1
|
Zhang J, Tang H, Wu H, Pang X, Jin R, Zhang Y. Thymic dendritic cell-derived IL-27p28 promotes the establishment of functional bias against IFN-γ production in newly generated CD4 + T cells through STAT1-related epigenetic mechanisms. eLife 2025; 13:RP96868. [PMID: 40366856 PMCID: PMC12077877 DOI: 10.7554/elife.96868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2025] Open
Abstract
The newly generated CD4 single-positive (SP) T lymphocytes are featured by enhanced IL-4 but repressed IFN-γ production. The mechanisms underlying this functional bias remain elusive. Previous studies have reported that CD4+ T cells from mice harboring dendritic cell (DC)-specific deletion of IL-27p28 display an increased capacity of IFN-γ production upon TCR stimulation. Here, we demonstrated that similarly altered functionality occurred in CD4SP thymocytes, recent thymic emigrants (RTEs), as well as naive T cells from either Cd11c-p28f/f mice or mice deficient in the α subunit of IL-27 receptor. Therefore, DC-derived IL-27p28-triggered, IL-27Rα-mediated signal is critically involved in the establishment of functional bias against IFN-γ production during their development in the thymus. Epigenetic analyses indicated reduced DNA methylation of the Ifng locus and increased trimethylation of H3K4 at both Ifng and Tbx21 loci in CD4SP thymocytes from Cd11c-p28f/f mice. Transcriptome profiling demonstrated that Il27p28 ablation resulted in the coordinated up-regulation of STAT1-activated genes. Concurrently, STAT1 was found to be constitutively activated. Moreover, we observed increased accumulation of STAT1 at the Ifng and Tbx21 loci and a strong correlation between STAT1 binding and H3K4me3 modification of these loci. Of note, Il27p28 deficiency exacerbated the autoimmune phenotype of Aire-/- mice. Collectively, this study reveals a novel mechanism underlying the functional bias of newly generated CD4+ T cells and the potential relevance of such a bias in autoimmunity.
Collapse
Affiliation(s)
- Jie Zhang
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking UniversityBeijingChina
| | - Hui Tang
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking UniversityBeijingChina
| | - Haoming Wu
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking UniversityBeijingChina
| | - Xuewen Pang
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking UniversityBeijingChina
| | - Rong Jin
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking UniversityBeijingChina
| | - Yu Zhang
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking UniversityBeijingChina
- Institute of Life Sciences, Jinzhou Medical UniversityJinzhouChina
| |
Collapse
|
2
|
Belmares-Ortega J, Zara Issoufou Kapran F, Denkers EY. Influence of MyD88 and αβ T cells on mesenteric lymph node innate lymphoid cell populations during Toxoplasma gondii infection. PLoS One 2025; 20:e0322116. [PMID: 40299872 PMCID: PMC12040133 DOI: 10.1371/journal.pone.0322116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 03/17/2025] [Indexed: 05/01/2025] Open
Abstract
First encounter of Toxoplasma with the host immune system occurs within tissues of the intestine, including the intestinal mucosa and draining lymph nodes. In this study, we focused on the mesenteric lymph node compartment, the central hub of adaptive immune induction following orally acquired infection. We examined innate lymphoid cells (ILC) in mesenteric lymph nodes during Toxoplasma infection, determining the influence of MyD88 and the T lymphocyte compartment on ILC subset distribution, IFN-γ production, MHC class II expression and proliferation. Collectively, we observed an ILC1-dominated response that was impacted by both MyD88 and T lymphocytes. We also found a population of putative ILC that were negative for signature transcription factors associated with ILC1, 2 and 3 subsets. This study increases our understanding of ILC-mediated immunity during Toxoplasma infection and points to the complex interactions with which these cells engage T cell and MyD88-dependent immunity.
Collapse
Affiliation(s)
- Jessica Belmares-Ortega
- Center for Evolutionary and Theoretical Immunology and Department of Biology, University of New Mexico, Albuquerque, New Mexico, United States of America
| | - Fatouma Zara Issoufou Kapran
- Center for Evolutionary and Theoretical Immunology and Department of Biology, University of New Mexico, Albuquerque, New Mexico, United States of America
| | - Eric Y. Denkers
- Center for Evolutionary and Theoretical Immunology and Department of Biology, University of New Mexico, Albuquerque, New Mexico, United States of America
| |
Collapse
|
3
|
Eberhard JN, Shallberg LA, Winn A, Chandrasekaran S, Giuliano CJ, Merritt EF, Willis E, Konradt C, Christian DA, Aldridge DL, Bunkofske ME, Jacquet M, Dzierszinski F, Katifori E, Lourido S, Koshy AA, Hunter CA. Immune targeting and host-protective effects of the latent stage of Toxoplasma gondii. Nat Microbiol 2025; 10:992-1005. [PMID: 40148566 PMCID: PMC11964939 DOI: 10.1038/s41564-025-01967-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 02/19/2025] [Indexed: 03/29/2025]
Abstract
Latency is a microbial strategy for persistence. For Toxoplasma gondii the bradyzoite stage forms long-lived cysts critical for transmission, and its presence in neurons is considered important for immune evasion. However, the extent to which cyst formation escapes immune pressure and mediates persistence remained unclear. Here we developed a mathematical model highlighting that bradyzoite-directed immunity contributes to control of cyst numbers. In vivo studies demonstrated that transgenic CD8+ T cells recognized a cyst-derived antigen, and neuronal STAT1 signalling promoted cyst control in mice. Modelling and experiments with parasites unable to form bradyzoites (Δbfd1) revealed that the absence of cyst formation in the central nervous system did not prevent long-term persistence but resulted in increased tachyzoite replication with associated tissue damage and mortality. These findings suggest the latent form of T. gondii is under immune pressure, mitigates infection-induced damage and promotes survival of host and parasite.
Collapse
Affiliation(s)
- Julia N Eberhard
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Lindsey A Shallberg
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Aaron Winn
- Department of Physics and Astronomy, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA
| | | | - Christopher J Giuliano
- Whitehead Institute for Biomedical Research, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Emily F Merritt
- Department of Immunology, University of Arizona, Tucson, AZ, USA
| | - Elinor Willis
- Comparative Pathology Core, Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Christoph Konradt
- Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA
| | - David A Christian
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Daniel L Aldridge
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Molly E Bunkofske
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Maxime Jacquet
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Florence Dzierszinski
- The Royal Ottawa Mental Health Center, Institute of Mental Health Research, Ottawa, Ontario, Canada
| | - Eleni Katifori
- Department of Physics and Astronomy, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA
- Center for Computational Biology, Flatiron Institute, New York, NY, USA
| | - Sebastian Lourido
- Whitehead Institute for Biomedical Research, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Anita A Koshy
- BIO5 Institute, University of Arizona, Tucson, AZ, USA
- Department of Immunology, University of Arizona, Tucson, AZ, USA
- Department of Neurology, University of Arizona, Tucson, AZ, USA
| | - Christopher A Hunter
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| |
Collapse
|
4
|
Phan AT, Aunins E, Cruz-Morales E, Dwivedi G, Bunkofske M, Eberhard JN, Aldridge DL, Said H, Banda O, Tam Y, Christian DA, Vonderheide RH, Kedl RM, Weissman D, Alameh MG, Hunter CA. The type I IFN-IL-27 axis promotes mRNA vaccine-induced CD8 + T cell responses. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.16.633383. [PMID: 39896632 PMCID: PMC11785111 DOI: 10.1101/2025.01.16.633383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
The ability of lipid nanoparticle (LNP)-delivered mRNA vaccines to induce type I IFNs is critical to promote CD8 + T cell responses. The studies presented here indicate that immunization with nucleoside modified mRNA-LNP vaccines drives myeloid cell expression of the cytokine IL-27, which acts on antigen-specific CD8 + T cells to sustain T cell expansion. In vitro and in vivo studies revealed that type I IFN signaling is necessary for mRNA-LNP-induced IL-27 production, that immunization failed in IL-27 KO mice, and that immunization of IFNAR1-deficient mice with mRNA-LNP particles that also encode IL-27 mRNA restored antigen-specific CD8 + T cell responses. In addition, IL-27 mRNA-LNPs served as an adjuvant that improved cytolytic CD8 + T cell responses and the therapeutic efficacy of mRNA-LNPs to drive anti-pathogen and anti-tumor immunity. These studies highlight the central role of IL-27 in mRNA-LNP induced CD8 + T cell responses and the ability of this cytokine to augment the functionality of the CD8 + T cell response for prophylactic or therapeutic immunization.
Collapse
|
5
|
Aldridge DL, Lanzar Z, Phan AT, Christian DA, Pardy R, Min B, Kedl RM, Hunter CA. IL-27 limits HSPC differentiation during infection and protects from stem cell exhaustion. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.15.633135. [PMID: 39868131 PMCID: PMC11761129 DOI: 10.1101/2025.01.15.633135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Many inflammatory stimuli can induce progenitor cells in the bone marrow to produce increased numbers of myeloid cells as part of the process of emergency myelopoiesis. These events are associated with innate training and can have long-term impacts on hematopoietic stem and progenitor cell (HSPC) development but can also compromise their function. While many cytokines support emergency myelopoiesis, less is known about the mechanisms that temper these events. When mice that lack the cytokine IL-27 were infected with Toxoplasma gondii, there was enhanced generation of monocyte progenitors and increased numbers of inflammatory monocytes. In the bone marrow of infected mice there was increased production of IL-27 that localized with HSPCs and a survey of cytokine receptor expression highlighted that HSPCs were uniquely poised to respond to IL-27. Furthermore, the use of in vitro differentiation assays and mixed bone marrow chimeras revealed that HSPCs from IL-27 deficient mice are pre-disposed towards the monocyte lineage. Additional studies highlighted that after infection loss of the IL-27R resulted in reduced HSPC fitness that manifested as reduced proliferative responses and a decreased ability to reconstitute the hematopoietic system. Thus, the ability of IL-27 to act on HSPC provides a regulatory brake on differentiation to limit monocyte induction and preserve HSPC stemness.
Collapse
Affiliation(s)
- Daniel L Aldridge
- University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
| | - Zachary Lanzar
- University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
| | - Anthony T Phan
- University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
| | - David A Christian
- University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
| | - Ryan Pardy
- University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
| | - Booki Min
- Department of Microbiology and Immunology, Feinber School of Medicine, Northwestern University, Chicago, IL, USA
| | - Ross M Kedl
- University of Colorado, Anschuitz Medical Campus, Aurora, CO, USA
| | | |
Collapse
|
6
|
Hadifar S, Masoudzadeh N, Andersson B, Heydari H, Mashayekhi Goyonlo V, Kerachian M, Persson J, Rahimi-Tamandegani H, Erfanian Salim R, Rafati S, Harandi AM. Integrated analysis of lncRNA and mRNA expression profiles in cutaneous leishmaniasis lesions caused by Leishmania tropica. Front Cell Infect Microbiol 2024; 14:1416925. [PMID: 39639867 PMCID: PMC11617529 DOI: 10.3389/fcimb.2024.1416925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 10/25/2024] [Indexed: 12/07/2024] Open
Abstract
Background Cutaneous leishmaniasis (CL), caused by Leishmania (L.) species, remains a neglected tropical disease in many developing countries. We and others have shown that different Leishmania species can alter the gene expression profile of human host cells. Long non-coding RNAs (lncRNAs) have been found to play a role in the pathogenesis of leishmaniasis through dysregulation of transcriptome signatures. Understanding the regulatory roles of lncRNAs in the biological networks involved in leishmaniasis can improve our understanding of the disease. Methods Herein, we used our previous RNA sequencing data (GSE216638) to investigate the profile of lncRNAs in the skin lesions of L. tropica-infected patients. We employed the weighted gene correlation network analysis (WGCNA) algorithm to establish co-expression networks of shared genes between CL patients and infer the potential role of lncRNAs in CL patients. We identified hub genes and trans- and cis-acting lncRNAs, and carried out functional enrichment analysis on a key co-expressed module related to L. tropica-infected patients. Results We found substantial involvement of lncRNAs in the CL patient dataset. Using the WGCNA method, we classified all included genes into seven modules, with a module (turquoise) being significantly correlated with the studied clinical traits and identified as the key module. This module was mainly involved in the "interferon gamma signaling" and "cytokine signaling" pathways. We highlighted several lncRNAs and their co-expressed mRNA pairs, like SIRPG-AS1, IL21R-AS1, IL24, and TLDC2, as hub genes of the key module. Quantitative RT-PCR validated the expression of several genes in the lesions of an independent cohort of L. tropica-infected patients. Conclusions These findings enhance our understanding of the human skin response to L. tropica infection. Furthermore, the hub genes identified in this study are worthy of further evaluation as potential targets in the development of more effective treatments and preventive measures for CL caused by L. tropica.
Collapse
Affiliation(s)
- Shima Hadifar
- Department of Immunotherapy and Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran
| | - Nasrin Masoudzadeh
- Department of Immunotherapy and Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran
| | - Björn Andersson
- Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Hossein Heydari
- Department of Immunotherapy and Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran
| | | | - Mohammadali Kerachian
- Cutaneous Leishmaniasis Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Josefine Persson
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | | | | | - Sima Rafati
- Department of Immunotherapy and Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran
| | - Ali M. Harandi
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| |
Collapse
|
7
|
Madan U, Verma B, Awasthi A. Cenicriviroc, a CCR2/CCR5 antagonist, promotes the generation of type 1 regulatory T cells. Eur J Immunol 2024; 54:e2350847. [PMID: 38643381 DOI: 10.1002/eji.202350847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 04/01/2024] [Accepted: 04/03/2024] [Indexed: 04/22/2024]
Abstract
Cenicriviroc, a dual CCR2/CCR5 antagonist, initially developed as an anti-HIV drug, has shown promising results in nonalcoholic steatohepatitis phase 2 clinical trials. It inhibits the infiltration and activation of CCR2+/CCR5+ monocytes and macrophages to the site of liver injury, preventing liver fibrosis. However, the role of Cenicriviroc in the modulation of helper T cell differentiation and functions remains to be explored. In inflamed colons of Crohn's disease patients, CCR2+ and CCR5+ CD4+ T cells are enriched. Considering the role of CCR2+ and CCR5+ T cells in IBD pathogenesis, we investigated the potential role of Cenicriviroc in colitis. Our in vitro studies revealed that Cenicriviroc inhibits Th1-, Th2-, and Th17-cell differentiation while promoting the generation of type 1 regulatory T cells (Tr1), known for preventing inflammation through induction of IL-10. This study is the first to report that Cenicriviroc promotes Tr1 cell generation by up-regulating the signature of Tr1 cell transcription factors such as c-Maf, Prdm1, Irf-1, Batf, and EGR-2. Cenicriviroc displayed a protective effect in experimental colitis models by preventing body weight loss and intestinal inflammation and preserving epithelial barrier integrity. We show that Cenicriviroc induced IL-10 and inhibited the generation of pro-inflammatory cytokines IFN-γ, IL-17, IL-6, and IL-1β during colitis. Based on our data, we propose Cenicriviroc as a potential therapeutic in controlling tissue inflammation by inhibiting the generation and functions of effector T cells and promoting the induction of anti-inflammatory Tr1 cells.
