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Gao Y, Deng Y, Li W, Wang J, Liu M, Dai H. CXCR3 inhibition ameliorates mitochondrial function to mitigate oxidative damage through NCOA4-mediated ferritinophagy and improves the gut microbiota in mice. Free Radic Biol Med 2025; 229:384-398. [PMID: 39827924 DOI: 10.1016/j.freeradbiomed.2025.01.034] [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: 12/04/2024] [Revised: 01/14/2025] [Accepted: 01/16/2025] [Indexed: 01/22/2025]
Abstract
Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy contributes to maintain intracellular iron balance by regulating ferritin degradation, which is essential for redox homeostasis. CXC-motif chemokine receptor 3 (CXCR3) is involved in the regulation of oxidative stress and autophagy. However, its role in modulating intestinal oxidative damage through ferritinophagy and the gut microbiota remains unclear. In this study, the impacts of CXCR3 inhibition on intestine oxidative damage, ferritinophagy, and the gut microbiota, as well as the mitochondrial quality control were investigated both in vivo and in vitro. The results show that CXCR3 inhibition by AMG487 relieves Diquat-induced intestinal damage, enhances the expression of tight junction proteins, and promotes antioxidant capacity in mice. Simultaneously, CXCR3 inhibition improves gut microbiota composition, and triggers NCOA4-mediated ferritinophagy. Mechanistically, the effects of CXCR3 inhibition on ferritinophagy were explored in IPEC-J2 cells. Co-localization and interaction between CXCR3 and NCOA4 were observed. Downregulation of NCOA4-mediated ferritinophagy leads to increase the expression of tight junction proteins, reduces iron levels, restricts ROS accumulation, and enhances GPX4 expression. Moreover, CXCR3 suppression facilitates mitochondrial biogenesis and mitochondrial fusion, increases antioxidative capacity, and results in the elevation of tight junction proteins expression. These findings suggest that CXCR3 inhibition reverses Diquat-induced intestinal oxidative damage, enhances mitochondrial function, and improves gut microbiota composition by elevating NCOA4-mediated ferritinophagy, which implies that CXCR3 may serve as a potential therapeutic intervention targeting iron metabolism for treating intestinal diseases.
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Affiliation(s)
- Yuan Gao
- College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Hongshan District, Wuhan, 430070, Hubei, China
| | - Yian Deng
- College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Hongshan District, Wuhan, 430070, Hubei, China
| | - Wenjie Li
- College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Hongshan District, Wuhan, 430070, Hubei, China
| | - Junjie Wang
- College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Hongshan District, Wuhan, 430070, Hubei, China
| | - Mingze Liu
- College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Hongshan District, Wuhan, 430070, Hubei, China
| | - Hanchuan Dai
- College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Hongshan District, Wuhan, 430070, Hubei, China.
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Chen YF, Li JW, Li FF, Bo L, Xiao Y, Jin QX, Jin GH, Meng FP, Huang XZ, Jin D. Therapeutic potential of Inonotus obliquus polysaccharide-induced tolerogenic bone marrow-derived dendritic cells via regulation of CD4 + T cell differentiation in a colitis mouse model. Int J Biol Macromol 2025:141505. [PMID: 40015397 DOI: 10.1016/j.ijbiomac.2025.141505] [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: 04/24/2024] [Revised: 02/18/2025] [Accepted: 02/24/2025] [Indexed: 03/01/2025]
Abstract
Over-proliferation, activation, or aberrant CD4+ T cell differentiation causes various immune-related diseases. DCs are significant professional APCs that regulate the differentiation of CD4+ T cells to participate in an inflammatory response. IOP is an edible fungal polysaccharide with immunoregulatory and anti-inflammatory bioactivities, however, the cellular mechanisms by which they regulate the immune system to exert their anti-inflammatory effects remain unclear. The present study aimed to investigate the effects of IOP on the regulation of CD4+ T cell differentiation and the correlative mechanisms related to DCs. IOP did not regulate the proliferation and activation of CD4+ T cells. However, it inhibited the differentiation of Th1 and Th17 cells and promoted the differentiation of Treg cells. IOP maintained the immature phenotype of BMDCs, which induces immune tolerance and promotes the differentiation of CD4+ T cells into Treg cells. Transfusion of IOPL-BMDC into colitis mice markedly alleviated colitis-associated inflammation and maintained the colon's integrity. IOPL-BMDCs inhibited the differentiation of CD4+ T cells into inflammatory effective Th1 cells in the spleen and MLN while promoting their differentiation into immune-tolerant, anti-inflammatory Treg cells. In conclusion, this research demonstrated that IOP strongly regulates the polarization of CD4+ T cells to Treg subsets with inflammatory suppressive effects by inducing immature tolerant DCs, which provides strategic evidence for the therapeutic application of IOP in colitis, and IOP-induced tolerant DCs provide a new therapeutic approach to the development of a DC vaccine for colitis.
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Affiliation(s)
- Yi-Fang Chen
- Department of Immunology and Pathogenic Biology, Yanbian University, Yanji 133000, China
| | - Jia-Wei Li
- Department of Immunology and Pathogenic Biology, Yanbian University, Yanji 133000, China
| | - Fang-Fang Li
- Department of Immunology and Pathogenic Biology, Yanbian University, Yanji 133000, China
| | - Lin Bo
- Department of Immunology and Pathogenic Biology, Yanbian University, Yanji 133000, China
| | - Yao Xiao
- Department of Immunology and Pathogenic Biology, Yanbian University, Yanji 133000, China
| | - Quan-Xin Jin
- Department of Immunology and Pathogenic Biology, Yanbian University, Yanji 133000, China
| | - Gui-Hua Jin
- Department of Immunology and Pathogenic Biology, Yanbian University, Yanji 133000, China
| | - Fan-Ping Meng
- Department of Immunology and Pathogenic Biology, Yanbian University, Yanji 133000, China
| | - Xue-Zhu Huang
- Department of Anaesthesiology, The Affiliated Hospital of Yanbian University, Yan Ji 133000, China.
| | - Dan Jin
- Department of Immunology and Pathogenic Biology, Yanbian University, Yanji 133000, China.
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Bell B, Flores-Lovon K, Cueva-Chicaña LA, Macedo R. Role of chemokine receptors in gastrointestinal mucosa. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 388:20-52. [PMID: 39260937 DOI: 10.1016/bs.ircmb.2024.02.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
Chemokine receptors are essential for the immune response in the oral and gut mucosa. The gastrointestinal mucosa is characterized by the presence of immune populations because it is susceptible to inflammatory and infectious diseases, necessitating immune surveillance. Chemokine receptors are expressed on immune cells and play a role in gastrointestinal tissue-homing, although other non-immune cells also express them for various biological functions. CCR9, CXCR3 and CXCR6 play an important role in the T cell response in inflammatory and neoplastic conditions of the gastrointestinal mucosa. However, CXCR6 could also be found in gastric cancer cells, highlighting the different roles of chemokine receptors in different pathologies. On the other hand, CCR4 and CCR8 are critical for Treg migration in gastrointestinal tissues, correlating with poor prognosis in mucosal cancers. Other chemokine receptors are also important in promoting myeloid infiltration with context-dependent roles. Further, CXCR4 and CXCR7 are also present in gastrointestinal tumor cells and are known to stimulate proliferation, migration, and invasion into other tissues, among other pro-tumorigenic functions. Determining the processes underlying mucosal immunity and creating tailored therapeutic approaches for gastrointestinal diseases requires an understanding of the complex interactions that occur between chemokine receptors and their ligands in these mucosal tissues.
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Affiliation(s)
- Brett Bell
- Albert Einstein College of Medicine, New York, NY, United States
| | - Kevin Flores-Lovon
- Universidad Nacional de San Agustín de Arequipa, Arequipa, Peru; Grupo de Investigación en Inmunología (GII), Arequipa, Peru
| | - Luis A Cueva-Chicaña
- Universidad Nacional de San Agustín de Arequipa, Arequipa, Peru; Grupo de Investigación en Inmunología (GII), Arequipa, Peru
| | - Rodney Macedo
- Albert Einstein College of Medicine, New York, NY, United States; Grupo de Investigación en Inmunología (GII), Arequipa, Peru; Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, United States.
