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Jinshun Pan
- Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Shi Hu
- Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Chen Zhang
- Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Juan Zhang
- Department of Drug Clinical Trial Institution, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Chao Wang
- Department of Surgery, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Jiajia Shen
- Department of Surgery, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Yin Che
- Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Zheng Liu
- Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Yuanfang Lv
- Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Hao Wen
- Department of Surgery, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Qiang You
- Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
- Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
- Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
- Key Laboratory for Aging & Disease, Nanjing Medical University, Nanjing, Jiangsu, China
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49
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Mohammadi S, Saghaeian-Jazi M, Sedighi S, Memarian A. Sodium valproate modulates immune response by alternative activation of monocyte-derived macrophages in systemic lupus erythematosus. Clin Rheumatol 2018; 37:719-727. [PMID: 29196891 DOI: 10.1007/s10067-017-3922-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 10/21/2017] [Accepted: 11/17/2017] [Indexed: 02/05/2023]
Abstract
The anti-inflammatory role of macrophages in apoptotic cells (ACs) clearance is involved in Systemic Lupus Erythematosus (SLE) pathogenesis. The efferocytic capability of macrophages is altered by M1/M2 polarization. Histone deacetylase inhibitors (HDACi) are proposed to enhance the expansion of M2 macrophages. Sodium valproate (VPA) is an HDACi with different anti-inflammatory properties. Here, we aimed to investigate the effects of HDACi by VPA on the polarization of monocyte-derived macrophages (MDMs) and regulating the expression of anti-inflammatory cytokines in SLE. We studied the ex vivo alterations of MDMs among 15 newly diagnosed SLE patients and 10 normal subjects followed by ACs and VPA treatments. M1/M2 polarization was assessed by expression of CD86/CD163, IL1-β, IDO-1, and MRC-1 among treated and non-treated MDMs. We also evaluated the production of IL-10, IL-12, TGF-β1, and TNF-α cytokines in the cell culture supernatants. CD163 was overexpressed upon VPA treatment, while CD86 showed no significant change. IL1-β and IDO-1 genes were significantly downregulated, and the mRNA expression of MRC-1 was increased among VPA-treated MDMs of SLE patients. The anti-inflammatory cytokines (IL-10 and TGF-β1) were overproduced while TNF-α level was decreased in response to VPA. The population of classically activated macrophages was more prevalent among SLE patients and efferocytosis was defected. VPA could successfully enhance the anti-inflammatory immune response through alternative activation of MDMs in SLE patients.
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Affiliation(s)
- Saeed Mohammadi
- Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Marie Saghaeian-Jazi
- Biochemistry and Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Sima Sedighi
- Joint, Bone and Connective tissue Research Center (JBCRC), Golestan University of Medical Sciences, Gorgan, Iran.
| | - Ali Memarian
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran.
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50
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Xue P, Fu J, Zhou Y. The Aryl Hydrocarbon Receptor and Tumor Immunity. Front Immunol 2018; 9:286. [PMID: 29487603 PMCID: PMC5816799 DOI: 10.3389/fimmu.2018.00286] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 01/31/2018] [Indexed: 01/31/2023] Open
Abstract
The aryl hydrocarbon receptor (AhR) is an important cytosolic, ligand-dependent transcription factor. Emerging evidence suggests the promoting role of the AhR in the initiation, promotion, progression, invasion, and metastasis of cancer cells. Studies on various tumor types and tumor cell lines have shown high AhR expression, suggesting that AhR is activated constitutively in tumors and facilitates their growth. Interestingly, immune evasion has been recognized as an emerging hallmark feature of cancer. A connection between the AhR and immune system has been recognized, which has been suggested as an immunosuppressive effector on different types of immune cells. Certain cancers can escape immune recognition via AhR signaling pathways. This review discusses the role of the AhR in tumor immunity and its potential mechanism of action in the tumor microenvironment.
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Affiliation(s)
- Ping Xue
- Children's Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jinrong Fu
- Children's Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yufeng Zhou
- Children's Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai, China.,Key Laboratory of Neonatal Diseases, Ministry of Health, Shanghai, China
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