Collapse
Affiliation(s)
- Upasna Madan
- Centre for Immuno-biology and Immunotherapy, NCR-Biotech Science Cluster, Translational Health Science and Technology Institute, Faridabad, Haryana, India
| | - Bhawna Verma
- Centre for Immuno-biology and Immunotherapy, NCR-Biotech Science Cluster, Translational Health Science and Technology Institute, Faridabad, Haryana, India
| | - Amit Awasthi
- Centre for Immuno-biology and Immunotherapy, NCR-Biotech Science Cluster, Translational Health Science and Technology Institute, Faridabad, Haryana, India
- Immunology-Core Lab, NCR Biotech Science Cluster, Translational Health Science and Technology Institute, Faridabad, Haryana, India
| |
Collapse
|
8
|
Andres-Martin F, James C, Catalfamo M. IL-27 expression regulation and its effects on adaptive immunity against viruses. Front Immunol 2024; 15:1395921. [PMID: 38966644 PMCID: PMC11222398 DOI: 10.3389/fimmu.2024.1395921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 06/03/2024] [Indexed: 07/06/2024] Open
Abstract
IL-27, a member of the IL-6/IL-12 cytokine superfamily, is primarily secreted by antigen presenting cells, specifically by dendric cells, macrophages and B cells. IL-27 has antiviral activities and modulates both innate and adaptive immune responses against viruses. The role of IL-27 in the setting of viral infections is not well defined and both pro-inflammatory and anti-inflammatory functions have been described. Here, we discuss the latest advancements in the role of IL-27 in several viral infection models of human disease. We highlight important aspects of IL-27 expression regulation, the critical cell sources at different stages of the infection and their impact in cell mediated immunity. Lastly, we discuss the need to better define the antiviral and modulatory (pro-inflammatory vs anti-inflammatory) properties of IL-27 in the context of human chronic viral infections.
Collapse
Affiliation(s)
| | | | - Marta Catalfamo
- Department of Microbiology Immunology, Georgetown University School of Medicine, Washington, DC, United States
| |
Collapse
|
9
|
Aldridge DL, Moodley D, Park J, Phan AT, Rausch M, White KF, Ren Y, Golin K, Radaelli E, Kedl R, Holland PM, Hill J, Hunter CA. Endogenous IL-27 during toxoplasmosis limits early monocyte responses and their inflammatory activation by pathological T cells. mBio 2024; 15:e0008324. [PMID: 38376210 PMCID: PMC10936422 DOI: 10.1128/mbio.00083-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 01/24/2024] [Indexed: 02/21/2024] Open
Abstract
Mice that lack the genes for IL-27, or the IL-27 receptor, and infected with Toxoplasma gondii develop T cell-mediated pathology. Here, studies were performed to determine the impact of endogenous IL-27 on the immune response to T. gondii in wild-type (WT) mice. Analysis of infected mice revealed the early production of IL-27p28 by a subset of Ly6Chi, inflammatory monocytes, and sustained IL-27p28 production at sites of acute and chronic infection. Administration of anti-IL-27p28 prior to infection resulted in an early (day 5) increase in levels of macrophage and granulocyte activation, as well as enhanced effector T cell responses, as measured by both cellularity, cytokine production, and transcriptional profiling. This enhanced acute response led to immune pathology, while blockade during the chronic phase of infection resulted in enhanced T cell responses but no systemic pathology. In the absence of IL-27, the enhanced monocyte responses observed at day 10 were a secondary consequence of activated CD4+ T cells. Thus, in WT mice, IL-27 has distinct suppressive effects that impact innate and adaptive immunity during different phases of this infection. IMPORTANCE The molecule IL-27 is critical in limiting the immune response to the parasite Toxoplasma gondii. In the absence of IL-27, a lethal, overactive immune response develops during infection. However, when exactly in the course of infection this molecule is needed was unclear. By selectively inhibiting IL-27 during this parasitic infection, we discovered that IL-27 was only needed during, but not prior to, infection. Additionally, IL-27 is only needed in the active areas in which the parasite is replicating. Finally, our work found that a previously unstudied cell type, monocytes, was regulated by IL-27, which contributes further to our understanding of the regulatory networks established by this molecule.
Collapse
Affiliation(s)
- Daniel L. Aldridge
- University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA
| | | | - Jeongho Park
- University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA
- Kangwon National University College of Veterinary Medicine and Institute of Veterinary Science, Chuncheon, South Korea
- Multidimensional Genomics Research Center, Kangwon National University, Chuncheon, South Korea
| | - Anthony T. Phan
- University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA
| | | | | | - Yue Ren
- Surface Oncology, Cambridge, Massachusetts, USA
| | - Karin Golin
- Surface Oncology, Cambridge, Massachusetts, USA
| | - Enrico Radaelli
- Comparative Pathology Core, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Ross Kedl
- Surface Oncology, Cambridge, Massachusetts, USA
- University of Colorado, Anschuitz Medical Campus, Aurora, Colorado, USA
| | | | | | - Christopher A. Hunter
- University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA
| |
Collapse
|
10
|
Bradford SD, Ryan KJ, Divens AM, Povroznik JM, Bonigala S, Robinson CM. IL-27 alters inflammatory cytokine expression and limits protective immunity against Mycobacterium tuberculosis in a neonatal BCG vaccination model. Front Immunol 2024; 15:1217098. [PMID: 38390338 PMCID: PMC10881868 DOI: 10.3389/fimmu.2024.1217098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 01/19/2024] [Indexed: 02/24/2024] Open
Abstract
Background Efforts to control tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis (Mtb), have been hampered by the immense variability in protection from BCG vaccination. While BCG protects young children from some forms of TB disease, long-term protection against pulmonary disease is more limited, suggesting a poor memory response. New vaccines or vaccination strategies are required to have a realistic chance of eliminating TB disease. In TB endemic areas, routine immunization occurs during the neonatal period and as such, we hypothesized that inadequate protective immunity elicited by BCG vaccination could be the result of the unique early-life immune landscape. Interleukin (IL)-27 is a heterodimeric cytokine with immune suppressive activity that is elevated in the neonatal period. Objective We investigated the impact of IL-27 on regulation of immune responses during neonatal BCG vaccination and protection against Mtb. Methods Here, we used a novel model of neonatal vaccination and adult aerosol challenge that models the human timeline of vaccine delivery and disease transmission. Results Overall, we observed improved control of Mtb in mice unresponsive to IL-27 (IL-27Rα-/-) that was consistent with altered expression patterns of IFN-γ and IL-17 in the lungs. The balance of these cytokines with TNF-α expression may be key to effective bacterial clearance. Conclusions Our findings suggest the importance of evaluating new vaccines and approaches to combat TB in the neonatal population most likely to receive them as part of global vaccination campaigns. They further indicate that temporal strategies to antagonize IL-27 during early life vaccination may improve protection.
Collapse
Affiliation(s)
- Shelby D. Bradford
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
- Vaccine Development Center, West Virginia University Health Sciences Center, Morgantown, WV, United States
| | - Kenneth J. Ryan
- Department of Statistics, West Virginia University, Morgantown, WV, United States
| | - Ashley M. Divens
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Jessica M. Povroznik
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
- Vaccine Development Center, West Virginia University Health Sciences Center, Morgantown, WV, United States
| | - Sunilkanth Bonigala
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Cory M. Robinson
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
- Vaccine Development Center, West Virginia University Health Sciences Center, Morgantown, WV, United States
| |
Collapse
|
11
|
Jana M, Mondal S, Jana A, Pahan K. Induction of IL-2 by interleukin-12 p40 homodimer and IL-12, but not IL-23, in microglia and macrophages: Implications for multiple sclerosis. Cytokine 2024; 174:156457. [PMID: 38056248 PMCID: PMC10872483 DOI: 10.1016/j.cyto.2023.156457] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 11/11/2023] [Accepted: 11/26/2023] [Indexed: 12/08/2023]
Abstract
The level of IL-2 increases markedly in serum and central nervous system (CNS) of patients with multiple sclerosis (MS) and animals with experimental allergic encephalomyelitis (EAE). However, mechanisms by which IL-2 is induced under autoimmune demyelinating conditions are poorly understood. The present study underlines the importance of IL-12p40 homodimer (p402), the so-called biologically inactive molecule, in inducing the expression of IL-2 in mouse BV-2 microglial cells, primary mouse and human microglia, mouse peritoneal macrophages, RAW264.7 macrophages, and T cells. Interestingly, we found that p402 and IL-12p70 (IL-12), but not IL-23, dose-dependently induced the production of IL-2 and the expression of IL-2 mRNA in microglial cells. Similarly, p402 also induced the activation of IL-2 promoter in microglial cells and RAW264.7 cells. Among various stimuli tested, p402 was the most potent stimulus followed by IFN-γ, bacterial lipopolysaccharide, HIV-1 gp120, and IL-12 in inducing the activation of IL-2 promoter in microglial cells. Moreover, p402, but not IL-23, increased NFATc2 mRNA expression and the transcriptional activity of NFAT. Furthermore, induction of IL-2 mRNA expression by over-expression of p40, but not by p19, cDNA indicated that p40, but not p19, is responsible for the induction of IL-2 mRNA in microglia. Finally, by using primary microglia from IL to 12 receptor β1 deficient (IL-12Rβ1-/-) and IL-12 receptor β2 deficient (IL-12Rβ2-/-) mice, we demonstrate that p402 induces the expression of IL-2 via IL-12Rβ1, but not IL-12Rβ2. In experimental autoimmune encephalomyelitis, an animal model of MS, neutralization of p402 by mAb a3-1d led to decrease in clinical symptoms and reduction in IL-2 in T cells and microglia. These results delineate a new biological function of p402, which is missing in the so-called autoimmune cytokine IL-23, and raise the possibility of controlling increased IL-2 and the disease process of MS via neutralization of p402.
Collapse
Affiliation(s)
- Malabendu Jana
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
| | - Susanta Mondal
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
| | - Arundhati Jana
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
| | - Kalipada Pahan
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA; Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, 820 South Damen Avenue, Chicago, IL, USA.
| |
Collapse
|
12
|
Sofia O, Amalia M, Thomassawa H, Fitri LE, Prayitnaningsih S, Susianti H. The Decreased Treg Cells Number Associated with Retinal Lesion Size in Ocular Toxoplasmosis. Interdiscip Perspect Infect Dis 2024; 2024:3495376. [PMID: 38314317 PMCID: PMC10830908 DOI: 10.1155/2024/3495376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 12/28/2023] [Accepted: 01/11/2024] [Indexed: 02/06/2024] Open
Abstract
Introduction The imbalance of the immune response is an important factor contributing to the incidence of ocular toxoplasmosis (OT). Regulatory T cells (Treg) play a key role in maintaining the balance between Th1 and Th17 immune responses, while interleukin-27 (IL-27) levels are related to the differentiation of Th17 cells. This study analyzes the differences in the number of Treg cells and the level of IL-27 between OT patients and seropositive individuals without ocular lesions and its correlation with retinal lesion size. Methods This analytic observational study, conducted for 8 months, involved 11 OT patients and 10 seropositive individuals without ocular lesions. All subjects underwent a comprehensive ophthalmological examination. Retinal lesions were documented by fundus photographs and the size was measured using Digimizer 4.2.2.0 software. Isolation of peripheral blood mononuclear cells (PBMC) was performed to measure the number of Treg cells using flow cytometry and interleukin-27 levels were assessed using the Sandwich enzyme-linked immunosorbent assay (ELISA) technique. Data were analyzed with SPSS. Result The number of Treg cells in the OT group (47.16 ± 15.66%) was lower than in the seropositive group without the ocular lesions (62.86 ± 17.08%) (p = 0.029). The serum IL-27 levels in the OT group were not significantly different from the seropositive group without the ocular lesions (p = 0.360). The number of Treg cells was significantly related to retinal lesion size (p = 0.043), with a correlation coefficient of -0.648, indicating a strong and inverse correlation. There was no significant correlation between serum IL-27 levels and retinal lesion size (p = 0.556). Conclusion Ocular toxoplasmosis patients have a low number of Treg cells that are inversely related to the retinal lesion size. The size of the retinal lesion increases as the number of Treg cells decreases.
Collapse
Affiliation(s)
- Ovi Sofia
- Doctoral Program in Medical Science, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia
- Department of Ophthalmology, Faculty of Medicine, Universitas Brawijaya, Dr. Saiful Anwar General Hospital, Malang, Indonesia
| | - Muna Amalia
- Residency Training Program, Department of Ophthalmology, Faculty of Medicine, Universitas Brawijaya, Dr. Saiful Anwar General Hospital, Malang, Indonesia
| | - Herryanto Thomassawa
- Residency Training Program, Department of Ophthalmology, Faculty of Medicine, Universitas Brawijaya, Dr. Saiful Anwar General Hospital, Malang, Indonesia
| | - Loeki Enggar Fitri
- Department of Clinical Parasitology, Faculty of Medicine, Universitas Brawijaya, Dr. Saiful Anwar General Hospital, Malang, Indonesia
| | - Seskoati Prayitnaningsih
- Department of Ophthalmology, Faculty of Medicine, Universitas Brawijaya, Dr. Saiful Anwar General Hospital, Malang, Indonesia
| | - Hani Susianti
- Department of Clinical Pathology, Faculty of Medicine, Universitas Brawijaya, Dr. Saiful Anwar General Hospital, Malang, Indonesia
| |
Collapse
|
13
|
Okamoto M, Yamamoto M. TCR Signals Controlling Adaptive Immunity against Toxoplasma and Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1444:177-193. [PMID: 38467980 DOI: 10.1007/978-981-99-9781-7_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/13/2024]
Abstract
T cells play a crucial role in adaptive immunity by recognizing and eliminating foreign pathogens and abnormal cells such as cancer cells. T cell receptor (TCR), which is expressed on the surface of T cells, recognizes and binds to specific antigens presented by major histocompatibility complex (MHC) molecules on antigen-presenting cells (APCs). This activation process leads to the proliferation and differentiation of T cells, allowing them to carry out their specific immune response functions. This chapter outlines the TCR signaling pathways that are common to different T cell subsets, as well as the recently elucidated TCR signaling pathway specific to CD8+ T cells and its role in controlling anti-Toxoplasma and anti-tumor immunity.
Collapse
Affiliation(s)
- Masaaki Okamoto
- Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
- Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Masahiro Yamamoto
- Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
- Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
- Department of Immunoparasitology, Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan.
| |
Collapse
|
14
|
Silva RCMC, Travassos LH, Dutra FF. The dichotomic role of single cytokines: Fine-tuning immune responses. Cytokine 2024; 173:156408. [PMID: 37925788 DOI: 10.1016/j.cyto.2023.156408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 10/19/2023] [Accepted: 10/23/2023] [Indexed: 11/07/2023]
Abstract
Cytokines are known for their pleiotropic effects. They can be classified by their function as pro-inflammatory, such as tumor necrosis factor (TNF), interleukin (IL) 1 and IL-12, or anti-inflammatory, like IL-10, IL-35 and transforming growth factor β (TGF-β). Though this type of classification is an important simplification for the understanding of the general cytokine's role, it can be misleading. Here, we discuss recent studies that show a dichotomic role of the so-called pro and anti-inflammatory cytokines, highlighting that their function can be dependent on the microenvironment and their concentrations. Furthermore, we discuss how the back-and-forth interplay between cytokines and immunometabolism can influence the dichotomic role of inflammatory responses as an important target to complement cytokine-based therapies.