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He Y, Xu M, Lu S, Zou W, Wang Y, Fakhar-E-Alam Kulyar M, Iqbal M, Li K. Seaweed polysaccharides treatment alleviates injury of inflammatory responses and gut barrier in LPS-induced mice. Microb Pathog 2023; 180:106159. [PMID: 37201636 DOI: 10.1016/j.micpath.2023.106159] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/14/2023] [Accepted: 05/15/2023] [Indexed: 05/20/2023]
Abstract
Gastrointestinal (GI) disease is a common digestive tract disease effects health of millions of human globally each year, thus the role of intestinal microflora had been emphasized. Seaweed polysaccharides featured a wide range of pharmacological activities, such as antioxidant activity and pharmacological action, but whether they can alleviate the dysbiosis of gut microbial ecology caused by lipopolysaccharide (LPS) exposure has not been well conducted. In this study, we investigated the effects of different concentration of seaweed polysaccharides on LPS-induced intestinal disorder by using microscope and 16S rRNA high-throughput sequencing. Histopathological results indicated that the intestinal structure in the LPS-induced group was damaged. Furthermore, LPS exposure not only reduced the intestinal microbial diversity in mice but also induced momentous transformation in its composition, including a significantly increased in some pathogenic bacteria (Helicobacter, Citrobacter and Mucispirillum) and decreased in several beneficial bacteria (Firmicutes, Lactobacillus, Akkermansia and Parabacteroides). Nonetheless, seaweed polysaccharide administration could recover the gut microbial dysbiosis and the loss of gut microbial diversity induced by LPS exposure. In summary, seaweed polysaccharides were effective against LPS-induced intestinal damage in mice via the modulation of intestinal microecology.
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Affiliation(s)
- Yuanyuan He
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China; College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, PR China
| | - Mengen Xu
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, PR China
| | - Sijia Lu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China
| | - Wen Zou
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China
| | - Yaping Wang
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, PR China
| | | | - Mudassar Iqbal
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, PR China; University College of Veterinary & Animal Sciences, Islamia University of Bahawalpur, 61100, Pakistan
| | - Kun Li
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China.
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Zheng J, Duan H, You S, Liang B, Chen Y, Huang H. Research progress on the pathogenesis of Graves’ ophthalmopathy: Based on immunity, noncoding RNA and exosomes. Front Immunol 2022; 13:952954. [PMID: 36081502 PMCID: PMC9445982 DOI: 10.3389/fimmu.2022.952954] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 07/29/2022] [Indexed: 11/13/2022] Open
Abstract
Graves’ ophthalmopathy (GO), also known as thyroid-associated ophthalmopathy, is a common potentially vision-threatening organ-specific autoimmune disease and the most common extrathyroidal manifestation of Graves’ disease. It can happen to those who have hyperthyroidism or euthyroidism. At present, the pathogenesis of GO has not been fully elucidated, and the majority of clinical treatments are symptomatic. Therefore, we are eager to discover any new therapeutic strategies that target the etiology of GO. To provide fresh ideas for the creation of new therapeutic techniques, this study primarily discusses the research state and progress of GO-related pathogenesis from the perspectives of GO’s cellular immunity, autoantigens, non-coding RNAs, and exosomes.
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Affiliation(s)
- Jingyi Zheng
- The Second Clinical Medical College of Fujian Medical University, Quanzhou, China
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Honghong Duan
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Sufang You
- The Second Clinical Medical College of Fujian Medical University, Quanzhou, China
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Bo Liang
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yuping Chen
- The Second Clinical Medical College of Fujian Medical University, Quanzhou, China
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Huibin Huang
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
- *Correspondence: Huibin Huang,
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Bamias G, Zampeli E, Domènech E. Targeting neutrophils in inflammatory bowel disease: revisiting the role of adsorptive granulocyte and monocyte apheresis. Expert Rev Gastroenterol Hepatol 2022; 16:721-735. [PMID: 35833363 DOI: 10.1080/17474124.2022.2100759] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
INTRODUCTION Inflammatory bowel disease (IBD) is a chronic immune-mediated disease of the gastrointestinal tract comprising Crohn's disease (CD) and ulcerative colitis (UC). While any part of the digestive tract can be affected in CD, mucosal inflammation in UC is limited to the colon. Differences and similarities between the two conditions are reflected by their pathophysiology. AREAS COVERED An overview of immunological aspects, pharmacological management, and biomarkers of IBD is provided. The role of adsorptive granulocyte and monocyte apheresis (GMA) is reviewed including its primary and secondary effects on the immune system, as well as clinical studies in IBD (mainly UC), and potential biomarkers for adsorptive GMA. EXPERT OPINION In UC, adsorptive GMA with Adacolumn (Adacolumn®, JIMRO Co., Ltd. Takasaki, Gunma, Japan) selectively depletes elevated myeloid lineage leukocytes and has a range of beneficial secondary immune effects. Adsorptive GMA is a safe and effective non-pharmacological treatment option for UC. Pilot studies have reported promising results for adsorptive GMA in combination with biological agents, although larger studies are required. Fecal calprotectin concentrations, neutrophil counts in histological samples and/or the neutrophil/lymphocyte ratio in peripheral blood may prove to be useful biomarkers for predicting GMA effectiveness in the future.
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Affiliation(s)
- Giorgos Bamias
- GI-Unit, 3rd Department of Internal Medicine National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece
| | - Evanthia Zampeli
- Gastroenterology Department, Alexandra General Hospital, Athens, Greece
| | - Eugeni Domènech
- Gastroenterology Department, Hospital Universitari Germans Trias I Pujol, Badalona, Catalonia, Spain, and Centro de Investigación Biomédica En Red de Enfermedades Hepáticas Y Digestivas (CIBEREHD), Madrid, Spain
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Luo Y, Liu S, Li H, Hou J, Lin W, Xu Z, Lu T, Li Y, Peng B, Zhang S, Han X, Kuang Z, Wen Y, Cai J, Liu F, Chen XL. Mass Cytometry and Single-Cell Transcriptome Analyses Reveal the Immune Cell Characteristics of Ulcerative Colitis. Front Mol Biosci 2022; 9:859645. [PMID: 35813827 PMCID: PMC9260076 DOI: 10.3389/fmolb.2022.859645] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 06/02/2022] [Indexed: 12/31/2022] Open
Abstract
Background: The pathogenesis of ulcerative colitis (UC) is closely related to immunity. The immune characteristic differences between active UC (UCa) and inactive UC (UCin) have not been completely explained. Mass cytometry (CyTOF) and single-cell RNA sequencing (scRNA-seq) were used to analyze the immune cells of UCa, UCin and healthy control (HC) subjects to determine the specific immune characteristics. Methods: The immune cell subsets among UCa, UCin, HC were distinguished using CyTOF analysis. scRNA-seq analysis was used to validate the results of CyTOF. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to understand the roles of differential immune cell subsets. Results: After CyTOF analysis and validation of scRNA-seq analysis, differential immune cell subsets mainly contained TNF+IL-17A++ effector memory (EM) Tregs, CXCR3+CTLA4+ EM Tregs, CXCR3++CCR7+ B cells, HLA-DR+CCR7+ dendritic cells (DCs) and CTLA-4+ natural killer (NK) cells. In comparison to HC, CCR6+TNF+CD161+ EM T cells were highly enriched in UCa and UCin. Besides, UCa was characterized by an increase in CD38+TNF+ EM Tregs, CXCR3+CCR4+ naïve B cells, HLA-DR+CD14+IL21+ macrophages/monocytes, HLA-DR+CCR7+ DCs, AHR+CD14+ cytotoxic NK (cNK) cells and CD8A+IFNG+ cNK cells. Decreases in CD38+CD27+ plasmablasts, CXCR3+CD38+ regulatory NK cells, and CXCR3+CCR7+ tolerant NK cells in UCa were discovered. Conclusions: Novel immune cell subsets which was used to distinguish UCa, UCin and HC were identified. This information might be utilized to distinguish the patients with UCa and UCin.