Collapse
Affiliation(s)
| | - Leonardo Holanda Travassos
- Laboratório de Receptores e Sinalização intracelular, Instituto de Biofísica Carlos Chagas Filho, UFRJ, Rio de Janeiro, Brazil
| | - Fabianno Ferreira Dutra
- Laboratório de Imunologia e Inflamação, Instituto de Microbiologia Paulo de Góes, UFRJ, Rio de Janeiro, Brazil
| |
Collapse
|
15
|
Khorshidvand Z, Shirian S, Amiri H, Zamani A, Maghsood AH. Immunomodulatory chitosan nanoparticles for Toxoplasma gondii infection: Novel application of chitosan in complex propranolol-hydrochloride as an adjuvant in vaccine delivery. Int J Biol Macromol 2023; 253:127228. [PMID: 37839605 DOI: 10.1016/j.ijbiomac.2023.127228] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 09/28/2023] [Accepted: 10/01/2023] [Indexed: 10/17/2023]
Abstract
The study aimed to investigate the immunomodulatory effects of propranolol hydrochloride (PRO) in combination with chitosan nanoparticles (CS NPs) as an adjuvant to develop an effective vaccine against T. gondii. A total of 105 BALB/c mice were randomly divided into seven equal groups including PBS alone, CS NPs, SAG1 (Surface antigen 1), CS-SAG1 NPs, CS-PRO NPs, SAG1-PRO, and CS-SAG1-PRO NPs. The immunostimulatory effect of each adjuvant used for vaccine delivery was evaluated in a mice immunization model. The results showed that the mice immunized with CS-SAG1-PRO NPs exhibited the highest lymphocyte proliferation rate, along with increased secretion of IFN-γ, TNF-α, IL-6, IL-12, IL-17, and IL-23, as well as elevated levels of protective cytokines such as TGF-β, IL-27, and IL-10. Although, the CS-SAG1-PRO NPs immunized mice showed the highest level of T. gondii specific IgG compared to the other groups, a significant production of IgG2a and IgG1 was observed in the sera of mice immunized with the CS-SAG1-PRO NPs compared to the other group (p <0.001). The higher IgG2a/IgG1 ratio observed in the CS-SAG1-PRO NPs group indicates a bias towards Th1 cell polarization, suggesting the promotion of Th1 cell-mediated immune responses. Considering the combination of the highest lymphocyte proliferation and survival rates, IgG2a/IgG1 ratio, and cytokine levels in the mice immunized with CS-SAG1-PRO NPs, this approach holds promise for immunostimulation and vaccine delivery against T. gondii infection.
Collapse
Affiliation(s)
- Zohreh Khorshidvand
- Department of Parasitology and Mycology, School of Medicine Hamadan University of Medical Sciences, Hamadan, Iran
| | - Sadegh Shirian
- Department of Pathology, School of Veterinary Medicine, Shahrekord University, Shahrekord, Iran; Shiraz Molecular Pathology Research Center, Dr Daneshbod Lab, Shiraz, Iran
| | - Hanieh Amiri
- Shiraz Molecular Pathology Research Center, Dr Daneshbod Lab, Shiraz, Iran; Department of Biology, Sanandaj Branch, Islamic Azad University, Sanandaj, Iran
| | - Alireza Zamani
- Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Amir Hossein Maghsood
- Department of Parasitology and Mycology, School of Medicine Hamadan University of Medical Sciences, Hamadan, Iran.
| |
Collapse
|
16
|
Geng M, Li K, Ai K, Liang W, Yang J, Wei X. Evolutionarily conserved IL-27β enhances Th1 cells potential by triggering the JAK1/STAT1/T-bet axis in Nile tilapia. FISH AND SHELLFISH IMMUNOLOGY REPORTS 2023; 4:100087. [PMID: 36873098 PMCID: PMC9978509 DOI: 10.1016/j.fsirep.2023.100087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 02/16/2023] [Accepted: 02/16/2023] [Indexed: 02/19/2023] Open
Abstract
As a pleiotropic cytokine in the interleukin (IL)-12 family, IL-27β plays a significant role in regulating immune cell responses, eliminating invading pathogens, and maintaining immune homeostasis. Although non-mammalian IL-27β homologs have been identified, the mechanism of whether and how it is involved in adaptive immunity in early vertebrates remains unclear. In this study, we identified an evolutionarily conserved IL-27β (defined as OnIL-27β) from Nile tilapia (Oreochromis niloticus), and explored its conserved status through gene collinearity, gene structure, functional domain, tertiary structure, multiple sequence alignment, and phylogeny analysis. IL-27β was widely expressed in the immune-related tissues/organ of tilapia. The expression of OnIL-27β in spleen lymphocytes increased significantly at the adaptive immune phase after Edwardsiella piscicida infection. OnIL-27β can bind to precursor cells, T cells, and other lymphocytes to varying degrees. Additionally, IL-27β may be involved in lymphocyte-mediated immune responses through activation of Erk and JNK pathways. More importantly, we found that IL-27β enhanced the mRNA expression of the Th1 cell-associated cytokine IFN-γ and the transcription factor T-bet. This potential enhancement of the Th1 response may be attributed to the activation of the JAK1/STAT1/T-bet axis by IL-27β, as it induced increased transcript levels of JAK1, STAT1 but not TYK2 and STAT4. This study provides a new perspective for understanding the origin, evolution and function of the adaptive immune system in teleost.
Collapse
Affiliation(s)
- Ming Geng
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Kang Li
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Kete Ai
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Wei Liang
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Jialong Yang
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai 200241, China.,Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China
| | - Xiumei Wei
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai 200241, China
| |
Collapse
|
17
|
Lin CH, Wu CJ, Cho S, Patkar R, Huth WJ, Lin LL, Chen MC, Israelsson E, Betts J, Niedzielska M, Patel SA, Duong HG, Gerner RR, Hsu CY, Catley M, Maciewicz RA, Chu H, Raffatellu M, Chang JT, Lu LF. Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of T H17 cell immunity. Nat Immunol 2023; 24:2108-2120. [PMID: 37932457 PMCID: PMC11058069 DOI: 10.1038/s41590-023-01667-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 10/02/2023] [Indexed: 11/08/2023]
Abstract
Regulatory T cells (Treg cells) are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, in the present study we show that interleukin (IL)-27 is specifically produced by intestinal Treg cells to regulate helper T17 cell (TH17 cell) immunity. Selectively increased intestinal TH17 cell responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+CD62Llo Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a new Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.
Collapse
Affiliation(s)
- Chia-Hao Lin
- School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Cheng-Jang Wu
- School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Sunglim Cho
- School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Rasika Patkar
- School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - William J Huth
- School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Ling-Li Lin
- School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Mei-Chi Chen
- School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Elisabeth Israelsson
- Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Joanne Betts
- Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Magdalena Niedzielska
- Bioscience, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Shefali A Patel
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Han G Duong
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Romana R Gerner
- Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
| | - Chia-Yun Hsu
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
| | - Matthew Catley
- Bioscience, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Rose A Maciewicz
- Bioscience, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Hiutung Chu
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
- UC San Diego Center for Mucosal Immunology, Allergy, and Vaccines, Chiba University, La Jolla, CA, USA
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA
| | - Manuela Raffatellu
- Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
- UC San Diego Center for Mucosal Immunology, Allergy, and Vaccines, Chiba University, La Jolla, CA, USA
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA
| | - John T Chang
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
- Department of Medicine, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
| | - Li-Fan Lu
- School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA.
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
| |
Collapse
|
18
|
Riehl DR, Sharma A, Roewe J, Murke F, Ruppert C, Eming SA, Bopp T, Kleinert H, Radsak MP, Colucci G, Subramaniam S, Reinhardt C, Giebel B, Prinz I, Guenther A, Strand D, Gunzer M, Waisman A, Ward PA, Ruf W, Schäfer K, Bosmann M. Externalized histones fuel pulmonary fibrosis via a platelet-macrophage circuit of TGFβ1 and IL-27. Proc Natl Acad Sci U S A 2023; 120:e2215421120. [PMID: 37756334 PMCID: PMC10556605 DOI: 10.1073/pnas.2215421120] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 08/22/2023] [Indexed: 09/29/2023] Open
Abstract
Externalized histones erupt from the nucleus as extracellular traps, are associated with several acute and chronic lung disorders, but their implications in the molecular pathogenesis of interstitial lung disease are incompletely defined. To investigate the role and molecular mechanisms of externalized histones within the immunologic networks of pulmonary fibrosis, we studied externalized histones in human and animal bronchoalveolar lavage (BAL) samples of lung fibrosis. Neutralizing anti-histone antibodies were administered in bleomycin-induced fibrosis of C57BL/6 J mice, and subsequent studies used conditional/constitutive knockout mouse strains for TGFβ and IL-27 signaling along with isolated platelets and cultured macrophages. We found that externalized histones (citH3) were significantly (P < 0.01) increased in cell-free BAL fluids of patients with idiopathic pulmonary fibrosis (IPF; n = 29) as compared to healthy controls (n = 10). The pulmonary sources of externalized histones were Ly6G+CD11b+ neutrophils and nonhematopoietic cells after bleomycin in mice. Neutralizing monoclonal anti-histone H2A/H4 antibodies reduced the pulmonary collagen accumulation and hydroxyproline concentration. Histones activated platelets to release TGFβ1, which signaled through the TGFbRI/TGFbRII receptor complex on LysM+ cells to antagonize macrophage-derived IL-27 production. TGFβ1 evoked multiple downstream mechanisms in macrophages, including p38 MAPK, tristetraprolin, IL-10, and binding of SMAD3 to the IL-27 promotor regions. IL-27RA-deficient mice displayed more severe collagen depositions suggesting that intact IL-27 signaling limits fibrosis. In conclusion, externalized histones inactivate a safety switch of antifibrotic, macrophage-derived IL-27 by boosting platelet-derived TGFβ1. Externalized histones are accessible to neutralizing antibodies for improving the severity of experimental pulmonary fibrosis.
Collapse
Affiliation(s)
- Dennis R. Riehl
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
| | - Arjun Sharma
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
- Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA02118
- Mainz Research School of Translational Biomedicine (TransMed), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
| | - Julian Roewe
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
| | - Florian Murke
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen45122, Germany
| | - Clemens Ruppert
- Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen35392, Germany
| | - Sabine A. Eming
- Department of Dermatology, University of Cologne, Cologne50931, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Cologne50931, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne50931, Germany
| | - Tobias Bopp
- Institute of Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
- Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
| | - Hartmut Kleinert
- Department of Pharmacology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz55131, Germany
| | - Markus P. Radsak
- Mainz Research School of Translational Biomedicine (TransMed), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
- Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
- Third Department of Medicine – Hematology, Oncology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
| | - Giuseppe Colucci
- Outer Corelab, Viollier AG, Allschwil4123, Switzerland
- Department of Hematology, University of Basel, Basel4031, Switzerland
| | - Saravanan Subramaniam
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
- Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA02118
| | - Christoph Reinhardt
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
- German Center for Cardiovascular Research, Partner Site Rhine-Main, Mainz55131, Germany
| | - Bernd Giebel
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen45122, Germany
| | - Immo Prinz
- Institute for Immunology, Hannover Medical School, Hannover30625, Germany
| | - Andreas Guenther
- Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen35392, Germany
| | - Dennis Strand
- First Department of Internal Medicine, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz55131, Germany
| | - Matthias Gunzer
- Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, Essen45122, Germany
- Leibniz-Institute for Analytical Sciences -ISAS- e.V., Dortmund44139, Germany
| | - Ari Waisman
- Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
| | - Peter A. Ward
- Department of Pathology, University of Michigan Medical School, Ann Arbor48109, MI
| | - Wolfram Ruf
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
| | - Katrin Schäfer
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
- Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
| | - Markus Bosmann
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
- Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA02118
- Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
| |
Collapse
|
19
|
Schultz AB, Kugler DG, Nivelo L, Vitari N, Doyle LP, Ristin S, Hennighausen L, O’Shea JJ, Jankovic D, Villarino AV. T cell intrinsic STAT1 signaling prevents aberrant Th1 responses during acute toxoplasmosis. Front Immunol 2023; 14:1212190. [PMID: 37559725 PMCID: PMC10407301 DOI: 10.3389/fimmu.2023.1212190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/04/2023] [Indexed: 08/11/2023] Open
Abstract
Infection-induced T cell responses must be properly tempered and terminated to prevent immuno-pathology. Using transgenic mice, we demonstrate that T cell intrinsic STAT1 signaling is required to curb inflammation during acute infection with Toxoplasma gondii. Specifically, we report that mice lacking STAT1 selectively in T cells expel parasites but ultimately succumb to lethal immuno-pathology characterized by aberrant Th1-type responses with reduced IL-10 and increased IL-13 production. We also find that, unlike STAT1, STAT3 is not required for induction of IL-10 or suppression of IL-13 during acute toxoplasmosis. Each of these findings was confirmed in vitro and ChIP-seq data mining showed that STAT1 and STAT3 co-localize at the Il10 locus, as well as loci encoding other transcription factors that regulate IL-10 production, most notably Maf and Irf4. These data advance basic understanding of how infection-induced T cell responses are managed to prevent immuno-pathology and provide specific insights on the anti-inflammatory properties of STAT1, highlighting its role in shaping the character of Th1-type responses.
Collapse
Affiliation(s)
- Aaron B. Schultz
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United States
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, United States
| | - David G. Kugler
- Immunoparasitology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Luis Nivelo
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United States
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, United States
| | - Nicolas Vitari
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United States
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, United States
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Laura P. Doyle
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, United States
- Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Svetlana Ristin
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United States
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, United States
| | - Lothar Hennighausen
- National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - John J. O’Shea
- Lymphocyte Cell Biology Section, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Dragana Jankovic
- Immunoparasitology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Alejandro V. Villarino
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United States
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, United States
| |
Collapse
|
20
|
Park BR, Bommireddy R, Chung DH, Kim KH, Subbiah J, Jung YJ, Bhatnagar N, Pack CD, Ramachandiran S, Reddy SJC, Selvaraj P, Kang SM. Hemagglutinin virus-like particles incorporated with membrane-bound cytokine adjuvants provide protection against homologous and heterologous influenza virus challenge in aged mice. Immun Ageing 2023; 20:20. [PMID: 37170231 PMCID: PMC10173218 DOI: 10.1186/s12979-023-00344-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 04/24/2023] [Indexed: 05/13/2023]
Abstract
BACKGROUND Current influenza vaccines deliver satisfactory results in young people but are less effective in the elderly. Development of vaccines for an ever-increasing aging population has been an arduous challenge due to immunosenescence that impairs the immune response in the aged, both quantitatively and qualitatively. RESULTS To potentially enhance vaccine efficacy in the elderly, we investigated the immunogenicity and cross-protection of influenza hemagglutinin virus-like particles (HA-VLP) incorporated with glycosylphosphatidylinositol (GPI)-anchored cytokine-adjuvants (GPI-GM-CSF and GPI-IL-12) via protein transfer in aged mice. Lung viral replication against homologous and heterologous influenza viruses was significantly reduced in aged mice after vaccination with cytokine incorporated VLPs (HA-VLP-Cyt) in comparison to HA-VLP alone. Enhanced IFN-γ+CD4+ and IFN-γ+CD8+ T cell responses were also observed in aged mice immunized with HA-VLP-Cyt when compared to HA-VLP alone. CONCLUSIONS Cytokine-adjuvanted influenza HA-VLP vaccine induced enhanced protective response against homologous influenza A virus infection in aged mice. Influenza HA-VLP vaccine with GPI-cytokines also induced enhanced T cell responses correlating with better protection against heterologous infection in the absence of neutralizing antibodies. The results suggest that a vaccination strategy using cytokine-adjuvanted influenza HA-VLPs could be used to enhance protection against influenza A virus in the elderly.