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Affiliation(s)
- Yongxin Luo
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shiying Liu
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Huibiao Li
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiangtao Hou
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wenjia Lin
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zewen Xu
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Tianyu Lu
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yanwu Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Pi-Wei Institute, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bin Peng
- The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shijing Zhang
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xue Han
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zuoliang Kuang
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yi Wen
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiazhong Cai
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Pi-Wei Institute, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fengbin Liu
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Fengbin Liu, ; Xin-Lin Chen,
| | - Xin-Lin Chen
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Fengbin Liu, ; Xin-Lin Chen,
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Contribution of CD4+ T cell mediated inflammation to diarrhoea in patients with COVID-19. Int J Infect Dis 2022; 120:1-11. [PMID: 35398299 PMCID: PMC8985416 DOI: 10.1016/j.ijid.2022.04.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 03/16/2022] [Accepted: 04/01/2022] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVES This study aimed to explore the role of CD4+ T cells in the mechanisms of COVID-19 related diarrhoea. METHODS Lymphocyte subsets were analysed in COVID-19 patients, and the expression of angiotensin-converting enzyme 2 (ACE2), the transmembrane protease, serine 2 (TMPRSS2), and CD4+ T cell-related indicators in the colon were compared between patients with and without diarrhoea. Correlation analyses were performed for ACE2 and other indicators to identify the relationship between SARS-CoV-2 infection and CD4+ mediated inflammation. The expression and distribution of CD4+ T cell-associated chemokines and their receptors were detected to determine the possibility of migration of CD4+ T cells to inflammation sites. RESULTS The CD4+ T cell counts and percentages and CD4/CD8 ratio showed the most significant differences between the two groups. The diarrhoea group expressed higher levels of ACE2, Tbet, and TNFα at both the mRNA and protein levels, with no difference from the non-diarrhoea group for the percentage of ACE2+TNFα+ cells, indicating an indirect association between ACE2 and TNFα. The mRNA expression of CXCL10, CXCL11, and CXCR3, and the number of CD4+CXCR3+T cells was increased in the diarrhoea group. CONCLUSIONS CD4+ T cell-mediated inflammation may contribute to COVID-19 related diarrhoea. CXCR3+ mediated migration of CD4+ T cells into the gut may perpetuate inflammation.
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Camba-Gómez M, Arosa L, Gualillo O, Conde-Aranda J. Chemokines and chemokine receptors in inflammatory bowel disease: Recent findings and future perspectives. Drug Discov Today 2021; 27:1167-1175. [PMID: 34896626 DOI: 10.1016/j.drudis.2021.12.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 11/11/2021] [Accepted: 12/06/2021] [Indexed: 11/03/2022]
Abstract
Despite the benefits of current therapeutic options for treating inflammatory bowel disease (IBD), there are still patients who are refractory to these therapies. Moreover, the relapses caused by incomplete intestinal mucosa healing are frequent. Therefore, there is a need for novel pharmacological targets that can improve the existing IBD therapeutic armamentarium. Chemokine and chemokine receptors have emerged as appealing options to this end. As well as controlling leukocyte trafficking to inflamed tissues, these proteins regulate many other processes related to the development of intestinal inflammation. In this review, we summarise the most recent preclinical studies, along with the putative application of chemokine-based therapies in patients with IBD.
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Affiliation(s)
- Miguel Camba-Gómez
- Molecular and Cellular Gastroenterology, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Laura Arosa
- Molecular and Cellular Gastroenterology, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Oreste Gualillo
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), The NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, Santiago de Compostela, Spain
| | - Javier Conde-Aranda
- Molecular and Cellular Gastroenterology, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
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Li J, Thomson AW, Rogers NM. Myeloid and Mesenchymal Stem Cell Therapies for Solid Organ Transplant Tolerance. Transplantation 2021; 105:e303-e321. [PMID: 33756544 PMCID: PMC8455706 DOI: 10.1097/tp.0000000000003765] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Transplantation is now performed globally as a routine procedure. However, the increased demand for donor organs and consequent expansion of donor criteria has created an imperative to maximize the quality of these gains. The goal is to balance preservation of allograft function against patient quality-of-life, despite exposure to long-term immunosuppression. Elimination of immunosuppressive therapy to avoid drug toxicity, with concurrent acceptance of the allograft-so-called operational tolerance-has proven elusive. The lack of recent advances in immunomodulatory drug development, together with advances in immunotherapy in oncology, has prompted interest in cell-based therapies to control the alloimmune response. Extensive experimental work in animals has characterized regulatory immune cell populations that can induce and maintain tolerance, demonstrating that their adoptive transfer can promote donor-specific tolerance. An extension of this large body of work has resulted in protocols for manufacture, as well as early-phase safety and feasibility trials for many regulatory cell types. Despite the excitement generated by early clinical trials in autoimmune diseases and organ transplantation, there is as yet no clinically validated, approved regulatory cell therapy for transplantation. In this review, we summarize recent advances in this field, with a focus on myeloid and mesenchymal cell therapies, including current understanding of the mechanisms of action of regulatory immune cells, and clinical trials in organ transplantation using these cells as therapeutics.
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Affiliation(s)
- Jennifer Li
- Center of Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, Australia
- Faculty of Medicine and Health, Sydney Medical School, University of Sydney, Sydney, Australia
| | - Angus W Thomson
- Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Natasha M Rogers
- Center of Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, Australia
- Faculty of Medicine and Health, Sydney Medical School, University of Sydney, Sydney, Australia
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11
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Magnusen AF, Rani R, McKay MA, Hatton SL, Nyamajenjere TC, Magnusen DNA, Köhl J, Grabowski GA, Pandey MK. C-X-C Motif Chemokine Ligand 9 and Its CXCR3 Receptor Are the Salt and Pepper for T Cells Trafficking in a Mouse Model of Gaucher Disease. Int J Mol Sci 2021; 22:ijms222312712. [PMID: 34884512 PMCID: PMC8657559 DOI: 10.3390/ijms222312712] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 11/08/2021] [Accepted: 11/18/2021] [Indexed: 02/07/2023] Open
Abstract
Gaucher disease is a lysosomal storage disease, which happens due to mutations in GBA1/Gba1 that encodes the enzyme termed as lysosomal acid β-glucosidase. The major function of this enzyme is to catalyze glucosylceramide (GC) into glucose and ceramide. The deficiency of this enzyme and resultant abnormal accumulation of GC cause altered function of several of the innate and adaptive immune cells. For example, augmented infiltration of T cells contributes to the increased production of pro-inflammatory cytokines, (e.g., IFNγ, TNFα, IL6, IL12p40, IL12p70, IL23, and IL17A/F). This leads to tissue damage in a genetic mouse model (Gba19V/-) of Gaucher disease. The cellular mechanism(s) by which increased tissue infiltration of T cells occurs in this disease is not fully understood. Here, we delineate role of the CXCR3 receptor and its exogenous C-X-C motif chemokine ligand 9 (CXCL9) in induction of increased tissue recruitment of CD4+ T and CD8+ T cells in Gaucher disease. Intracellular FACS staining of macrophages (Mϕs) and dendritic cells (DCs) from Gba19V/- mice showed elevated production of CXCL9. Purified CD4+ T cells and the CD8+ T cells from Gba19V/- mice showed increased expression of CXCR3. Ex vivo and in vivo chemotaxis experiments showed CXCL9 involvement in the recruitment of Gba19V/- T cells. Furthermore, antibody blockade of the CXCL9 receptor (CXCR3) on T cells caused marked reduction in CXCL9- mediated chemotaxis of T cells in Gba19V/- mice. These data implicate abnormalities of the CXCL9-CXCR3 axis leading to enhanced tissue recruitment of T cells in Gaucher disease. Such results provide a rationale for blockade of the CXCL9/CXCR3 axis as potential new therapeutic targets for the treatment of inflammation in Gaucher disease.
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Affiliation(s)
- Albert Frank Magnusen
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; (A.F.M.); (M.A.M.); (S.L.H.); (T.C.N.); (D.N.A.M.)
| | - Reena Rani
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA;
| | - Mary Ashley McKay
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; (A.F.M.); (M.A.M.); (S.L.H.); (T.C.N.); (D.N.A.M.)
| | - Shelby Loraine Hatton
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; (A.F.M.); (M.A.M.); (S.L.H.); (T.C.N.); (D.N.A.M.)
| | - Tsitsi Carol Nyamajenjere
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; (A.F.M.); (M.A.M.); (S.L.H.); (T.C.N.); (D.N.A.M.)
| | - Daniel Nii Aryee Magnusen
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; (A.F.M.); (M.A.M.); (S.L.H.); (T.C.N.); (D.N.A.M.)