Collapse
Affiliation(s)
- Bo Ryoung Park
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA
| | - Ramireddy Bommireddy
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - David Hyunjung Chung
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA
| | - Ki-Hye Kim
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA
| | - Jeeva Subbiah
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA
| | - Yu-Jin Jung
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA
| | - Noopur Bhatnagar
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA
| | | | | | | | - Periasamy Selvaraj
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Sang-Moo Kang
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA.
| |
Collapse
|
21
|
Clark JT, Weizman OE, Aldridge DL, Shallberg LA, Eberhard J, Lanzar Z, Wasche D, Huck JD, Zhou T, Ring AM, Hunter CA. IL-18BP mediates the balance between protective and pathological immune responses to Toxoplasma gondii. Cell Rep 2023; 42:112147. [PMID: 36827187 PMCID: PMC10131179 DOI: 10.1016/j.celrep.2023.112147] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 12/02/2022] [Accepted: 02/07/2023] [Indexed: 02/25/2023] Open
Abstract
Interleukin-18 (IL-18) promotes natural killer (NK) and T cell production of interferon (IFN)-γ, a key factor in resistance to Toxoplasma gondii, but previous work has shown a limited role for endogenous IL-18 in control of this parasite. Although infection with T. gondii results in release of IL-18, the production of IFN-γ induces high levels of the IL-18 binding protein (IL-18BP). Antagonism of IL-18BP with a "decoy-to-the-decoy" (D2D) IL-18 construct that does not signal but rather binds IL-18BP results in enhanced innate lymphoid cell (ILC) and T cell responses and improved parasite control. In addition, the use of IL-18 resistant to IL-18BP ("decoy-resistant" IL-18 [DR-18]) is more effective than exogenous IL-18 at promoting innate resistance to infection. DR-18 enhances CD4+ T cell production of IFN-γ but results in CD4+ T cell-mediated pathology. Thus, endogenous IL-18BP restrains aberrant immune pathology, and this study highlights strategies that can be used to tune this regulatory pathway for optimal anti-pathogen responses.
Collapse
Affiliation(s)
- Joseph T Clark
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
| | - Orr-El Weizman
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06519, USA
| | - Daniel L Aldridge
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
| | - Lindsey A Shallberg
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
| | - Julia Eberhard
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
| | - Zachary Lanzar
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
| | - Devon Wasche
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06519, USA
| | - John D Huck
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06519, USA
| | - Ting Zhou
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06519, USA
| | - Aaron M Ring
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06519, USA.
| | - Christopher A Hunter
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA.
| |
Collapse
|
22
|
Schepers M, Paes D, Tiane A, Rombaut B, Piccart E, van Veggel L, Gervois P, Wolfs E, Lambrichts I, Brullo C, Bruno O, Fedele E, Ricciarelli R, Ffrench-Constant C, Bechler ME, van Schaik P, Baron W, Lefevere E, Wasner K, Grünewald A, Verfaillie C, Baeten P, Broux B, Wieringa P, Hellings N, Prickaerts J, Vanmierlo T. Selective PDE4 subtype inhibition provides new opportunities to intervene in neuroinflammatory versus myelin damaging hallmarks of multiple sclerosis. Brain Behav Immun 2023; 109:1-22. [PMID: 36584795 DOI: 10.1016/j.bbi.2022.12.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 12/17/2022] [Accepted: 12/24/2022] [Indexed: 12/29/2022] Open
Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by focal inflammatory lesions and prominent demyelination. Even though the currently available therapies are effective in treating the initial stages of disease, they are unable to halt or reverse disease progression into the chronic progressive stage. Thus far, no repair-inducing treatments are available for progressive MS patients. Hence, there is an urgent need for the development of new therapeutic strategies either targeting the destructive immunological demyelination or boosting endogenous repair mechanisms. Using in vitro, ex vivo, and in vivo models, we demonstrate that selective inhibition of phosphodiesterase 4 (PDE4), a family of enzymes that hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP), reduces inflammation and promotes myelin repair. More specifically, we segregated the myelination-promoting and anti-inflammatory effects into a PDE4D- and PDE4B-dependent process respectively. We show that inhibition of PDE4D boosts oligodendrocyte progenitor cells (OPC) differentiation and enhances (re)myelination of both murine OPCs and human iPSC-derived OPCs. In addition, PDE4D inhibition promotes in vivo remyelination in the cuprizone model, which is accompanied by improved spatial memory and reduced visual evoked potential latency times. We further identified that PDE4B-specific inhibition exerts anti-inflammatory effects since it lowers in vitro monocytic nitric oxide (NO) production and improves in vivo neurological scores during the early phase of experimental autoimmune encephalomyelitis (EAE). In contrast to the pan PDE4 inhibitor roflumilast, the therapeutic dose of both the PDE4B-specific inhibitor A33 and the PDE4D-specific inhibitor Gebr32a did not trigger emesis-like side effects in rodents. Finally, we report distinct PDE4D isoform expression patterns in human area postrema neurons and human oligodendroglia lineage cells. Using the CRISPR-Cas9 system, we confirmed that pde4d1/2 and pde4d6 are the key targets to induce OPC differentiation. Collectively, these data demonstrate that gene specific PDE4 inhibitors have potential as novel therapeutic agents for targeting the distinct disease processes of MS.
Collapse
Affiliation(s)
- Melissa Schepers
- Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands; University MS Center (UMSC) Hasselt-Pelt, Hasselt, Belgium
| | - Dean Paes
- Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
| | - Assia Tiane
- Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands; University MS Center (UMSC) Hasselt-Pelt, Hasselt, Belgium
| | - Ben Rombaut
- Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
| | - Elisabeth Piccart
- Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium
| | - Lieve van Veggel
- Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands; University MS Center (UMSC) Hasselt-Pelt, Hasselt, Belgium
| | - Pascal Gervois
- Department of Cardio and Organ Systems, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Esther Wolfs
- Department of Cardio and Organ Systems, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Ivo Lambrichts
- Department of Cardio and Organ Systems, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Chiara Brullo
- Department of Pharmacy, Section of Medicinal Chemistry, University of Genoa, Genova, Italy
| | - Olga Bruno
- Department of Pharmacy, Section of Medicinal Chemistry, University of Genoa, Genova, Italy
| | - Ernesto Fedele
- Department of Pharmacy, Section of Pharmacology and Toxicology, University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Roberta Ricciarelli
- IRCCS Ospedale Policlinico San Martino, Genova, Italy; Department of Experimental Medicine, Section of General Pathology, University of Genova, Genova, Italy
| | - Charles Ffrench-Constant
- MRC Centre for Regenerative Medicine and MS Society Edinburgh Centre, Edinburgh bioQuarter, University of Edinburgh, Edinburgh, UK
| | - Marie E Bechler
- Department of Cell and Developmental Biology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Pauline van Schaik
- Department of Biomedical Sciences of Cells and Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Wia Baron
- Department of Biomedical Sciences of Cells and Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Evy Lefevere
- Rewind Therapeutics NV, Gaston Geenslaan 2, B-3001, Leuven, Belgium
| | - Kobi Wasner
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Anne Grünewald
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Catherine Verfaillie
- Stem Cell Institute, Department of Development and Regeneration, KU Leuven, Belgium
| | - Paulien Baeten
- University MS Center (UMSC) Hasselt-Pelt, Hasselt, Belgium; Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Bieke Broux
- University MS Center (UMSC) Hasselt-Pelt, Hasselt, Belgium; Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Paul Wieringa
- MERLN Institute for Technology-Inspired Regenerative Medicine, Complex Tissue Regeneration department, Maastricht University, Maastricht, the Netherlands
| | - Niels Hellings
- University MS Center (UMSC) Hasselt-Pelt, Hasselt, Belgium; Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Jos Prickaerts
- Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
| | - Tim Vanmierlo
- Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands; University MS Center (UMSC) Hasselt-Pelt, Hasselt, Belgium.
| |
Collapse
|
23
|
Lin CH, Wu CJ, Cho S, Patkar R, Lin LL, Chen MC, Israelsson E, Betts J, Niedzielska M, Patel SA, Duong HG, Gerner RR, Hsu CY, Catley M, Maciewicz RA, Chu H, Raffatellu M, Chang JT, Lu LF. Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of Th17 immunity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.20.529261. [PMID: 36865314 PMCID: PMC9980002 DOI: 10.1101/2023.02.20.529261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/23/2023]
Abstract
Regulatory T (Treg) cells are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, here we show that IL-27 is specifically produced by intestinal Treg cells to regulate Th17 immunity. Selectively increased intestinal Th17 responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+TCF1+ Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a novel Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue, and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.
Collapse
Affiliation(s)
- Chia-Hao Lin
- School of Biological Sciences, University of California, San Diego, La Jolla, California , CA, USA
| | - Cheng-Jang Wu
- School of Biological Sciences, University of California, San Diego, La Jolla, California , CA, USA
| | - Sunglim Cho
- School of Biological Sciences, University of California, San Diego, La Jolla, California , CA, USA
| | - Rasika Patkar
- School of Biological Sciences, University of California, San Diego, La Jolla, California , CA, USA
| | - Ling-Li Lin
- School of Biological Sciences, University of California, San Diego, La Jolla, California , CA, USA
| | - Mei-Chi Chen
- School of Biological Sciences, University of California, San Diego, La Jolla, California , CA, USA
| | - Elisabeth Israelsson
- Bioscience, Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Joanne Betts
- Bioscience, Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Magdalena Niedzielska
- Bioscience, Research and Early Development, Respiratory & Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Shefali A Patel
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Han G Duong
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Romana R Gerner
- Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
| | - Chia-Yun Hsu
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
| | - Matthew Catley
- Bioscience, Research and Early Development, Respiratory & Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Rose A Maciewicz
- Bioscience, Research and Early Development, Respiratory & Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Hiutung Chu
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
- Chiba University-UC San Diego Center for Mucosal Immunology, Allergy, and Vaccines (CU-UCSD cMAV), La Jolla, CA 92093, USA
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA
| | - Manuela Raffatellu
- Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
- Chiba University-UC San Diego Center for Mucosal Immunology, Allergy, and Vaccines (CU-UCSD cMAV), La Jolla, CA 92093, USA
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA
| | - John T Chang
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
- Department of Medicine, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
| | - Li-Fan Lu
- School of Biological Sciences, University of California, San Diego, La Jolla, California , CA, USA
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| |
Collapse
|
24
|
Povroznik JM, Akhter H, Vance JK, Annamanedi M, Dziadowicz SA, Wang L, Divens AM, Hu G, Robinson CM. Interleukin-27-dependent transcriptome signatures during neonatal sepsis. Front Immunol 2023; 14:1124140. [PMID: 36891292 PMCID: PMC9986606 DOI: 10.3389/fimmu.2023.1124140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 02/07/2023] [Indexed: 02/22/2023] Open
Abstract
Human newborns exhibit increased vulnerability and risk of mortality from infection that is consistent with key differences in the innate and adaptive immune responses relative to those in adult cells. We have previously shown an increase in the immune suppressive cytokine, IL-27, in neonatal cells and tissues from mice and humans. In a murine model of neonatal sepsis, mice deficient in IL-27 signaling exhibit reduced mortality, increased weight gain, and better control of bacteria with reduced systemic inflammation. To explore a reprogramming of the host response in the absence of IL-27 signaling, we profiled the transcriptome of the neonatal spleen during Escherichia coli-induced sepsis in wild-type (WT) and IL-27Rα-deficient (KO) mice. We identified 634 genes that were differentially expressed, and those most upregulated in WT mice were associated with inflammation, cytokine signaling, and G protein coupled receptor ligand binding and signaling. These genes failed to increase in the IL-27Rα KO mice. We further isolated an innate myeloid population enriched in macrophages from the spleens of control and infected WT neonates and observed similar changes in gene expression aligned with changes in chromatin accessibility. This supports macrophages as an innate myeloid population contributing to the inflammatory profile in septic WT pups. Collectively, our findings highlight the first report of improved pathogen clearance amidst a less inflammatory environment in IL-27Rα KO. This suggests a direct relationship between IL-27 signaling and bacterial killing. An improved response to infection that is not reliant upon heightened levels of inflammation offers new promise to the potential of antagonizing IL-27 as a host-directed therapy for neonates.
Collapse
Affiliation(s)
- Jessica M. Povroznik
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
- Vaccine Development Center, West Virginia University Health Sciences Center, Morgantown, WV, United States
| | - Halima Akhter
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Jordan K. Vance
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Madhavi Annamanedi
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Sebastian A. Dziadowicz
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Lei Wang
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Ashley M. Divens
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Gangqing Hu
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Cory M. Robinson
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
- Vaccine Development Center, West Virginia University Health Sciences Center, Morgantown, WV, United States
| |
Collapse
|
25
|
Tebben K, Yirampo S, Coulibaly D, Koné AK, Laurens MB, Stucke EM, Dembélé A, Tolo Y, Traoré K, Niangaly A, Berry AA, Kouriba B, Plowe CV, Doumbo OK, Lyke KE, Takala-Harrison S, Thera MA, Travassos MA, Serre D. Malian children infected with Plasmodium ovale and Plasmodium falciparum display very similar gene expression profiles. PLoS Negl Trop Dis 2023; 17:e0010802. [PMID: 36696438 PMCID: PMC9901758 DOI: 10.1371/journal.pntd.0010802] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 02/06/2023] [Accepted: 01/16/2023] [Indexed: 01/26/2023] Open
Abstract
Plasmodium parasites caused 241 million cases of malaria and over 600,000 deaths in 2020. Both P. falciparum and P. ovale are endemic to Mali and cause clinical malaria, with P. falciparum infections typically being more severe. Here, we sequenced RNA from nine pediatric blood samples collected during infections with either P. falciparum or P. ovale, and characterized the host and parasite gene expression profiles. We found that human gene expression varies more between individuals than according to the parasite species causing the infection, while parasite gene expression profiles cluster by species. Additionally, we characterized DNA polymorphisms of the parasites directly from the RNA-seq reads and found comparable levels of genetic diversity in both species, despite dramatic differences in prevalence. Our results provide unique insights into host-pathogen interactions during malaria infections and their variations according to the infecting Plasmodium species, which will be critical to develop better elimination strategies against all human Plasmodium parasites.
Collapse
Affiliation(s)
- Kieran Tebben
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore Maryland, United States of America
| | - Salif Yirampo
- Malaria Research and Training Center, University of Sciences, Techniques and Technologies, Bamako, Mali
| | - Drissa Coulibaly
- Malaria Research and Training Center, University of Sciences, Techniques and Technologies, Bamako, Mali
| | - Abdoulaye K. Koné
- Malaria Research and Training Center, University of Sciences, Techniques and Technologies, Bamako, Mali
| | - Matthew B. Laurens
- Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | - Emily M. Stucke
- Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | - Ahmadou Dembélé
- Malaria Research and Training Center, University of Sciences, Techniques and Technologies, Bamako, Mali
| | - Youssouf Tolo
- Malaria Research and Training Center, University of Sciences, Techniques and Technologies, Bamako, Mali
| | - Karim Traoré
- Malaria Research and Training Center, University of Sciences, Techniques and Technologies, Bamako, Mali
| | - Amadou Niangaly
- Malaria Research and Training Center, University of Sciences, Techniques and Technologies, Bamako, Mali
| | - Andrea A. Berry
- Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | - Bourema Kouriba
- Malaria Research and Training Center, University of Sciences, Techniques and Technologies, Bamako, Mali
| | - Christopher V. Plowe
- Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | - Ogobara K. Doumbo
- Malaria Research and Training Center, University of Sciences, Techniques and Technologies, Bamako, Mali
| | - Kirsten E. Lyke
- Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | - Shannon Takala-Harrison
- Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | - Mahamadou A. Thera
- Malaria Research and Training Center, University of Sciences, Techniques and Technologies, Bamako, Mali
| | - Mark A. Travassos
- Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | - David Serre
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore Maryland, United States of America
| |
Collapse
|
26
|
Bradford SD, Witt MR, Povroznik JM, Robinson CM. Interleukin-27 impairs BCG antigen clearance and T cell stimulatory potential by neonatal dendritic cells. CURRENT RESEARCH IN MICROBIAL SCIENCES 2022; 4:100176. [DOI: 10.1016/j.crmicr.2022.100176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
|
27
|
Interleukin-27 Ameliorates Atherosclerosis in ApoE-/- Mice through Regulatory T Cell Augmentation and Dendritic Cell Tolerance. Mediators Inflamm 2022; 2022:2054879. [PMID: 36405994 PMCID: PMC9674420 DOI: 10.1155/2022/2054879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 09/28/2022] [Accepted: 10/13/2022] [Indexed: 11/13/2022] Open
Abstract
Atherosclerosis, which is characterized by chronic inflammation in the arterial wall, is driven by immune cells and cytokines. Recent evidence indicated that interleukin (IL)-27 showed pleiotropic properties in immune diseases. However, precise mechanisms of IL-27, especially in atherosclerosis remains unknown. In our research, we examined the influence of the administration of IL-27 and an anti-IL-27p28 antibody (anti-IL-27p28-Ab) on both the initiation and the progression of atherosclerosis. In the groups (both the initiation and the progression) receiving recombinant IL-27 administration, the formation of atherosclerotic plaques was suspended, and the percentage of regulatory T cells (LAP+ or Foxp3+) in the spleen and peripheral blood was increased. Meanwhile, the number of T helper 1 (Th1) and T helper 17 (Th17) cells was decreased. In the peripheral blood plasma, TGF-β and IL-10 expression were increased, while the levels of IFN-γ and IL-17 were reduced. As for lesions, the mRNA expression of Foxp3, TGF-β, and IL-10 was increased, while that of IFN-γ and IL-17 was reduced. In the anti-IL-27p28 antibody groups, we obtained opposite results. We also observed that DCs treated with IL-27 display a tolerogenic phenotype and that IL-27–treated tolerogenic DCs (tDCs) are likely to play a protective role during atherosclerosis. Our study indicates that IL-27 or adoptive transfer of IL-27 loaded tDCs may be a new therapeutic approach in atherosclerosis.
Collapse
|
28
|
Aghayev T, Mazitova AM, Fang JR, Peshkova IO, Rausch M, Hung M, White KF, Masia R, Titerina EK, Fatkhullina AR, Cousineau I, Turcotte S, Zhigarev D, Marchenko A, Khoziainova S, Makhov P, Tan YF, Kossenkov AV, Wiest DL, Stagg J, Wang XW, Campbell KS, Dzutsev AK, Trinchieri G, Hill JA, Grivennikov SI, Koltsova EK. IL27 Signaling Serves as an Immunologic Checkpoint for Innate Cytotoxic Cells to Promote Hepatocellular Carcinoma. Cancer Discov 2022; 12:1960-1983. [PMID: 35723626 PMCID: PMC9357073 DOI: 10.1158/2159-8290.cd-20-1628] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 04/01/2022] [Accepted: 06/03/2022] [Indexed: 02/07/2023]
Abstract
Although inflammatory mechanisms driving hepatocellular carcinoma (HCC) have been proposed, the regulators of anticancer immunity in HCC remain poorly understood. We found that IL27 receptor (IL27R) signaling promotes HCC development in vivo. High IL27EBI3 cytokine or IL27RA expression correlated with poor prognosis for patients with HCC. Loss of IL27R suppressed HCC in vivo in two different models of hepatocarcinogenesis. Mechanistically, IL27R sig-naling within the tumor microenvironment restrains the cytotoxicity of innate cytotoxic lymphocytes. IL27R ablation enhanced their accumulation and activation, whereas depletion or functional impairment of innate cytotoxic cells abrogated the effect of IL27R disruption. Pharmacologic neutralization of IL27 signaling increased infiltration of innate cytotoxic lymphocytes with upregulated cytotoxic molecules and reduced HCC development. Our data reveal an unexpected role of IL27R signaling as an immunologic checkpoint regulating innate cytotoxic lymphocytes and promoting HCC of different etiologies, thus indicating a therapeutic potential for IL27 pathway blockade in HCC. SIGNIFICANCE HCC, the most common form of liver cancer, is characterized by a poor survival rate and limited treatment options. The discovery of a novel IL27-dependent mechanism controlling anticancer cytotoxic immune response will pave the road for new treatment options for this devastating disease. This article is highlighted in the In This Issue feature, p. 1825.
Collapse
Affiliation(s)
- Turan Aghayev
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Aleksandra M. Mazitova
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
- Cedars-Sinai Medical Center, Cedars-Sinai Cancer Institute, Department of Medicine, Department of Biomedical Sciences 8700 Beverly Blvd, Los Angeles, CA, 900048
| | - Jennifer R. Fang
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, 20892
| | - Iuliia O. Peshkova
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Matthew Rausch
- Surface Oncology Inc., 50 Hampshire St. Cambridge, MA, 02139
| | - Manhsin Hung
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, 20892
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, 20892
| | - Kerry F. White
- Surface Oncology Inc., 50 Hampshire St. Cambridge, MA, 02139
| | - Ricard Masia
- Surface Oncology Inc., 50 Hampshire St. Cambridge, MA, 02139
| | - Elizaveta K. Titerina
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Aliia R. Fatkhullina
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Isabelle Cousineau
- Centre Hospitalier de l’Université de Montréal Research Center, Montreal, Quebec, Canada
| | - Simon Turcotte
- Centre Hospitalier de l’Université de Montréal Research Center, Montreal, Quebec, Canada
| | - Dmitry Zhigarev
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Anastasiia Marchenko
- Cedars-Sinai Medical Center, Cedars-Sinai Cancer Institute, Department of Medicine, Department of Biomedical Sciences 8700 Beverly Blvd, Los Angeles, CA, 900048
| | - Svetlana Khoziainova
- Cedars-Sinai Medical Center, Cedars-Sinai Cancer Institute, Department of Medicine, Department of Biomedical Sciences 8700 Beverly Blvd, Los Angeles, CA, 900048
| | - Petr Makhov
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Yin Fei Tan
- Genomics Facility, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | | | - David L. Wiest
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - John Stagg
- Centre Hospitalier de l’Université de Montréal Research Center, Montreal, Quebec, Canada
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, 20892
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, 20892
| | - Kerry S. Campbell
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Amiran K. Dzutsev
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, 20892
| | - Giorgio Trinchieri
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, 20892
| | | | - Sergei I. Grivennikov
- Cedars-Sinai Medical Center, Cedars-Sinai Cancer Institute, Department of Medicine, Department of Biomedical Sciences 8700 Beverly Blvd, Los Angeles, CA, 900048
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Ekaterina K. Koltsova
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
- Cedars-Sinai Medical Center, Cedars-Sinai Cancer Institute, Department of Medicine, Department of Biomedical Sciences 8700 Beverly Blvd, Los Angeles, CA, 900048
| |
Collapse
|
29
|
Lei V, Handfield C, Kwock JT, Kirchner SJ, Lee MJ, Coates M, Wang K, Han Q, Wang Z, Powers JG, Wolfe S, Corcoran DL, Fanelli B, Dadlani M, Ji RR, Zhang JY, MacLeod AS. Skin Injury Activates a Rapid TRPV1-Dependent Antiviral Protein Response. J Invest Dermatol 2022; 142:2249-2259.e9. [PMID: 35007556 PMCID: PMC9259761 DOI: 10.1016/j.jid.2021.11.041] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 02/08/2023]
Abstract
The skin serves as the interface between the body and the environment and plays a fundamental role in innate antimicrobial host immunity. Antiviral proteins (AVPs) are part of the innate host defense system and provide protection against viral pathogens. How breach of the skin barrier influences innate AVP production remains largely unknown. In this study, we characterized the induction and regulation of AVPs after skin injury and identified a key role of TRPV1 in this process. Transcriptional and phenotypic profiling of cutaneous wounds revealed that skin injury induces high levels of AVPs in both mice and humans. Remarkably, pharmacologic and genetic ablation of TRPV1-mediated nociception abrogated the induction of AVPs, including Oas2, Oasl2, and Isg15 after skin injury in mice. Conversely, stimulation of TRPV1 nociceptors was sufficient to induce AVP production involving the CD301b+ cells‒IL-27‒mediated signaling pathway. Using IL-27 receptor‒knockout mice, we show that IL-27 signaling is required in the induction of AVPs after skin injury. Finally, loss of TRPV1 signaling leads to increased viral infectivity of herpes simplex virus. Together, our data indicate that TRPV1 signaling ensures skin antiviral competence on wounding.
Collapse
Affiliation(s)
- Vivian Lei
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Chelsea Handfield
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Jeffery T Kwock
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Stephen J Kirchner
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Min Jin Lee
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Margaret Coates
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Kaiyuan Wang
- Duke Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Qingjian Han
- Duke Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Zilong Wang
- Duke Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Jennifer G Powers
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Dermatology, Carver College of Medicine, University of Iowa Health Care, Iowa, USA
| | - Sarah Wolfe
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA
| | - David L Corcoran
- Duke Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, North Carolina, USA
| | | | | | - Ru-Rong Ji
- Duke Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Jennifer Y Zhang
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA.
| | - Amanda S MacLeod
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA
| |
Collapse
|
30
|
Bommireddy R, Stone S, Bhatnagar N, Kumari P, Munoz LE, Oh J, Kim KH, Berry JTL, Jacobsen KM, Jaafar L, Naing SH, Blackerby AN, der Gaag TV, Wright CN, Lai L, Pack CD, Ramachandiran S, Suthar MS, Kang SM, Kumar M, Reddy SJC, Selvaraj P. Influenza Virus-like Particle-Based Hybrid Vaccine Containing RBD Induces Immunity against Influenza and SARS-CoV-2 Viruses. Vaccines (Basel) 2022; 10:944. [PMID: 35746552 PMCID: PMC9230705 DOI: 10.3390/vaccines10060944] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/28/2022] [Accepted: 06/06/2022] [Indexed: 02/05/2023] Open
Abstract
Several approaches have produced an effective vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since millions of people are exposed to influenza virus and SARS-CoV-2, it is of great interest to develop a two-in-one vaccine that will be able to protect against infection of both viruses. We have developed a hybrid vaccine for SARS-CoV-2 and influenza viruses using influenza virus-like particles (VLP) incorporated by protein transfer with glycosylphosphatidylinositol (GPI)-anchored SARS-CoV-2 RBD fused to GM-CSF as an adjuvant. GPI-RBD-GM-CSF fusion protein was expressed in CHO-S cells, purified and incorporated onto influenza VLPs to develop the hybrid vaccine. Our results show that the hybrid vaccine induced a strong antibody response and protected mice from both influenza virus and mouse-adapted SARS-CoV-2 challenges, with vaccinated mice having significantly lower lung viral titers compared to naive mice. These results suggest that a hybrid vaccine strategy is a promising approach for developing multivalent vaccines to prevent influenza A and SARS-CoV-2 infections.
Collapse
Affiliation(s)
- Ramireddy Bommireddy
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; (R.B.); (L.E.M.); (J.T.L.B.)
| | - Shannon Stone
- Department of Biology, College of Arts and Sciences, Georgia State University, Atlanta, GA 30303, USA; (S.S.); (P.K.); (M.K.)
| | - Noopur Bhatnagar
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA; (N.B.); (J.O.); (K.-H.K.); (S.-M.K.)
| | - Pratima Kumari
- Department of Biology, College of Arts and Sciences, Georgia State University, Atlanta, GA 30303, USA; (S.S.); (P.K.); (M.K.)
| | - Luis E. Munoz
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; (R.B.); (L.E.M.); (J.T.L.B.)
| | - Judy Oh
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA; (N.B.); (J.O.); (K.-H.K.); (S.-M.K.)
| | - Ki-Hye Kim
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA; (N.B.); (J.O.); (K.-H.K.); (S.-M.K.)
| | - Jameson T. L. Berry
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; (R.B.); (L.E.M.); (J.T.L.B.)
| | - Kristen M. Jacobsen
- Metaclipse Therapeutics Corporation, Atlanta, GA 30340, USA; (K.M.J.); (L.J.); (S.-H.N.); (A.N.B.); (T.V.d.G.); (C.N.W.); (C.D.P.); (S.R.); (S.J.C.R.)
| | - Lahcen Jaafar
- Metaclipse Therapeutics Corporation, Atlanta, GA 30340, USA; (K.M.J.); (L.J.); (S.-H.N.); (A.N.B.); (T.V.d.G.); (C.N.W.); (C.D.P.); (S.R.); (S.J.C.R.)
| | - Swe-Htet Naing
- Metaclipse Therapeutics Corporation, Atlanta, GA 30340, USA; (K.M.J.); (L.J.); (S.-H.N.); (A.N.B.); (T.V.d.G.); (C.N.W.); (C.D.P.); (S.R.); (S.J.C.R.)
| | - Allison N. Blackerby
- Metaclipse Therapeutics Corporation, Atlanta, GA 30340, USA; (K.M.J.); (L.J.); (S.-H.N.); (A.N.B.); (T.V.d.G.); (C.N.W.); (C.D.P.); (S.R.); (S.J.C.R.)
| | - Tori Van der Gaag
- Metaclipse Therapeutics Corporation, Atlanta, GA 30340, USA; (K.M.J.); (L.J.); (S.-H.N.); (A.N.B.); (T.V.d.G.); (C.N.W.); (C.D.P.); (S.R.); (S.J.C.R.)
| | - Chloe N. Wright
- Metaclipse Therapeutics Corporation, Atlanta, GA 30340, USA; (K.M.J.); (L.J.); (S.-H.N.); (A.N.B.); (T.V.d.G.); (C.N.W.); (C.D.P.); (S.R.); (S.J.C.R.)
| | - Lilin Lai
- Department of Pediatrics, Emory Vaccine Center, Yerkes Primate Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA; (L.L.); (M.S.S.)
| | - Christopher D. Pack
- Metaclipse Therapeutics Corporation, Atlanta, GA 30340, USA; (K.M.J.); (L.J.); (S.-H.N.); (A.N.B.); (T.V.d.G.); (C.N.W.); (C.D.P.); (S.R.); (S.J.C.R.)
| | - Sampath Ramachandiran
- Metaclipse Therapeutics Corporation, Atlanta, GA 30340, USA; (K.M.J.); (L.J.); (S.-H.N.); (A.N.B.); (T.V.d.G.); (C.N.W.); (C.D.P.); (S.R.); (S.J.C.R.)
| | - Mehul S. Suthar
- Department of Pediatrics, Emory Vaccine Center, Yerkes Primate Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA; (L.L.); (M.S.S.)
| | - Sang-Moo Kang
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA; (N.B.); (J.O.); (K.-H.K.); (S.-M.K.)
| | - Mukesh Kumar
- Department of Biology, College of Arts and Sciences, Georgia State University, Atlanta, GA 30303, USA; (S.S.); (P.K.); (M.K.)
| | - Shaker J. C. Reddy
- Metaclipse Therapeutics Corporation, Atlanta, GA 30340, USA; (K.M.J.); (L.J.); (S.-H.N.); (A.N.B.); (T.V.d.G.); (C.N.W.); (C.D.P.); (S.R.); (S.J.C.R.)
| | - Periasamy Selvaraj
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; (R.B.); (L.E.M.); (J.T.L.B.)
| |
Collapse
|
31
|
Rajavel A, Klees S, Hui Y, Schmitt AO, Gültas M. Deciphering the Molecular Mechanism Underlying African Animal Trypanosomiasis by Means of the 1000 Bull Genomes Project Genomic Dataset. BIOLOGY 2022; 11:biology11050742. [PMID: 35625470 PMCID: PMC9138820 DOI: 10.3390/biology11050742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 05/05/2022] [Accepted: 05/10/2022] [Indexed: 11/16/2022]
Abstract
Simple Summary Climate change is increasing the risk of spreading vector-borne diseases such as African Animal Trypanosomiasis (AAT), which is causing major economic losses, especially in sub-Saharan African countries. Mainly considering this disease, we have investigated transcriptomic and genomic data from two cattle breeds, namely Boran and N‘Dama, where the former is known for its susceptibility and the latter one for its tolerance to the AAT. Despite the rich literature on this disease, there is still a need to investigate underlying genetic mechanisms to decipher the complex interplay of regulatory SNPs (rSNPs), their corresponding gene expression profiles and the downstream effectors associated with the AAT disease. The findings of this study complement our previous results, which mainly involve the upstream events, including transcription factors (TFs) and their co-operations as well as master regulators. Moreover, our investigation of significant rSNPs and effectors found in the liver, spleen and lymph node tissues of both cattle breeds could enhance the understanding of distinct mechanisms leading to either resistance or susceptibility of cattle breeds. Abstract African Animal Trypanosomiasis (AAT) is a neglected tropical disease and spreads by the vector tsetse fly, which carries the infectious Trypanosoma sp. in their saliva. Particularly, this parasitic disease affects the health of livestock, thereby imposing economic constraints on farmers, costing billions of dollars every year, especially in sub-Saharan African countries. Mainly considering the AAT disease as a multistage progression process, we previously performed upstream analysis to identify transcription factors (TFs), their co-operations, over-represented pathways and master regulators. However, downstream analysis, including effectors, corresponding gene expression profiles and their association with the regulatory SNPs (rSNPs), has not yet been established. Therefore, in this study, we aim to investigate the complex interplay of rSNPs, corresponding gene expression and downstream effectors with regard to the AAT disease progression based on two cattle breeds: trypanosusceptible Boran and trypanotolerant N’Dama. Our findings provide mechanistic insights into the effectors involved in the regulation of several signal transduction pathways, thereby differentiating the molecular mechanism with regard to the immune responses of the cattle breeds. The effectors and their associated genes (especially MAPKAPK5, CSK, DOK2, RAC1 and DNMT1) could be promising drug candidates as they orchestrate various downstream regulatory cascades in both cattle breeds.