| | - Jörg Köhl
- Institute for Systemic Inflammation Research, University of Lübeck, 23562 Lübeck, Germany;
- Department of Pediatrics and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, College of Medicine, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
| | - Gregory Alex Grabowski
- Department of Molecular Genetics, Biochemistry and Microbiology, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, College of Medicine, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229, USA;
- Department of Pediatrics, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, College of Medicine, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
| | - Manoj Kumar Pandey
- Department of Pediatrics, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, College of Medicine, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
- Correspondence:
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12
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Ala M, Kheyri Z. The rationale for selenium supplementation in inflammatory bowel disease: A mechanism-based point of view. Nutrition 2021; 85:111153. [PMID: 33578241 DOI: 10.1016/j.nut.2021.111153] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 12/19/2020] [Accepted: 01/05/2021] [Indexed: 02/07/2023]
Abstract
Management of inflammatory bowel disease (IBD) has always been a challenge for physicians. Current treatment protocols may cause numerous adverse effects. Selenium is known for its putative antiinflammatory properties. Selenium is needed for the biosynthesis of enzymatically active selenoproteins, which contribute to antioxidative defense, and effective function of immune systems. Several studies have shown that patients with IBD have a lower selenium level compared to healthy subjects. Hence, experimental studies mimicking ulcerative colitis and Crohn's disease investigated the effect of selenium supplementation on IBD. Previous studies indicated the following: 1) Selenoproteins can curb the inflammatory response and attenuate oxidative stress. This antiinflammatory property caused remission in animal models of colitis. 2) Selenium supports protective gut microbiota, which indirectly improves management of IBD. 3) Selenium may block some of the predominant tumorigenesis pathways proposed in colitis-associated colorectal cancer. 4) Selenium supplementation showed promising results in preliminary clinical studies, particularly in patients with selenium deficiency. While selenium supplementation seems to be beneficial for IBD, clinical studies have remained too preliminary in this regard. Randomized clinical trials are needed to measure the short-term and long-term effects of selenium on both active and quiescent IBD, particularly in patients with IBD who have documented selenium deficiency.
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Affiliation(s)
- Moein Ala
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Zahedin Kheyri
- Baharloo Hospital, Tehran University of Medical Sciences, Tehran, Iran
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13
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Zöller J, Ebel JF, Khairnar V, Schmitt V, Klopfleisch R, Meiners J, Seiffart V, Hansen W, Buer J, Singer BB, Lang KS, Westendorf AM. CEACAM1 regulates CD8 + T cell immunity and protects from severe pathology during Citrobacter rodentium induced colitis. Gut Microbes 2020; 11:1790-1805. [PMID: 32521208 PMCID: PMC7524155 DOI: 10.1080/19490976.2020.1775464] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 05/11/2020] [Accepted: 05/14/2020] [Indexed: 02/07/2023] Open
Abstract
The incidence of gastrointestinal infections continues to increase, and infectious colitis contributes significantly to morbidity and mortality worldwide. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) has been discovered to be strongly involved in the intestinal homeostasis. However, whether intestinal CEACAM1 expression has an impact on the control of infectious colitis remains elusive. Citrobacter rodentium (C. rodentium) is a gram-negative enteric pathogen that induces colonic inflammation in mice, with a critical role for CD4+ T cell but not CD8+ T cell immunity to primary infection. Here, we show that Ceacam1-/- mice are much more susceptible to C. rodentium infection than wildtype mice, which is mediated by a defect in the intestinal barrier and, surprisingly, by a dysregulated CD8+ T cell but not CD4+ T cell response in the colon. CEACAM1 expression is essential for the control of CD8+ T cell immunity, as CEACAM1 deficiency during C. rodentium infection inhibits CD8+ T cell exhaustion. We conclude that CEACAM1 is an important regulator of CD8+ T cell function in the colon, and blocking CEACAM1 signaling to activate CD8+ T cells may have unforeseen side effects.
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Affiliation(s)
- Julia Zöller
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Jana-Fabienne Ebel
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Vishal Khairnar
- Institute for Immunology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, CA, USA
| | - Verena Schmitt
- Institute of Anatomy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Robert Klopfleisch
- Institute of Veterinary Pathology, Free University of Berlin, Berlin, Germany
| | - Jana Meiners
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Virginia Seiffart
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Wiebke Hansen
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Jan Buer
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Bernhard B. Singer
- Institute of Anatomy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Karl S. Lang
- Institute for Immunology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Astrid M. Westendorf
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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14
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Caligiuri A, Pastore M, Lori G, Raggi C, Di Maira G, Marra F, Gentilini A. Role of Chemokines in the Biology of Cholangiocarcinoma. Cancers (Basel) 2020; 12:cancers12082215. [PMID: 32784743 PMCID: PMC7463556 DOI: 10.3390/cancers12082215] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/03/2020] [Accepted: 08/05/2020] [Indexed: 02/07/2023] Open
Abstract
Cholangiocarcinoma (CCA), a heterogeneous tumor with poor prognosis, can arise at any level in the biliary tree. It may derive from epithelial cells in the biliary tracts and peribiliary glands and possibly from progenitor cells or even hepatocytes. Several risk factors are responsible for CCA onset, however an inflammatory milieu nearby the biliary tree represents the most common condition favoring CCA development. Chemokines play a key role in driving the immunological response upon liver injury and may sustain tumor initiation and development. Chemokine receptor-dependent pathways influence the interplay among various cellular components, resulting in remodeling of the hepatic microenvironment towards a pro-inflammatory, pro-fibrogenic, pro-angiogenic and pre-neoplastic setting. Moreover, once tumor develops, chemokine signaling may influence its progression. Here we review the role of chemokines in the regulation of CCA development and progression, and the modulation of angiogenesis, metastasis and immune control. The potential role of chemokines and their receptors as possible biomarkers and/or therapeutic targets for hepatobiliary cancer is also discussed.
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Affiliation(s)
| | | | | | | | | | - Fabio Marra
- Correspondence: (F.M.); (A.G.); Tel.: +39-055-2758095 or +39-055-2758498 or +39-055-2758499 (F.M.); +39-055-2751801 (A.G.)
| | - Alessandra Gentilini
- Correspondence: (F.M.); (A.G.); Tel.: +39-055-2758095 or +39-055-2758498 or +39-055-2758499 (F.M.); +39-055-2751801 (A.G.)
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15
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Kamalian A, Sohrabi Asl M, Dolatshahi M, Afshari K, Shamshiri S, Momeni Roudsari N, Momtaz S, Rahimi R, Abdollahi M, Abdolghaffari AH. Interventions of natural and synthetic agents in inflammatory bowel disease, modulation of nitric oxide pathways. World J Gastroenterol 2020; 26:3365-3400. [PMID: 32655263 PMCID: PMC7327787 DOI: 10.3748/wjg.v26.i24.3365] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/09/2020] [Accepted: 06/03/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) refers to a group of disorders characterized by chronic inflammation of the gastrointestinal (GI) tract. The elevated levels of nitric oxide (NO) in serum and affected tissues; mainly synthesized by the inducible nitric oxide synthase (iNOS) enzyme; can exacerbate GI inflammation and is one of the major biomarkers of GI inflammation. Various natural and synthetic agents are able to ameliorate GI inflammation and decrease iNOS expression to the extent comparable with some IBD drugs. Thereby, the purpose of this study was to gather a list of natural or synthetic mediators capable of modulating IBD through the NO pathway. Electronic databases including Google Scholar and PubMed were searched from 1980 to May 2018. We found that polyphenols and particularly flavonoids are able to markedly attenuate NO production and iNOS expression through the nuclear factor κB (NF-κB) and JAK/STAT signaling pathways. Prebiotics and probiotics can also alter the GI microbiota and reduce NO expression in IBD models through a broad array of mechanisms. A number of synthetic molecules have been found to suppress NO expression either dependent on the NF-κB signaling pathway (i.e., dexamethasone, pioglitazone, tropisetron) or independent from this pathway (i.e., nicotine, prednisolone, celecoxib, β-adrenoceptor antagonists). Co-administration of natural and synthetic agents can affect the tissue level of NO and may improve IBD symptoms mainly by modulating the Toll like receptor-4 and NF-κB signaling pathways.
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Affiliation(s)
- Aida Kamalian
- Department of Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Masoud Sohrabi Asl
- Department of Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Mahsa Dolatshahi
- Department of Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Khashayar Afshari
- Department of Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Shiva Shamshiri
- Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Nazanin Momeni Roudsari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran 1941933111, Iran
| | - Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran 1417614411, Iran
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran
- Gastrointestinal Pharmacology Interest Group, Universal Scientific Education and Research Network, Tehran 1417614411, Iran
| | - Roja Rahimi
- Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Amir Hossein Abdolghaffari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran 1941933111, Iran
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran 1417614411, Iran
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran
- Gastrointestinal Pharmacology Interest Group, Universal Scientific Education and Research Network, Tehran 1417614411, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran
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16
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Controlling leukocyte trafficking in IBD. Pharmacol Res 2020; 159:105050. [PMID: 32598943 DOI: 10.1016/j.phrs.2020.105050] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 06/24/2020] [Accepted: 06/24/2020] [Indexed: 12/11/2022]
Abstract
Inflammatory bowel disease (IBD) is characterized by the accumulation of immune cells, myeloid cells and lymphocytes in the inflamed intestine. The presence and persistence of these cells, together with the production of pro-inflammatory mediators, perpetuate intestinal inflammation in both ulcerative colitis and Crohn's disease. Thus, blockade of leukocyte migration to the intestine is a main strategy used to control the disease and alleviate symptoms. Vedolizumab is the only anti-integrin drug approved for the treatment of IBD but several other drugs also targeting integrins, chemokines or receptors involved in leukocyte intestinal trafficking are under development and investigated for their efficacy and safety in IBD. The challenge now is to better understand the specific mechanism of action underlying each drug and to identify biomarkers that would guide drug selection in the individual patient.
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17
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Wang D, Yu W, Lian J, Wu Q, Liu S, Yang L, Li F, Huang L, Chen X, Zhang Z, Li A, Liu J, Sun Z, Wang J, Yuan W, Zhang Y. Th17 cells inhibit CD8 + T cell migration by systematically downregulating CXCR3 expression via IL-17A/STAT3 in advanced-stage colorectal cancer patients. J Hematol Oncol 2020; 13:68. [PMID: 32503584 PMCID: PMC7275425 DOI: 10.1186/s13045-020-00897-z] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 05/08/2020] [Indexed: 02/06/2023] Open
Abstract
Background CD8+ T cell trafficking to the tumor site is essential for effective colorectal cancer (CRC) immunotherapy. However, the mechanism underlying CD8+ T cell infiltration in colorectal tumor tissues is not fully understood. In the present study, we investigated CD8+ T cell infiltration in CRC tissues and the role of chemokine–chemokine receptor signaling in regulation of T cell recruitment. Methods We screened chemokines and cytokines in healthy donor and CRC tissues from early- and advanced-stage patients using multiplex assays and PCR screening. We also utilized transcription factor activation profiling arrays and established a xenograft mouse model. Results Compared with tumor tissues of early-stage CRC patients, CD8+ T cell density was lower in advanced-stage tumor tissues. PCR screening showed that CXCL10 levels were significantly increased in advanced-stage tumor tissues. CXCR3 (the receptor of CXCL10) expression on CD8+ T cells was lower in the peripheral blood of advanced-stage patients. The migratory ability of CD8+ T cells to CXCL10 depended on CXCR3 expression. Multiplex arrays showed that IL-17A was increased in advanced-stage patient sera, which markedly downregulated CXCR3 expression via activating STAT3 signaling and reduced CD8+ T cell migration. Similar results were found after CD8+ T cells were treated with Th17 cell supernatant. Adding anti-IL-17A or the STAT3 inhibitor, Stattic, rescued these effects in vitro and in vivo. Moreover, survival analysis showed that patients with low CD8 and CXCR3 expression and high IL-17A levels had significantly worse prognosis. Conclusions CD8+ T cell infiltration in advanced-stage tumor was systematically inhibited by Th17 cells via IL-17A/STAT3/CXCR3 axis. Our findings indicate that the T cell infiltration in the tumor microenvironment may be improved by inhibiting STAT3 signaling.
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Affiliation(s)
- Dan Wang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.,Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Weina Yu
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.,Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Jingyao Lian
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.,Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Qian Wu
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.,Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Shasha Liu
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.,Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Li Yang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.,Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Feng Li
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.,Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Lan Huang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.,Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Xinfeng Chen
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.,Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Zhen Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.,Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Aitian Li
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.,Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Jinbo Liu
- Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Zhenqiang Sun
- Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Junxia Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Weitang Yuan
- Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Yi Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China. .,Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China. .,School of Life Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China. .,Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, 450052, Henan, People's Republic of China.
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18
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Motwani K, Peters LD, Vliegen WH, El-sayed AG, Seay HR, Lopez MC, Baker HV, Posgai AL, Brusko MA, Perry DJ, Bacher R, Larkin J, Haller MJ, Brusko TM. Human Regulatory T Cells From Umbilical Cord Blood Display Increased Repertoire Diversity and Lineage Stability Relative to Adult Peripheral Blood. Front Immunol 2020; 11:611. [PMID: 32351504 PMCID: PMC7174770 DOI: 10.3389/fimmu.2020.00611] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Accepted: 03/17/2020] [Indexed: 12/22/2022] Open
Abstract
The human T lymphocyte compartment is highly dynamic over the course of a lifetime. Of the many changes, perhaps most notable is the transition from a predominantly naïve T cell state at birth to the acquisition of antigen-experienced memory and effector subsets following environmental exposures. These phenotypic changes, including the induction of T cell exhaustion and senescence, have the potential to negatively impact efficacy of adoptive T cell therapies (ACT). When considering ACT with CD4+CD25+CD127-/lo regulatory T cells (Tregs) for the induction of immune tolerance, we previously reported ex vivo expanded umbilical cord blood (CB) Tregs remained more naïve, suppressed responder T cells equivalently, and exhibited a more diverse T cell receptor (TCR) repertoire compared to expanded adult peripheral blood (APB) Tregs. Herein, we hypothesized that upon further characterization, we would observe increased lineage heterogeneity and phenotypic diversity in APB Tregs that might negatively impact lineage stability, engraftment capacity, and the potential for Tregs to home to sites of tissue inflammation following ACT. We compared the phenotypic profiles of human Tregs isolated from CB versus the more traditional source, APB. We conducted analysis of fresh and ex vivo expanded Treg subsets at both the single cell (scRNA-seq and flow cytometry) and bulk (microarray and cytokine profiling) levels. Single cell transcriptional profiles of pre-expansion APB Tregs highlighted a cluster of cells that showed increased expression of genes associated with effector and pro-inflammatory phenotypes (CCL5, GZMK, CXCR3, LYAR, and NKG7) with low expression of Treg markers (FOXP3 and IKZF2). CB Tregs were more diverse in TCR repertoire and homogenous in phenotype, and contained fewer effector-like cells in contrast with APB Tregs. Interestingly, expression of canonical Treg markers, such as FOXP3, TIGIT, and IKZF2, were increased in CB CD4+CD127+ conventional T cells (Tconv) compared to APB Tconv, post-expansion, implying perinatal T cells may adopt a default regulatory program. Collectively, these data identify surface markers (namely CXCR3) that could be depleted to improve purity and stability of APB Tregs, and support the use of expanded CB Tregs as a potentially optimal ACT modality for the treatment of autoimmune and inflammatory diseases.
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Affiliation(s)
- Keshav Motwani
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Leeana D. Peters
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Willem H. Vliegen
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Ahmed Gomaa El-sayed
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Howard R. Seay
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, United States
| | - M. Cecilia Lopez
- Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Henry V. Baker
- Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Amanda L. Posgai
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Maigan A. Brusko
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Daniel J. Perry
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Rhonda Bacher
- Department of Biostatistics, University of Florida, Gainesville, FL, United States
| | - Joseph Larkin
- Department of Microbiology and Cell Science, University of Florida, Gainesville, FL, United States
| | - Michael J. Haller
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Todd M. Brusko
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, United States
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, United States
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19
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Wang Y, Zhang H, He H, Ai K, Yu W, Xiao X, Qin Y, Zhang L, Xiong H, Zhou G. LRCH1 suppresses migration of CD4 + T cells and refers to disease activity in ulcerative colitis. Int J Med Sci 2020; 17:599-608. [PMID: 32210709 PMCID: PMC7085219 DOI: 10.7150/ijms.39106] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 01/13/2020] [Indexed: 01/05/2023] Open
Abstract
Background: Ulcerative colitis (UC) is a chronically remittent and progressive inflammatory disorder. LRCH1 is reported to be involved in the immune-regulation of several diseases. However, the exact roles of LRCH1 in UC are still obscure. Materials and Methods: LRCH1 expression was analyzed in the inflamed mucosa and peripheral blood mononuclear cells (PBMCs) from patients with UC by quantitative RT-PCR and immunohistochemistry. Peripheral blood CD4+ T cells were transfected with lentivirus-expressing LRCH1 (LV-LRCH1) or LV-sh-LRCH1, and cytokine expression was determined by using flow cytometry, quantitative RT-PCR and ELISA. Transfected CD4+ T cells were harvested to examine the capacity of chemotaxis using Transwell plate. Results: LRCH1 expression was highly decreased in colonic mucosa and PBMCs from patients with A-UC, and negatively correlated with disease activity. Up or down regulation of LRCH1 did not affect the differentiation of CD4+ T cells, and the related cytokines expression. Moreover, LRCH1 inhibited migratory capacity of CD4+ T cells toward CXCL12 by PKCα. Conclusion: LRCH1 plays an important role in the pathogenesis of UC, possibly through modulating the migration of CD4+ T cells. Therefore, targeting LRCH1 might serve as a novel therapeutic approach in the management of UC.