Collapse
Affiliation(s)
- Abirami Rajavel
- Breeding Informatics Group, Department of Animal Sciences, Georg-August University, Margarethe von Wrangell-Weg 7, 37075 Göttingen, Germany; (S.K.); (Y.H.); (A.O.S.)
- Center for Integrated Breeding Research (CiBreed), Georg-August University, Carl-Sprengel-Weg 1, 37075 Göttingen, Germany
- Correspondence: (A.R.); (M.G.)
| | - Selina Klees
- Breeding Informatics Group, Department of Animal Sciences, Georg-August University, Margarethe von Wrangell-Weg 7, 37075 Göttingen, Germany; (S.K.); (Y.H.); (A.O.S.)
- Center for Integrated Breeding Research (CiBreed), Georg-August University, Carl-Sprengel-Weg 1, 37075 Göttingen, Germany
| | - Yuehan Hui
- Breeding Informatics Group, Department of Animal Sciences, Georg-August University, Margarethe von Wrangell-Weg 7, 37075 Göttingen, Germany; (S.K.); (Y.H.); (A.O.S.)
| | - Armin Otto Schmitt
- Breeding Informatics Group, Department of Animal Sciences, Georg-August University, Margarethe von Wrangell-Weg 7, 37075 Göttingen, Germany; (S.K.); (Y.H.); (A.O.S.)
- Center for Integrated Breeding Research (CiBreed), Georg-August University, Carl-Sprengel-Weg 1, 37075 Göttingen, Germany
| | - Mehmet Gültas
- Center for Integrated Breeding Research (CiBreed), Georg-August University, Carl-Sprengel-Weg 1, 37075 Göttingen, Germany
- Faculty of Agriculture, South Westphalia University of Applied Sciences, Lübecker Ring 2, 59494 Soest, Germany
- Correspondence: (A.R.); (M.G.)
| |
Collapse
|
32
|
Cheng J, Myers TG, Levinger C, Kumar P, Kumar J, Goshu BA, Bosque A, Catalfamo M. IL-27 induces IFN/STAT1-dependent genes and enhances function of TIGIT + HIVGag-specific T cells. iScience 2022; 25:103588. [PMID: 35005538 PMCID: PMC8717455 DOI: 10.1016/j.isci.2021.103588] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 11/03/2021] [Accepted: 12/06/2021] [Indexed: 02/07/2023] Open
Abstract
HIV-specific T cells have diminished effector function and fail to control/eliminate the virus. IL-27, a member of the IL-6/IL-12 cytokine superfamily has been shown to inhibit HIV replication. However, whether or not IL-27 can enhance HIV-specific T cell function is largely unknown. In the present manuscript, we investigated the role of IL-27 signaling in human T cells by evaluating the global transcriptional changes related to the function of HIV-specific T cells. We found that T cells from people living with HIV (PLWH), expressed higher levels of STAT1 leading to enhanced STAT1 activation upon IL-27 stimulation. Observed IL-27 induced transcriptional changes were associated with IFN/STAT1-dependent pathways in CD4 and CD8 T cells. Importantly, IL-27 dependent modulation of T-bet expression promoted IFNγ secretion by TIGIT+HIVGag-specific T cells. This new immunomodulatory effect of IL-27 on HIV-specific T cell function suggests its potential therapeutic use in cure strategies.
Collapse
Affiliation(s)
- Jie Cheng
- Department of Microbiology and Immunology, Georgetown University School of Medicine, 3970 Reservoir Road, N.W, New Research Building, Room EG19A, Washington, DC 20057, USA
| | - Timothy G. Myers
- Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Callie Levinger
- Department of Microbiology, Immunology and Tropical Medicine, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA
| | - Princy Kumar
- Division of Infectious Diseases and Travel Medicine, Georgetown University School of Medicine, Washington, DC 20057, USA
| | - Jai Kumar
- Division of Infectious Diseases and Travel Medicine, Georgetown University School of Medicine, Washington, DC 20057, USA
| | - Bruktawit A. Goshu
- Department of Microbiology and Immunology, Georgetown University School of Medicine, 3970 Reservoir Road, N.W, New Research Building, Room EG19A, Washington, DC 20057, USA
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Alberto Bosque
- Department of Microbiology, Immunology and Tropical Medicine, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA
| | - Marta Catalfamo
- Department of Microbiology and Immunology, Georgetown University School of Medicine, 3970 Reservoir Road, N.W, New Research Building, Room EG19A, Washington, DC 20057, USA
| |
Collapse
|
33
|
Ritter K, Rousseau J, Hölscher C. Interleukin-27 in Tuberculosis: A Sheep in Wolf’s Clothing? Front Immunol 2022; 12:810602. [PMID: 35116036 PMCID: PMC8803639 DOI: 10.3389/fimmu.2021.810602] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 12/22/2021] [Indexed: 12/12/2022] Open
Abstract
In tuberculosis (TB), protective inflammatory immune responses and the pathological sequelae of chronic inflammation significantly depend on a timely balance of cytokine expression. In contrast to other anti-inflammatory cytokines, interleukin (IL)-27 has fundamental effects in experimental Mycobacterium tuberculosis (Mtb) infection: the absence of IL-27-mediated signalling promotes a better control of mycobacterial growth on the one hand side but also leads to a chronic hyperinflammation and immunopathology later during infection. Hence, in the context of novel host-directed therapeutic approaches and vaccination strategies for the management of TB, the timely restricted blockade of IL-27 signalling may represent an advanced treatment option. In contrast, administration of IL-27 itself may allow to treat the immunopathological consequences of chronic TB. In both cases, a better knowledge of the cell type-specific and kinetic effects of IL-27 after Mtb infection is essential. This review summarizes IL-27-mediated mechanisms affecting protection and immunopathology in TB and discusses possible therapeutic applications.
Collapse
Affiliation(s)
- Kristina Ritter
- Infection Immunology, Research Centre Borstel, Borstel, Germany
| | - Jasmin Rousseau
- Infection Immunology, Research Centre Borstel, Borstel, Germany
| | - Christoph Hölscher
- Infection Immunology, Research Centre Borstel, Borstel, Germany
- German Centre for Infection Research (DZIF), Partner Site Hamburg-Borstel-Lübeck-Riems, Borstel, Germany
- *Correspondence: Christoph Hölscher,
| |
Collapse
|
34
|
Rahimi Z, Yaghobi R, Afshari A, Roozbeh J, Mokhtari MJ, Hosseini AM. The effect of BKV reactivation on cytokines behavior in kidney transplanted patients. BMC Nephrol 2022; 23:20. [PMID: 34996392 PMCID: PMC8739991 DOI: 10.1186/s12882-021-02645-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 12/20/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND BK virus associated nephropathy (BKVAN) is one of the common causes of graft loss among kidney transplanted recipients (KTRs). The current treatment for BKV nephropathy is decreasing the immunosuppressive regimen in KTRs. Interleukin-27 (IL-27) is a multifunctional cytokine that might be the front-runner of an important pathway in this regard. Therefore, in current study it is tried to evaluate the changes in the expression level of IL-27 and some related molecules, resulting from BKV reactivation in KTR patients. METHODS EDTA-treated blood samples were collected from all participants. Patients were divided into two groups, 31 kidney transplant recipients with active and 32 inactive BKV infection, after being monitored by Real time PCR (Taq-Man) in plasma. Total of 30 normal individuals were considered as healthy control group. Real time PCR (SYBR Green) technique is used to determine the expression level of studied genes. RESULTS The results of gene expression comparisons showed that the expression level of IL-27, IFN-γ, TNF-α, TNFR2 and IRF7 genes was significantly higher in inactive group in comparison to active group. The expression level of TLR4 was lower in both active and inactive groups in comparison to control group. ROC curve analysis showed that IL-27 and IRF7 are significantly different amongst other studied genes. Finally, the analyses revealed that the expression level of most of the studied genes (except for TNF-α and TLR4) have significant correlation with viral load. CONCLUSIONS Our findings revealed that IL-27, IFN-γ, TNF-α, TNFR2 and IRF7 expression level is higher in inactive group and TLR4 expression level is lower in patients' groups in comparison to control group. Also, ROC curve analysis showed IL-27 and IRF7 can significantly differentiate studied groups (BKV active vs. inactive). Therefore, these results might help elucidating the pattern in charge of BKV reactivation in kidney transplanted patients.
Collapse
Affiliation(s)
- Zahra Rahimi
- Department of Biology, Zarghan branch, Islamic Azad University, Zarghan, Iran
| | - Ramin Yaghobi
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Afsoon Afshari
- Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Jamshid Roozbeh
- Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Ali Malek Hosseini
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| |
Collapse
|
35
|
Warunek J, Jin RM, Blair SJ, Garis M, Marzullo B, Wohlfert EA. Tbet Expression by Regulatory T Cells Is Needed to Protect against Th1-Mediated Immunopathology during Toxoplasma Infection in Mice. Immunohorizons 2021; 5:931-943. [PMID: 34893511 DOI: 10.4049/immunohorizons.2100080] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 11/14/2021] [Indexed: 11/19/2022] Open
Abstract
Toxoplasma gondii infection has proven to be an ideal model to understand the delicate balance between protective immunity and immune-mediated pathology during infection. Lethal infection causes a collapse of T regulatory cells (Tregs) mediated by the loss of IL-2 and conversion of Tregs to IFN-γ-producing cells. Importantly, these Tregs highly express the Th1 transcription factor Tbet. To determine the role of Tbet in Tregs, we infected Tbx21f/f -Foxp3YFPCre and control Foxp3YFPCre mice with the type II strain of T. gondii, ME49. The majority of Tbx21f/f -Foxp3YFPCre mice succumbed to a nonlethal dose. Notably, parasite burden was reduced in Tbx21f/f -Foxp3YFPCre compared with Foxp3YFPCre control mice. We found that Tbx21f/f -Foxp3YFPCre mice have significantly higher serum levels of proinflammatory cytokines IFN-γ and TNF-α, suggestive of a heightened immune response. To test if CD4+ T cells were driving immunopathology, we treated Tbx21f/f -Foxp3YFPCre mice with anti-CD4-depleting Abs and partially rescued these mice. Broad-spectrum antibiotic treatment also improved survival, demonstrating a role for commensal flora in immunopathology in Tbx21f/f -Foxp3YFPCre mice. RNA sequencing analysis reinforced that Tbet regulates several key cellular pathways, including leukocyte activation, regulation of lymphocyte activation, and cell cycle progression, that help to maintain fitness in Tregs during Th1 responses. Taken together, our data show an important role for Tbet in Tregs in preventing lethal immunopathology during T. gondii infection, further highlighting the protective role of Treg plasticity in controlling immune responses to infection and the microbiota.
Collapse
Affiliation(s)
- Jordan Warunek
- Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Amherst, NY; and
| | - Richard M Jin
- Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Amherst, NY; and
| | - Sarah J Blair
- Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Amherst, NY; and
| | - Matthew Garis
- Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Amherst, NY; and
| | - Brandon Marzullo
- Genomics and Bioinformatics Core, State University of New York at Buffalo, Amherst, NY
| | - Elizabeth A Wohlfert
- Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Amherst, NY; and
| |
Collapse
|
36
|
Huang D, Ran Y, Liu Z, He J, Yin N, Qi H. IL-27 Mediates Pro-Inflammatory Effects via the ERK Signaling Pathway During Preterm Labor. Front Immunol 2021; 12:709229. [PMID: 34691022 PMCID: PMC8531808 DOI: 10.3389/fimmu.2021.709229] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 09/21/2021] [Indexed: 11/13/2022] Open
Abstract
Preterm labor (PTL) is a multifactorial syndrome that results in birth prior to 37 weeks of gestation. However, the specific molecular mechanisms underlying this condition have yet to be elucidated. Previous research demonstrated that the abnormal expression of IL-27, and its receptors, played a role in the pathophysiology of preterm labor. In the present study, we established a Lipopolysaccharide (LPS)-stimulated, infection-induced, preterm mouse model based on wild-type C57BL/6 mice and WSX-1-/-C57BL/6 mice. WSX-1 knockdown led to a significant delay in birth by 11.32 ± 2.157h. In addition, compared with wild-type C57B/6 mice, the expression levels of IFN-γ, IL-1β, IL-6, TNF-α, and CXCL10, in the fetal membrane and myometrium of WSX-1-/-mice were significantly lower, particularly in the myometrium. We also confirmed similar pro-inflammatory effects arising from IL-27 in human amniotic cell line (WISH) and human myometrial smooth muscle cell line (HMSMC). Once stimulated by LPS, the pro-inflammatory action exhibited a synergistic effect and appeared to be time-dependent. Finally, we demonstrated that LY3214996, an inhibitor of the ERK pathway, significantly inhibited the pro-inflammatory effect mediated by IL-27. Overall, our data confirmed that the inflammatory effect mediated by the IL-27/IFN-r/ERK axis is involved in preterm labor. Our findings, therefore, provide an enhancement in our etiological understanding of the mechanisms underlying PTL.