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Affiliation(s)
- Yibo Wang
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Hairong Zhang
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Heng He
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Kuankuan Ai
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Wei Yu
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Xiao Xiao
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Yufen Qin
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Lingming Zhang
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Huabao Xiong
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Guangxi Zhou
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, P.R. China
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20
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Pontes Ferreira C, Cariste LM, Ferri Moraschi B, Ferrarini Zanetti B, Won Han S, Araki Ribeiro D, Vieira Machado A, Lannes-Vieira J, Gazzinelli RT, Vasconcelos JRC. CXCR3 chemokine receptor guides Trypanosoma cruzi-specific T-cells triggered by DNA/adenovirus ASP2 vaccine to heart tissue after challenge. PLoS Negl Trop Dis 2019; 13:e0007597. [PMID: 31356587 PMCID: PMC6687206 DOI: 10.1371/journal.pntd.0007597] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 08/08/2019] [Accepted: 07/02/2019] [Indexed: 12/15/2022] Open
Abstract
CD8+ T lymphocytes play an important role in controlling infections by intracellular pathogens. Chemokines and their receptors are crucial for the migration of CD8+ T-lymphocytes, which are the main IFNγ producers and cytotoxic effectors cells. Although the participation of chemokine ligands and receptors has been largely explored in viral infection, much less is known in infection by Trypanosoma cruzi, the causative agent of Chagas disease. After T. cruzi infection, CXCR3 chemokine receptor is highly expressed on the surface of CD8+ T-lymphocytes. Here, we hypothesized that CXCR3 is a key molecule for migration of parasite-specific CD8+ T-cells towards infected tissues, where they may play their effector activities. Using a model of induction of resistance to highly susceptible A/Sn mice using an ASP2-carrying DNA/adenovirus prime-boost strategy, we showed that CXCR3 expression was upregulated on CD8+ T-cells, which selectively migrated towards its ligands CXCL9 and CXCL10. Anti-CXCR3 administration reversed the vaccine-induced resistance to T. cruzi infection in a way associated with hampered cytotoxic activity and increased proapoptotic markers on the H2KK-restricted TEWETGQI-specific CD8+ T-cells. Furthermore, CXCR3 receptor critically guided TEWETGQI-specific effector CD8+ T-cells to the infected heart tissue that express CXCL9 and CXCL10. Overall, our study pointed CXCR3 and its ligands as key molecules to drive T. cruzi-specific effector CD8+ T-cells into the infected heart tissue. The unveiling of the process driving cell migration and colonization of infected tissues by pathogen-specific effector T-cells is a crucial requirement to the development of vaccine strategies.
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Affiliation(s)
- Camila Pontes Ferreira
- Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo, São Paulo, Brazil
| | | | - Barbara Ferri Moraschi
- Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo, São Paulo, Brazil
| | | | - Sang Won Han
- Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil
| | | | | | - Joseli Lannes-Vieira
- Laboratory of Biology of the Interactions, Oswaldo Cruz Institute/Fiocruz, Rio de Janeiro, Brazil
| | - Ricardo Tostes Gazzinelli
- René Rachou Research Center, Fiocruz, Minas Gerais, Brazil
- Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, United States ofAmerica
| | - José Ronnie Carvalho Vasconcelos
- Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo, São Paulo, Brazil
- Department of Biosciences, Federal University of São Paulo, Santos, Brazil
- * E-mail:
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21
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Duarte-Silva M, Afonso PC, de Souza PR, Peghini BC, Rodrigues-Júnior V, de Barros Cardoso CR. Reappraisal of antibodies against Saccharomyces cerevisiae (ASCA) as persistent biomarkers in quiescent Crohn's disease. Autoimmunity 2019; 52:37-47. [PMID: 30884988 DOI: 10.1080/08916934.2019.1588889] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A clear correlation exists between microbiota and the dysregulation of the immune response in Inflammatory Bowel Diseases (IBD), which comprise Crohn's disease (CD) and ulcerative colitis (UC). These unbalanced reactions also involve humoral responses, with antibodies against Saccharomyces cerevisiae. Thus, here we aimed to quantify IgA and IgG specific to S. cerevisiae (ASCA) in quiescent CD and UC, to correlate the production of these antibodies with patient's inflammatory response and disease clinical presentation. Twenty-nine subjects (16 CD and 13 UC) and 45 healthy controls were enrolled in this study and had plasma samples tested for ASCA and cytokines (IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α), besides clinical evaluation. IBD patients had increase IgA and IgG ASCA, especially those with colonic (L2) and fistulizing (B3) CD. Similarly, patients who dropped out the treatment had augmented ASCA, while IgG was reduced in those receiving sulfasalazine treatment. Furthermore, the quiescent CD patients had elevated IL-6 on plasma, especially in the absence of treatment, together with increased counter regulatory response of IL-10. There was a positive correlation between IgA and IgG on CD but not UC, as well as between IgA and TNF in total IBD patients. In addition, the levels of IgG x TNF, IgA x IL-10 and IgG x IL-10 were also correlated in CD, indicating that ASCA production may be influenced by the inflammatory response. Finally, we concluded that ASCA could be pointed as relevant biomarker of CD presentation and residual inflammation, even in clinical remission patients.
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Affiliation(s)
- Murillo Duarte-Silva
- a Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto , Universidade de São Paulo , Ribeirão Preto , São Paulo , Brazil.,b Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto , Universidade de São Paulo , Ribeirão Preto , São Paulo , Brazil
| | - Poliana Cristina Afonso
- c Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro , Uberaba , Brazil
| | - Patrícia Reis de Souza
- a Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto , Universidade de São Paulo , Ribeirão Preto , São Paulo , Brazil.,c Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro , Uberaba , Brazil
| | - Bethânea Crema Peghini
- c Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro , Uberaba , Brazil
| | - Virmondes Rodrigues-Júnior
- c Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro , Uberaba , Brazil
| | - Cristina Ribeiro de Barros Cardoso
- a Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto , Universidade de São Paulo , Ribeirão Preto , São Paulo , Brazil
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22
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Wu XZ, Zhai K, Yi FS, Wang Z, Wang W, Wang Y, Pei XB, Shi XY, Xu LL, Shi HZ. IL-10 promotes malignant pleural effusion in mice by regulating T H 1- and T H 17-cell differentiation and migration. Eur J Immunol 2019; 49:653-665. [PMID: 30695099 DOI: 10.1002/eji.201847685] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Revised: 12/10/2018] [Accepted: 01/28/2019] [Indexed: 01/23/2023]
Abstract
The role of IL-10 in malignant pleural effusion (MPE) remains unknown. By using murine MPE models, we observed that an increase in pleural IL-10 was a significant predictor of increased risk of death. We noted that TH 1- and TH 17-cell content in MPE was higher in IL-10-/- mice than in WT mice, and IL-10 deficiency promoted differentiation into TH 1 but not into TH 17 cells. A higher fraction of TH 1 and TH 17 cells in the MPE of IL-10-/- mice expressed CXCR3 compared with WT mice. We also demonstrated that Lewis lung cancer and colon adenocarcinoma cells secreted large amounts of CXCL10, a ligand of CXCR3, which induced the migration of TH 1 and TH 17 cells into the MPE, and IFN-γ could promote this signaling cascade. Furthermore, intrapleural injection of mice with CXCL10-deficient tumor cells led to decreased TH 1- and TH 17-cell content in MPE, increased MPE volume, and reduced survival of MPE-bearing mice. Taken together, we demonstrated that IL-10 deficiency promoted T-cell differentiation into TH 1 cells and upregulated the CXCR3-CXCL10 signaling pathway that recruits TH 1 and TH 17 cells into MPE, ultimately resulting in decreased MPE formation and longer survival time of mice-bearing MPE.