Collapse
Affiliation(s)
- Dongni Huang
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China.,Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Yuxin Ran
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China.,Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Zheng Liu
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China.,Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Jie He
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China.,Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Nanlin Yin
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China.,Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.,Center for Reproductive Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hongbo Qi
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China.,Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.,Center for Reproductive Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
37
|
Takahashi H, Nomura H, Iriki H, Kubo A, Isami K, Mikami Y, Mukai M, Sasaki T, Yamagami J, Kudoh J, Ito H, Kamata A, Kurebayashi Y, Yoshida H, Yoshimura A, Sun HW, Suematsu M, O’Shea JJ, Kanno Y, Amagai M. Cholesterol 25-hydroxylase is a metabolic switch to constrain T cell-mediated inflammation in the skin. Sci Immunol 2021; 6:eabb6444. [PMID: 34623903 PMCID: PMC9780739 DOI: 10.1126/sciimmunol.abb6444] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Interleukin-27 (IL-27) is an immunoregulatory cytokine whose essential function is to limit immune responses. We found that the gene encoding cholesterol 25-hydroxylase (Ch25h) was induced in CD4+ T cells by IL-27, enhanced by transforming growth factor–β (TGF-β), and antagonized by T-bet. Ch25h catalyzes cholesterol to generate 25-hydroxycholesterol (25OHC), which was subsequently released to the cellular milieu, functioning as a modulator of T cell response. Extracellular 25OHC suppressed cholesterol biosynthesis in T cells, inhibited cell growth, and induced nutrient deprivation cell death without releasing high-mobility group box 1 (HMGB1). This growth inhibitory effect was specific to actively proliferating cells with high cholesterol demand and was reversed when extracellular cholesterol was replenished. Ch25h-expressing CD4+ T cells that received IL-27 and TGF-β signals became refractory to 25OHC-mediated growth inhibition in vitro. Nonetheless, IL-27–treated T cells negatively affected viability of bystander cells in a paracrine manner, but only if the bystander cells were in the early phases of activation. In mouse models of skin inflammation due to autoreactive T cells or chemically induced hypersensitivity, genetic deletion of Ch25h or Il27ra led to worse outcomes. Thus, Ch25h is an immunoregulatory metabolic switch induced by IL-27 and dampens excess bystander T effector expansion in tissues through its metabolite derivative, 25OHC. This study reveals regulation of cholesterol metabolism as a modality for controlling tissue inflammation and thus represents a mechanism underlying T cell immunoregulatory functions.
Collapse
Affiliation(s)
- Hayato Takahashi
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Hisashi Nomura
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Hisato Iriki
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Akiko Kubo
- Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Koichi Isami
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yohei Mikami
- Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda MD 20892, USA
- Present address: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Miho Mukai
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Takashi Sasaki
- Center for Supercentenarian Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Jun Yamagami
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Jun Kudoh
- Laboratory of Gene Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Hiromi Ito
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Aki Kamata
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yutaka Kurebayashi
- Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Hiroki Yoshida
- Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Akihiko Yoshimura
- Department of Immunology and Microbiology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Hong-Wei Sun
- Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda MD 20892, USA
| | - Makoto Suematsu
- Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Jonh J. O’Shea
- Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda MD 20892, USA
| | - Yuka Kanno
- Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda MD 20892, USA
| | - Masayuki Amagai
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
- Laboratory for Skin Homeostasis, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan
| |
Collapse
|
38
|
Chen YH, Spencer S, Laurence A, Thaventhiran JE, Uhlig HH. Inborn errors of IL-6 family cytokine responses. Curr Opin Immunol 2021; 72:135-145. [PMID: 34044328 PMCID: PMC8591178 DOI: 10.1016/j.coi.2021.04.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 04/15/2021] [Accepted: 04/19/2021] [Indexed: 01/25/2023]
Abstract
The IL-6 family of cytokines mediates functions in host protective immunity, development of multiple organs, tissue regeneration and metabolism. Inborn errors in cytokines or cytokine receptor units highlight specific roles for IL-6, IL-11, LIF, OSM, and CLC signaling whereas incomplete loss-of-function variants in the common receptor chain GP130 encoded by IL6ST or the transcription factor STAT3, as well as genes that affect either GP130 glycosylation (PGM3) or STAT3 transcriptional control (ZNF341) lead to complex phenotypes including features of hyper-IgE syndrome. Gain-of-function variants in the GP130-STAT3 signaling pathway cause immune dysregulation disorders. Insights into IL-6 family cytokine signaling inform on therapeutic application in immune-mediated disorders and potential side effects such as infection susceptibility.
Collapse
Affiliation(s)
- Yin-Huai Chen
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Sarah Spencer
- MRC Toxicology Unit, Gleeson Building, Tennis Court Road, Cambridge, UK
| | - Arian Laurence
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK; Department of Haematology, University College Hospital, UCLH Hospitals NHS Trust, UK
| | | | - Holm H Uhlig
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK; Biomedical Research Center, University of Oxford, Oxford, UK; Department of Pediatrics, University of Oxford, Oxford, UK.
| |
Collapse
|
39
|
The dual role of IL-27 in CD4+T cells. Mol Immunol 2021; 138:172-180. [PMID: 34438225 DOI: 10.1016/j.molimm.2021.08.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 07/02/2021] [Accepted: 08/01/2021] [Indexed: 12/19/2022]
Abstract
Interleukin-27 (IL-27), a member of the IL-6/IL-12 family, has diverse regulatory functions in various immune responses, and is recognised as a potent agonist and antagonist of CD4+T cells in different contexts. However, this dual role and underlying mechanisms have not been completely defined. In the present review, we summarise the dual role of IL-27 in CD4+T cells. In particular, we aimed to decipher its mechanism to better understand the context-dependent function of IL-27 in CD4+T cells. Furthermore, we propose a possible mechanism for the dual role of IL-27. This may be helpful for the development of appropriate IL-27 treatments in various clinical settings.
Collapse
|
40
|
Khalil M, Wang D, Hashemi E, Terhune SS, Malarkannan S. Implications of a 'Third Signal' in NK Cells. Cells 2021; 10:cells10081955. [PMID: 34440725 PMCID: PMC8393955 DOI: 10.3390/cells10081955] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/17/2022] Open
Abstract
Innate and adaptive immune systems are evolutionarily divergent. Primary signaling in T and B cells depends on somatically rearranged clonotypic receptors. In contrast, NK cells use germline-encoded non-clonotypic receptors such as NCRs, NKG2D, and Ly49H. Proliferation and effector functions of T and B cells are dictated by unique peptide epitopes presented on MHC or soluble humoral antigens. However, in NK cells, the primary signals are mediated by self or viral proteins. Secondary signaling mediated by various cytokines is involved in metabolic reprogramming, proliferation, terminal maturation, or memory formation in both innate and adaptive lymphocytes. The family of common gamma (γc) cytokine receptors, including IL-2Rα/β/γ, IL-7Rα/γ, IL-15Rα/β/γ, and IL-21Rα/γ are the prime examples of these secondary signals. A distinct set of cytokine receptors mediate a ‘third’ set of signaling. These include IL-12Rβ1/β2, IL-18Rα/β, IL-23R, IL-27R (WSX-1/gp130), IL-35R (IL-12Rβ2/gp130), and IL-39R (IL-23Rα/gp130) that can prime, activate, and mediate effector functions in lymphocytes. The existence of the ‘third’ signal is known in both innate and adaptive lymphocytes. However, the necessity, context, and functional relevance of this ‘third signal’ in NK cells are elusive. Here, we define the current paradigm of the ‘third’ signal in NK cells and enumerate its clinical implications.
Collapse
Affiliation(s)
- Mohamed Khalil
- Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI 53226, USA; (M.K.); (D.W.); (E.H.)
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Dandan Wang
- Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI 53226, USA; (M.K.); (D.W.); (E.H.)
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Elaheh Hashemi
- Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI 53226, USA; (M.K.); (D.W.); (E.H.)
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Scott S. Terhune
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Correspondence: (S.S.T.); (S.M.)
| | - Subramaniam Malarkannan
- Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI 53226, USA; (M.K.); (D.W.); (E.H.)
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Correspondence: (S.S.T.); (S.M.)
| |
Collapse
|
41
|
Hill DG, Ward A, Nicholson LB, Jones GW. Emerging roles for IL-6 family cytokines as positive and negative regulators of ectopic lymphoid structures. Cytokine 2021; 146:155650. [PMID: 34343865 DOI: 10.1016/j.cyto.2021.155650] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 07/06/2021] [Accepted: 07/09/2021] [Indexed: 02/07/2023]
Abstract
IL-6 family cytokines display broad effects in haematopoietic and non-haematopoietic cells that regulate immune homeostasis, host defence, haematopoiesis, development, reproduction and wound healing. Dysregulation of these activities places this cytokine family as important mediators of autoimmunity, chronic inflammation and cancer. In this regard, ectopic lymphoid structures (ELS) are a pathological hallmark of many tissues affected by chronic disease. These inducible lymphoid aggregates form compartmentalised T cell and B cell zones, germinal centres, follicular dendritic cell networks and high endothelial venules, which are defining qualities of peripheral lymphoid organs. Accordingly, ELS can support local antigen-specific responses to self-antigens, alloantigens, pathogens and tumours. ELS often correlate with severe disease progression in autoimmune conditions, while tumour-associated ELS are associated with enhanced anti-tumour immunity and a favourable prognosis in cancer. Here, we discuss emerging roles for IL-6 family cytokines as regulators of ELS development, maintenance and activity and consider how modulation of these activities has the potential to aid the successful treatment of autoimmune conditions and cancers where ELS feature.
Collapse
Affiliation(s)
- David G Hill
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
| | - Amy Ward
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
| | - Lindsay B Nicholson
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
| | - Gareth W Jones
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
| |
Collapse
|
42
|
Wu S, Ma R, Zhong Y, Chen Z, Zhou H, Zhou M, Chong W, Chen J. Deficiency of IL-27 Signaling Exacerbates Experimental Autoimmune Uveitis with Elevated Uveitogenic Th1 and Th17 Responses. Int J Mol Sci 2021; 22:ijms22147517. [PMID: 34299138 PMCID: PMC8305313 DOI: 10.3390/ijms22147517] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/24/2021] [Accepted: 07/11/2021] [Indexed: 01/31/2023] Open
Abstract
Human uveitis is an autoimmune disease of the central nervous system that is characterized by ocular inflammation with the involvement of uveitogenic Th1 and Th17 responses. In experimental autoimmune uveitis (EAU), the animal model for human uveitis, both responses are proven to be critical in disease development. Therefore, targeting both Th1 and Th17 cells has therapeutic implication for disease resolution. IL-27 is a multifunctional cytokine that can either promote or inhibit T cell responses and is implicated in both autoimmune and infectious diseases. The aim of this study is to characterize the role of IL-27/IL-27R signaling in regulating uveitogenic Th1/Th17 responses in EAU. By immunizing IL-27Rα-/- mice and their wild-type (WT) littermates for EAU, we demonstrated that IL-27 signaling deficiency exacerbated EAU with severe ocular inflammation and impairment of visual function. Furthermore, there was a significant increase in the eye-infiltrating Th1 and Th17 cells in IL-27Rα-/- EAU mice compared to WT. Their retinal antigen-specific Th1 and Th17 responses were also significantly increased, as represented by the elevation of their signature cytokines, IFN-γ and IL-17A, respectively. We also observed the upregulation of another pathogenic cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), from effector T cells in IL-27Rα-/- EAU mice. Mechanistic studies confirmed that IL-27 inhibited GM-CSF production from Th17 cells. In addition, the induction of IL-10 producing type 1 regulatory T (Tr1) cells was impaired in IL-27Rα-/- EAU mice. These results identified that IL-27 signaling plays a suppressive role in EAU by regulating multiple CD4+ cell subsets, including the effector Th1 and Th17 cells and the regulatory Tr1 cells. Our findings provide new insights for therapeutic potential in controlling uveitis by enhancing IL-27 signaling.
Collapse
|
43
|
Chehuen Bicalho V, da Fontoura Galvão G, Lima Fontes-Dantas F, Paulo da Costa Gonçalves J, Dutra de Araujo A, Carolina França L, Emílio Corrêa Leite P, Campolina Vidal D, Castro Filho R, Vieira Alves-Leon S, Marcondes de Souza J. Asymptomatic cerebral cavernous angiomas associated with plasma marker signature. J Clin Neurosci 2021; 89:258-263. [PMID: 34119277 DOI: 10.1016/j.jocn.2021.04.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 04/18/2021] [Accepted: 04/19/2021] [Indexed: 11/30/2022]
Affiliation(s)
- Vítor Chehuen Bicalho
- Federal University of the State of Rio de Janeiro, Translational Neuroscience Laboratory, Post-Graduation Program in Neurology, Rio de Janeiro RJ, Brazil
| | - Gustavo da Fontoura Galvão
- Federal University of the State of Rio de Janeiro, Translational Neuroscience Laboratory, Post-Graduation Program in Neurology, Rio de Janeiro RJ, Brazil; Federal University of Rio de Janeiro, University Hospital Clementino Fraga Filho, Department of de Neurosurgery, Rio de Janeiro RJ, Brazil.
| | - Fabrícia Lima Fontes-Dantas
- Federal University of the State of Rio de Janeiro, Translational Neuroscience Laboratory, Post-Graduation Program in Neurology, Rio de Janeiro RJ, Brazil
| | - João Paulo da Costa Gonçalves
- Federal University of the State of Rio de Janeiro, Translational Neuroscience Laboratory, Post-Graduation Program in Neurology, Rio de Janeiro RJ, Brazil
| | - Amanda Dutra de Araujo
- Federal University of the State of Rio de Janeiro, Translational Neuroscience Laboratory, Post-Graduation Program in Neurology, Rio de Janeiro RJ, Brazil
| | - Laise Carolina França
- Federal University of the State of Rio de Janeiro, Translational Neuroscience Laboratory, Post-Graduation Program in Neurology, Rio de Janeiro RJ, Brazil; Fluminense Federal University, Post-Graduation Program in Neurology and Neuroscience, Rio de Janeiro RJ, Brazil
| | - Paulo Emílio Corrêa Leite
- Laboratory of Bioengineering and in Vitro Toxicology, Applied to Life Sciences - Dimav, National Institute of Metrology Quality and Technology
| | - Diego Campolina Vidal
- Federal University of Rio de Janeiro, University Hospital Clementino Fraga Filho, Department of de Neurosurgery, Rio de Janeiro RJ, Brazil
| | - Ricardo Castro Filho
- Federal University of Rio de Janeiro, University Hospital Clementino Fraga Filho, Department of de Neurosurgery, Rio de Janeiro RJ, Brazil
| | - Soniza Vieira Alves-Leon
- Federal University of the State of Rio de Janeiro, Translational Neuroscience Laboratory, Post-Graduation Program in Neurology, Rio de Janeiro RJ, Brazil; Federal University of Rio de Janeiro, University Hospital Clementino Fraga Filho, Department of de Neurosurgery, Rio de Janeiro RJ, Brazil
| | - Jorge Marcondes de Souza
- Federal University of Rio de Janeiro, University Hospital Clementino Fraga Filho, Department of de Neurosurgery, Rio de Janeiro RJ, Brazil
| |
Collapse
|
44
|
Min B, Kim D, Feige MJ. IL-30 † (IL-27A): a familiar stranger in immunity, inflammation, and cancer. Exp Mol Med 2021; 53:823-834. [PMID: 34045653 PMCID: PMC8178335 DOI: 10.1038/s12276-021-00630-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 03/12/2021] [Accepted: 03/29/2021] [Indexed: 12/16/2022] Open
Abstract
Over the years, interleukin (IL)-27 has received much attention because of its highly divergent, sometimes even opposing, functions in immunity. IL-30, the p28 subunit that forms IL-27 together with Ebi3 and is also known as IL-27p28 or IL-27A, has been considered a surrogate to represent IL-27. However, it was later discovered that IL-30 can form complexes with other protein subunits, potentially leading to overlapping or discrete functions. Furthermore, there is emerging evidence that IL-30 itself may perform immunomodulatory functions independent of Ebi3 or other binding partners and that IL-30 production is strongly associated with certain cancers in humans. In this review, we will discuss the biology of IL-30 and other IL-30-associated cytokines and their functions in inflammation and cancer. Studying the ways that interleukin IL-30 regulates immune responses may provide novel insights into tumor development and inflammatory conditions. Interleukins are a diverse family of proteins involved in intercellular communications and immunity, where they can exert divergent and even opposing functions. Booki Min at Northwestern University in Chicago, USA, and co-workers reviewed the current understanding of IL-30 and its links to inflammation and cancer. IL-30 forms the IL-27 complex with the Ebi3 protein and was thought to be a surrogate for IL-27 in terms of activity. However, recent insights suggest that IL-30 may perform discrete immune modulation functions. Elevated IL-30 secretion is linked to prostate and breast cancer development. Extensive research is needed into the formation of IL-30, its associated protein interactions, and the development of a suitable animal model.
Collapse
Affiliation(s)
- Booki Min
- Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. .,Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
| | - Dongkyun Kim
- Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Matthias J Feige
- Department of Chemistry and Institute for Advanced Study, Technical University of Munich, 85748, Garching, Germany
| |
Collapse
|
45
|
Zha X, Yang S, Niu W, Tan L, Xu Y, Zeng J, Tang Y, Sun L, Pang G, Qiao S, Zhang H, Liu T, Zhao H, Zheng N, Zhang Y, Bai H. IL-27/IL-27R Mediates Protective Immunity against Chlamydial Infection by Suppressing Excessive Th17 Responses and Reducing Neutrophil Inflammation. THE JOURNAL OF IMMUNOLOGY 2021; 206:2160-2169. [PMID: 33863788 DOI: 10.4049/jimmunol.2000957] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 02/22/2021] [Indexed: 01/30/2023]
Abstract
IL-27, a heterodimeric cytokine of the IL-12 family, has diverse influences on the development of multiple inflammatory diseases. In this study, we identified the protective role of IL-27/IL-27R in host defense against Chlamydia muridarum respiratory infection and further investigated the immunological mechanism. Our results showed that IL-27 was involved in C. muridarum infection and that IL-27R knockout mice (WSX-1-/- mice) suffered more severe disease, with greater body weight loss, higher chlamydial loads, and more severe inflammatory reactions in the lungs than C57BL/6 wild-type mice. There were excessive IL-17-producing CD4+ T cells and many more neutrophils, neutrophil-related proteins, cytokines, and chemokines in the lungs of WSX-1-/- mice than in wild-type mice following C. muridarum infection. In addition, IL-17/IL-17A-blocking Ab treatment improved disease after C. muridarum infection in WSX-1-/- mice. Overall, we conclude that IL-27/IL-27R mediates protective immunity during chlamydial respiratory infection in mice by suppressing excessive Th17 responses and reducing neutrophil inflammation.
Collapse
Affiliation(s)
- Xiaoyu Zha
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, Tianjin, People's Republic of China
| | - Shuaini Yang
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, Tianjin, People's Republic of China
| | - Wenhao Niu
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, Tianjin, People's Republic of China
| | - Lu Tan
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, Tianjin, People's Republic of China
| | - Yueyue Xu
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, Tianjin, People's Republic of China
| | - Jiajia Zeng
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, Tianjin, People's Republic of China
| | - Yingying Tang
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, Tianjin, People's Republic of China
| | - Lida Sun
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, Tianjin, People's Republic of China
| | - Gaoju Pang
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, Tianjin, People's Republic of China
| | - Sai Qiao
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, Tianjin, People's Republic of China
| | - Hong Zhang
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, Tianjin, People's Republic of China
| | - Tengli Liu
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, Tianjin, People's Republic of China
| | - Huili Zhao
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, Tianjin, People's Republic of China
| | - Ningbo Zheng
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, Tianjin, People's Republic of China
| | - Yongci Zhang
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, Tianjin, People's Republic of China
| | - Hong Bai
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, Tianjin, People's Republic of China
| |
Collapse
|
46
|
Rindler K, Krausgruber T, Thaler FM, Alkon N, Bangert C, Kurz H, Fortelny N, Rojahn TB, Jonak C, Griss J, Bock C, Brunner PM. Spontaneously Resolved Atopic Dermatitis Shows Melanocyte and Immune Cell Activation Distinct From Healthy Control Skin. Front Immunol 2021; 12:630892. [PMID: 33717163 PMCID: PMC7943477 DOI: 10.3389/fimmu.2021.630892] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 02/01/2021] [Indexed: 01/11/2023] Open
Abstract
Atopic dermatitis (AD) typically starts in infancy or early childhood, showing spontaneous remission in a subset of patients, while others develop lifelong disease. Despite an increased understanding of AD, factors guiding its natural course are only insufficiently elucidated. We thus performed suction blistering in skin of adult patients with stable, spontaneous remission from previous moderate-to-severe AD during childhood. Samples were compared to healthy controls without personal or familial history of atopy, and to chronic, active AD lesions. Skin cells and tissue fluid obtained were used for single-cell RNA sequencing and proteomic multiplex assays, respectively. We found overall cell composition and proteomic profiles of spontaneously healed AD to be comparable to healthy control skin, without upregulation of typical AD activity markers (e.g., IL13, S100As, and KRT16). Among all cell types in spontaneously healed AD, melanocytes harbored the largest numbers of differentially expressed genes in comparison to healthy controls, with upregulation of potentially anti-inflammatory markers such as PLA2G7. Conventional T-cells also showed increases in regulatory markers, and a general skewing toward a more Th1-like phenotype. By contrast, gene expression of regulatory T-cells and keratinocytes was essentially indistinguishable from healthy skin. Melanocytes and conventional T-cells might thus contribute a specific regulatory milieu in spontaneously healed AD skin.
Collapse
Affiliation(s)
- Katharina Rindler
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Thomas Krausgruber
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Felix M. Thaler
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Natalia Alkon
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Christine Bangert
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Harald Kurz
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Nikolaus Fortelny
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Thomas B. Rojahn
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Constanze Jonak
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Johannes Griss
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Christoph Bock
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Center for Medical Statistics, Informatics, and Intelligent Systems, Institute of Artificial Intelligence and Decision Support, Medical University of Vienna, Vienna, Austria
| | - Patrick M. Brunner
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
47
|
Abstract
Tumor necrosis factor (TNF)/inducible nitric oxide synthase (iNOS)-producing dendritic cells (Tip-DCs) have profound impacts on host immune responses during infections. The mechanisms regulating Tip-DC development remain largely unknown. Here, using a mouse model of infection with African trypanosomes, we show that a deficiency in interleukin-27 receptor (IL-27R) signaling results in escalated intrahepatic accumulation of Ly6C-positive (Ly6C+) monocytes and their differentiation into Tip-DCs. Blocking Tip-DC development significantly ameliorates liver injury and increases the survival of infected IL-27R−/− mice. Mechanistically, Ly6C+ monocyte differentiation into pathogenic Tip-DCs in infected IL-27R−/− mice is driven by a CD4+ T cell-interferon gamma (IFN-γ) axis via cell-intrinsic IFN-γ signaling. In parallel, hyperactive IFN-γ signaling induces cell death of Ly6C-negative (Ly6C−) monocytes in a cell-intrinsic manner, which in turn aggravates the development of pathogenic Tip-DCs due to the loss of the negative regulation of Ly6C− monocytes on Ly6C+ monocyte differentiation into Tip-DCs. Thus, IL-27 inhibits the dual-track exacerbation of Tip-DC development induced by a CD4+ T cell–IFN-γ axis. We conclude that IL-27 negatively regulates Tip-DC development by preventing the cell-intrinsic effects of IFN-γ and that the regulation involves CD4+ T cells and Ly6C− monocytes. Targeting IL-27 signaling may manipulate Tip-DC development for therapeutic intervention.
Collapse
|
48
|
Morrow KN, Liang Z, Xue M, Chihade DB, Sun Y, Chen CW, Coopersmith CM, Ford ML. The IL-27 receptor regulates TIGIT on memory CD4 + T cells during sepsis. iScience 2021; 24:102093. [PMID: 33615199 PMCID: PMC7881227 DOI: 10.1016/j.isci.2021.102093] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 08/19/2020] [Accepted: 01/18/2021] [Indexed: 12/19/2022] Open
Abstract
Sepsis is a leading cause of morbidity and mortality associated with significant impairment in memory T cells. These changes include the upregulation of co-inhibitory markers, a decrease in functionality, and an increase in apoptosis. Due to recent studies describing IL-27 regulation of TIGIT and PD-1, we assessed whether IL-27 impacts these co-inhibitory molecules in sepsis. Based on these data, we hypothesized that IL-27 was responsible for T cell dysfunction during sepsis. Using the cecal ligation and puncture (CLP) sepsis model, we found that IL-27Rα was associated with the upregulation of TIGIT on memory CD4+ T cells following CLP. However, IL-27 was not associated with sepsis mortality.
Numbers of IL-27Rα+ memory T cells are decreased following cecal ligation and puncture TIGIT is expressed on more IL-27Rα+ versus IL-27Rα− memory CD4+ T cells during sepsis Il27ra−/− and WT T cells exhibit similar effector function and apoptosis during sepsis IL-27 signaling does not impact sepsis mortality
Collapse
Affiliation(s)
- Kristen N Morrow
- Immunology and Molecular Pathogenesis Program, Laney Graduate School, Emory University, Atlanta, GA 30324, USA.,Department of Surgery, Emory University School of Medicine, Atlanta, GA 30324, USA
| | - Zhe Liang
- Department of Surgery, Emory University School of Medicine, Atlanta, GA 30324, USA
| | - Ming Xue
- Department of Surgery, Emory University School of Medicine, Atlanta, GA 30324, USA.,Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Deena B Chihade
- Department of Surgery, Emory University School of Medicine, Atlanta, GA 30324, USA
| | - Yini Sun
- Department of Surgery, Emory University School of Medicine, Atlanta, GA 30324, USA.,Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang 110000, China
| | - Ching-Wen Chen
- Immunology and Molecular Pathogenesis Program, Laney Graduate School, Emory University, Atlanta, GA 30324, USA.,Department of Surgery, Emory University School of Medicine, Atlanta, GA 30324, USA
| | - Craig M Coopersmith
- Department of Surgery, Emory University School of Medicine, Atlanta, GA 30324, USA.,Emory Critical Care Center, Emory University School of Medicine, Atlanta, GA 30324, USA
| | - Mandy L Ford
- Department of Surgery, Emory University School of Medicine, Atlanta, GA 30324, USA.,Emory Transplant Center, Emory University School of Medicine, Atlanta, GA 30324, USA
| |
Collapse
|
49
|
Ritter K, Rousseau J, Hölscher C. The Role of gp130 Cytokines in Tuberculosis. Cells 2020; 9:E2695. [PMID: 33334075 PMCID: PMC7765486 DOI: 10.3390/cells9122695] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 12/01/2020] [Accepted: 12/10/2020] [Indexed: 12/13/2022] Open
Abstract
Protective immune responses to Mycobacterium tuberculosis (Mtb) infection substantially depend on a delicate balance within cytokine networks. Thus, immunosuppressive therapy by cytokine blockers, as successfully used in the management of various chronic inflammatory diseases, is often connected with an increased risk for tuberculosis (TB) reactivation. Hence, identification of alternative therapeutics which allow the treatment of inflammatory diseases without compromising anti-mycobacterial immunity remains an important issue. On the other hand, in the context of novel therapeutic approaches for the management of TB, host-directed adjunct therapies, which combine administration of antibiotics with immunomodulatory drugs, play an increasingly important role, particularly to reduce the duration of treatment. In both respects, cytokines/cytokine receptors related to the common receptor subunit gp130 may serve as promising target candidates. Within the gp130 cytokine family, interleukin (IL)-6, IL-11 and IL-27 are most explored in the context of TB. This review summarizes the differential roles of these cytokines in protection and immunopathology during Mtb infection and discusses potential therapeutic implementations with respect to the aforementioned approaches.
Collapse
Affiliation(s)
- Kristina Ritter
- Infection Immunology, Research Centre Borstel, D-23845 Borstel, Germany; (K.R.); (J.R.)
| | - Jasmin Rousseau
- Infection Immunology, Research Centre Borstel, D-23845 Borstel, Germany; (K.R.); (J.R.)
| | - Christoph Hölscher
- Infection Immunology, Research Centre Borstel, D-23845 Borstel, Germany; (K.R.); (J.R.)
- German Centre for Infection Research (DZIF), Partner Site Hamburg-Borstel-Lübeck-Riems, D-23845 Borstel, Germany
| |
Collapse
|
50
|
Pereira ABM, de Oliveira JR, Teixeira MM, da Silva PR, Rodrigues Junior V, Rogerio ADP. IL-27 regulates IL-4-induced chemokine production in human bronchial epithelial cells. Immunobiology 2020; 226:152029. [PMID: 33278712 DOI: 10.1016/j.imbio.2020.152029] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 10/29/2020] [Accepted: 11/12/2020] [Indexed: 11/25/2022]
Abstract
IL-4 coordinates the Th2-type immune response in inflammatory diseases such as asthma. IL-27 can inhibit the development of both Th2 and Th1 cells. However, IL-27 can also drive naïve T cells to differentiate toward the Th1 phenotype. In this study, we investigated the effects of IL-27 on the activation of IL-4-induced human bronchial epithelial cells (BEAS-2B). Compared to controls, both IL-4 and IL-27 (25-100 ng/mL) increased the concentrations of CCL2 and IL-8 in a dose-dependent manner. However, compared to cells stimulated individually with IL-4 or IL-27, treatment with a combination of both cytokines reduced CCL2 and IL-8 concentrations in a dose- and time-dependent manner. IL-4 increased the activation of p38 MAPK, ERK1/2, STAT6 and NF-κB, while IL-27 increased the activation of p38 MAPK and ERK1/2 but not STAT6 and NF-κB. Compared to IL-4-stimulated cells, cells treated with both IL-27 and IL-4 displayed decreased activation of STAT6 and NF-κB but not ERK1/2 and p38 MAPK. Taken together, these results suggest that IL-27 plays a pro-inflammatory role when administered alone but downregulates bronchial epithelial cell activation when combined with IL-4. Therefore, IL-27 may be an interesting target for the treatment of Th2 inflammatory diseases.
Collapse
Affiliation(s)
- Aline Beatriz Mahler Pereira
- Institute of Health Sciences, Department of Clinical Medicine, Laboratory of Experimental Immunopharmacology, Federal University of Triangulo Mineiro, Uberaba, MG 38025-350, Brazil
| | - Jhony Robison de Oliveira
- Institute of Health Sciences, Department of Clinical Medicine, Laboratory of Experimental Immunopharmacology, Federal University of Triangulo Mineiro, Uberaba, MG 38025-350, Brazil
| | - Maxelle Martins Teixeira
- Institute of Health Sciences, Department of Clinical Medicine, Laboratory of Experimental Immunopharmacology, Federal University of Triangulo Mineiro, Uberaba, MG 38025-350, Brazil
| | - Paulo Roberto da Silva
- Institute of Health Sciences, Department of Clinical Medicine, Laboratory of Experimental Immunopharmacology, Federal University of Triangulo Mineiro, Uberaba, MG 38025-350, Brazil
| | - Virmondes Rodrigues Junior
- Institute of Health Sciences, Department of Clinical Medicine, Laboratory of Experimental Immunopharmacology, Federal University of Triangulo Mineiro, Uberaba, MG 38025-350, Brazil
| | - Alexandre de Paula Rogerio
- Institute of Health Sciences, Department of Clinical Medicine, Laboratory of Experimental Immunopharmacology, Federal University of Triangulo Mineiro, Uberaba, MG 38025-350, Brazil.
| |
Collapse
|