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Affiliation(s)
- Xiu-Zhi Wu
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Kan Zhai
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Feng-Shuang Yi
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Zhen Wang
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Wen Wang
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Yao Wang
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Xue-Bin Pei
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Xin-Yu Shi
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Li-Li Xu
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Huan-Zhong Shi
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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23
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Barrios BE, Maccio-Maretto L, Nazar FN, Correa SG. A selective window after the food-intake period favors tolerance induction in mesenteric lymph nodes. Mucosal Immunol 2019; 12:108-116. [PMID: 30327533 DOI: 10.1038/s41385-018-0095-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 09/03/2018] [Accepted: 09/16/2018] [Indexed: 02/04/2023]
Abstract
Biological rhythms are periodic oscillations that occur in the physiology of the organism and the cells. The rhythms of the immune system are strictly regulated and the circadian alteration seems to have serious consequences. Even so, it is not clear how the immune cells of the intestinal mucosa synchronize with the external environment. Besides, little is known about the way in which biological rhythms affect the critical functions of intestinal immunity, such as oral tolerance. We studied fluctuations in the relevant parameters of intestinal immunity at four different times throughout the day. By using multivariate statistical tools, we found that these oscillations represent at least three different time frames with different conditions for tolerance induction that are altered in Per2ko mice lacking one of the clock genes. Our results allowed us to characterize a window in the final stage of the dark phase that promotes the induction of specific regulatory populations and favors its location in the lamina propria. We show here that, at the end of the intake, the entry of luminal antigens, soluble factors, and leukocyte populations converge in the mesenteric lymph nodes (MLN) and display the greatest potential of the tolerogenic machinery.
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Affiliation(s)
- Bibiana E Barrios
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI, CONICET-UNC), Departamento de Bioquímica Clínica-Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, CP 5000, Argentina
| | - Lisa Maccio-Maretto
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI, CONICET-UNC), Departamento de Bioquímica Clínica-Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, CP 5000, Argentina
| | - F Nicolás Nazar
- Instituto de Investigaciones Biológicas y Tecnológicas (IIByT, CONICET-UNC) e Instituto de Ciencia y Tecnología de los Alimentos, Facultad de Ciencias Exactas, Físicas y Naturales, Universidad Nacional de Córdoba, Córdoba, CP 5000, Argentina
| | - Silvia G Correa
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI, CONICET-UNC), Departamento de Bioquímica Clínica-Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, CP 5000, Argentina.
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24
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Zhou M, Xu W, Wang J, Yan J, Shi Y, Zhang C, Ge W, Wu J, Du P, Chen Y. Boosting mTOR-dependent autophagy via upstream TLR4-MyD88-MAPK signalling and downstream NF-κB pathway quenches intestinal inflammation and oxidative stress injury. EBioMedicine 2018; 35:345-360. [PMID: 30170968 PMCID: PMC6161481 DOI: 10.1016/j.ebiom.2018.08.035] [Citation(s) in RCA: 228] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 08/16/2018] [Accepted: 08/16/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND AND AIMS Defective autophagy has been proposed as an important event in a growing number of autoimmune and inflammatory diseases such as rheumatoid arthritis and lupus. However, the precise role of mechanistic target of rapamycin (mTOR)-dependent autophagy and its underlying regulatory mechanisms in the intestinal epithelium in response to inflammation and oxidative stress remain poorly understood. METHODS The levels of p-mTOR, LC3B, p62 and autophagy in mice and LPS-treated cells were examined by immunoblotting, immunohistochemistry, confocal microscopy and transmission electron microscopy (TEM). We evaluated the expression of IL-1β, IL-8, TNF-α, MDA, SOD and T-AOC by quantitative real time-polymerase chain reaction (qRT-PCR) and commercially available kits after silencing of mTOR and ATG5. In vivo modulation of mTOR and autophagy was achieved by using AZD8055, rapamycin and 3-methyladenine. Finally, to verify the involvement of TLR4 signalling and the NF-κB pathway in cells and active ulcerative colitis (UC) patients, immunofluorescence, qRT-PCR, immunoblotting and TEM were performed to determine TLR4 signalling relevance to autophagy and inflammation. RESULTS The mTOR-dependent autophagic flux impairment in a murine model of colitis, human intestinal epithelial cells and active UC patients is probably regulated by TLR4-MyD88-MAPK signalling and the NF-κB pathway. Silencing mTOR remarkably attenuated, whereas inhibiting ATG5 aggravated, LPS-induced inflammation and oxidative injury. Pharmacological administration of mTOR inhibitors and autophagy stimulators markedly ameliorated experimental colitis and oxidative stress in vivo. CONCLUSIONS Our findings not only shed light on the regulatory mechanism of mTOR-dependent autophagy, but also provided potential therapeutic targets for intestinal inflammatory diseases such as refractory inflammatory bowel disease.
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Affiliation(s)
- Mingxia Zhou
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
| | - Weimin Xu
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Jiazheng Wang
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
| | - Junkai Yan
- Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
| | - Yingying Shi
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
| | - Cong Zhang
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
| | - Wensong Ge
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Jin Wu
- Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
| | - Peng Du
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Yingwei Chen
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
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25
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Insight into structural requirements for selective and/or dual CXCR3 and CXCR4 allosteric modulators. Eur J Med Chem 2018; 154:68-90. [PMID: 29777988 DOI: 10.1016/j.ejmech.2018.05.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 04/18/2018] [Accepted: 05/09/2018] [Indexed: 11/21/2022]
Abstract
Based on the previously published pyrazolopyridine-based hit compound for which negative allosteric modulation of both CXCR3 and CXCR4 receptors was disclosed, we designed, synthesized and biologically evaluated a set of novel, not only negative, but also positive allosteric modulators with preserved pyrazolopyridine core. Compound 9e is a dual negative modulator, inhibiting G protein activity of both receptors. For CXCR4 receptor para-substituted aromatic group of compounds distinguishes between negative and positive modulation. Para-methoxy substitution leads to functional antagonism, while para-chloro triggers agonism. Additionally, we discovered that chemotaxis is not completely correlated with G protein pathways. This is the first work in which we have on a series of compounds successfully demonstrated that it is possible to produce selective as well as dual-acting modulators of chemokine receptors, which is very promising for future research in the field of discovery of selective or dual modulators of chemokine receptors.
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26
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Shi Y, He C, Ma C, Yu T, Cong Y, Cai W, Liu Z. Smad nuclear interacting protein 1 (SNIP1) inhibits intestinal inflammation through regulation of epithelial barrier function. Mucosal Immunol 2018; 11:835-845. [PMID: 29426045 DOI: 10.1038/mi.2017.95] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Accepted: 09/29/2017] [Indexed: 02/08/2023]
Abstract
Smad nuclear interacting protein 1 (SNIP1) has been implicated in the pathogenesis of inflammatory bowel disease (IBD). However, the mechanisms involved are still largely unknown. Our results demonstrated that SNIP1 was markedly decreased in intestinal epithelial cells (IEC) from IBD patients compared with healthy controls. Impaired expression of SNIP1 caused a significant decrease of transepithelial electrical resistance but an increase of fluorescein isothiocyanate-dextran flux in Caco-2 monolayers, whereas overexpression of SNIP1 reversed such effects. Overexpression of SNIP1 also inhibited the activity of NF-κB p65 and proinflammatory cytokine production (e.g., TNF-α, IL-1β, and IL-8) by IEC. Importantly, supplementation of exogenous SNIP1 significantly ameliorated intestinal mucosal inflammation in experimental colitis, characterized by less-severe intestinal epithelial barrier damage and decreased proinflammatory cytokine production. Our data thus demonstrated a novel mechanism whereby SNIP1 regulates intestinal inflammation through modulating intestinal epithelial barrier function. Targeting SNIP1 may provide a therapeutic approach for the treatment of IBD.
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Affiliation(s)
- Y Shi
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - C He
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - C Ma
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - T Yu
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Y Cong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.,Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - W Cai
- Department of General Surgery, Ruijin Hospital of Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Z Liu
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
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27
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Targeting JAK2 reduces GVHD and xenograft rejection through regulation of T cell differentiation. Proc Natl Acad Sci U S A 2018; 115:1582-1587. [PMID: 29382747 DOI: 10.1073/pnas.1712452115] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Janus kinase 2 (JAK2) signal transduction is a critical mediator of the immune response. JAK2 is implicated in the onset of graft-versus-host disease (GVHD), which is a significant cause of transplant-related mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Transfer of JAK2-/- donor T cells to allogeneic recipients leads to attenuated GVHD yet maintains graft-versus-leukemia. Th1 differentiation among JAK2-/- T cells is significantly decreased compared with wild-type controls. Conversely, iTreg and Th2 polarization is significantly increased among JAK2-/- T cells. Pacritinib is a multikinase inhibitor with potent activity against JAK2. Pacritinib significantly reduces GVHD and xenogeneic skin graft rejection in distinct rodent models and maintains donor antitumor immunity. Moreover, pacritinib spares iTregs and polarizes Th2 responses as observed among JAK2-/- T cells. Collectively, these data clearly identify JAK2 as a therapeutic target to control donor alloreactivity and promote iTreg responses after allo-HCT or solid organ transplantation. As such, a phase I/II acute GVHD prevention trial combining pacritinib with standard immune suppression after allo-HCT is actively being investigated (https://clinicaltrials.gov/ct2/show/NCT02891603).
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28
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Adamczyk A, Gageik D, Frede A, Pastille E, Hansen W, Rueffer A, Buer J, Büning J, Langhorst J, Westendorf AM. Differential expression of GPR15 on T cells during ulcerative colitis. JCI Insight 2017; 2:90585. [PMID: 28422750 DOI: 10.1172/jci.insight.90585] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 03/14/2017] [Indexed: 12/16/2022] Open
Abstract
G protein-coupled receptor 15 (GPR15) was recently highlighted as a colon-homing receptor for murine and human CD4+ T cells. The aim of this study was to explore the functional phenotype of human GPR15+CD4+ T cells, focusing on Tregs and effector T cells (Teffs), and to determine whether GPR15 is the driver for the migration of T cells to the colon during ulcerative colitis (UC). In the peripheral blood, GPR15 was expressed on Tregs and Teffs; both GPR15+ T cell subsets produced less IFN-γ and IL-4 but more IL-17 after stimulation and showed a higher migration activity compared with GPR15-CD4+ T cells. In UC patients, GPR15 expression was increased on Tregs in the peripheral blood but not on Teffs. Interestingly, the expression of GPR15 was significantly enhanced on colonic T cells of UC patients in noninflamed biopsies but not in inflamed biopsies. The differential expression of GPR15 in UC patients was accompanied by a significant reduction of bacterial immunoregulatory metabolites in the feces. In conclusion, GPR15 expression on CD4+ T cells is altered in UC patients, which may have implications for the development of therapeutic approaches to target T cell trafficking to the colon.
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Affiliation(s)
- Alexandra Adamczyk
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Daniel Gageik
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Annika Frede
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Eva Pastille
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Wiebke Hansen
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | | | - Jan Buer
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Jürgen Büning
- Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Lübeck, Germany
| | - Jost Langhorst
- Center of Integrative Gastroenterology, Kliniken Essen-Mitte, Essen, Germany
| | - Astrid M Westendorf
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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Fasching P, Stradner M, Graninger W, Dejaco C, Fessler J. Therapeutic Potential of Targeting the Th17/Treg Axis in Autoimmune Disorders. Molecules 2017; 22:E134. [PMID: 28098832 PMCID: PMC6155880 DOI: 10.3390/molecules22010134] [Citation(s) in RCA: 169] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 01/05/2017] [Accepted: 01/10/2017] [Indexed: 02/08/2023] Open
Abstract
A disruption of the crucial balance between regulatory T-cells (Tregs) and Th17-cells was recently implicated in various autoimmune disorders. Tregs are responsible for the maintenance of self-tolerance, thus inhibiting autoimmunity, whereas pro-inflammatory Th17-cells contribute to the induction and propagation of inflammation. Distortion of the Th17/Treg balance favoring the pro-inflammatory Th17 side is hence suspected to contribute to exacerbation of autoimmune disorders. This review aims to summarize recent data and advances in targeted therapeutic modification of the Th17/Treg-balance, as well as information on the efficacy of candidate therapeutics with respect to the treatment of autoimmune diseases.
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MESH Headings
- Animals
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal, Humanized
- Autoimmune Diseases/drug therapy
- Autoimmune Diseases/genetics
- Autoimmune Diseases/immunology
- Autoimmune Diseases/pathology
- Forkhead Transcription Factors/antagonists & inhibitors
- Forkhead Transcription Factors/genetics
- Forkhead Transcription Factors/immunology
- Gene Expression Regulation
- Humans
- Immunologic Factors/therapeutic use
- Inflammation
- Interleukin-17/antagonists & inhibitors
- Interleukin-17/genetics
- Interleukin-17/immunology
- Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors
- Nuclear Receptor Subfamily 1, Group F, Member 3/genetics
- Nuclear Receptor Subfamily 1, Group F, Member 3/immunology
- Piperidines/therapeutic use
- Pyrimidines/therapeutic use
- Pyrroles/therapeutic use
- Signal Transduction
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/pathology
- Th17 Cells/drug effects
- Th17 Cells/immunology
- Th17 Cells/pathology
- Ustekinumab/therapeutic use
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Affiliation(s)
- Patrizia Fasching
- Department of Rheumatology and Immunology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
| | - Martin Stradner
- Department of Rheumatology and Immunology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
| | - Winfried Graninger
- Department of Rheumatology and Immunology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
| | - Christian Dejaco
- Department of Rheumatology and Immunology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
| | - Johannes Fessler
- Department of Rheumatology and Immunology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
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Gregor CE, Foeng J, Comerford I, McColl SR. Chemokine-Driven CD4 + T Cell Homing: New Concepts and Recent Advances. Adv Immunol 2017; 135:119-181. [DOI: 10.1016/bs.ai.2017.03.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Ding Q, Lu P, Xia Y, Ding S, Fan Y, Li X, Han P, Liu J, Tian D, Liu M. CXCL9: evidence and contradictions for its role in tumor progression. Cancer Med 2016; 5:3246-3259. [PMID: 27726306 PMCID: PMC5119981 DOI: 10.1002/cam4.934] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 08/06/2016] [Accepted: 09/06/2016] [Indexed: 01/01/2023] Open
Abstract
Chemokines are a group of low molecular weight peptides. Their major function is the recruitment of leukocytes to inflammation sites, but they also play a key role in tumor growth, angiogenesis, and metastasis. In the last few years, accumulated experimental evidence supports that monokine induced by interferon (IFN)‐gamma (CXCL9), a member of CXC chemokine family and known to attract CXCR3‐ (CXCR3‐A and CXCR3‐B) T lymphocytes, is involved in the pathogenesis of a variety of physiologic diseases during their initiation and their maintenance. This review for the first time presents the most comprehensive summary for the role of CXCL9 in different types of tumors, and demonstrates its contradictory role of CXCL9 in tumor progression. Altogether, this is a useful resource for researchers investigating therapeutic opportunities for cancer.
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Affiliation(s)
- Qiang Ding
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China
| | - Panpan Lu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China
| | - Yujia Xia
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China
| | - Shuping Ding
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China
| | - Yuhui Fan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China
| | - Xin Li
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China
| | - Ping Han
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China
| | - Jingmei Liu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China
| | - Mei Liu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China
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Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets. Transl Res 2016; 176:38-68. [PMID: 27220087 DOI: 10.1016/j.trsl.2016.04.009] [Citation(s) in RCA: 129] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Revised: 03/17/2016] [Accepted: 04/28/2016] [Indexed: 12/14/2022]
Abstract
Ulcerative colitis and Crohn's disease are the 2 major phenotypes of inflammatory bowel disease (IBD), which are influenced by a complex interplay of immunological and genetic elements, though the precise etiology still remains unknown. With IBD developing into a globally prevailing disease, there is a need to explore new targets and a thorough understanding of the pathophysiological differences between the healthy and diseased gut could unearth new therapeutic opportunities. In this review, we provide an overview of the major aspects of IBD pathogenesis and thereafter present a comprehensive analysis of the gut pathophysiology leading to a discussion on some of the most promising targets and biologic therapies currently being explored. These include various gut proteins (CXCL-10, GATA-3, NKG2D, CD98, microRNAs), immune cells recruited to the gut (mast cells, eosinophils, toll-like receptors 2, 4), dysregulated proinflammatory cytokines (interleukin-6, -13, -18, -21), and commensal microbiota (probiotics and fecal microbiota transplantation). We also evaluate some of the emerging nonconventional therapies being explored in IBD treatment focusing on the latest developments in stem cell research, oral targeting of the gut-associated lymphoid tissue, novel anti-inflammatory signaling pathway targeting, adenosine deaminase inhibition, and the beneficial effects of antioxidant and nutraceutical therapies. In addition, we highlight the growth of biologics and their targets in IBD by providing information on the preclinical and clinical development of over 60 biopharmaceuticals representing the state of the art in ulcerative colitis and Crohn's disease drug development.
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