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Hao Y, Wang W, Zhang L, Li W. Pyroptosis in asthma: inflammatory phenotypes, immune and non-immune cells, and novel treatment approaches. Front Pharmacol 2024; 15:1452845. [PMID: 39611173 PMCID: PMC11603363 DOI: 10.3389/fphar.2024.1452845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 11/06/2024] [Indexed: 11/30/2024] Open
Abstract
Pyroptosis is a form of inflammatory programmed cell death, and is activated by pathogen infections or endogenous danger signals. The canonical pyroptosis process is characterized by the inflammasome (typically NLRP3)-mediated activation of caspase-1, which in turn cleaves and activates IL-1β and IL-18, as well as gasdermin D, which is a pore-forming executor protein, leading to cell membrane rupture, and the release of proinflammatory cytokines and damage-associated molecular pattern molecules. Pyroptosis is considered a part of the innate immune response. A certain level of pyroptosis can help eliminate pathogenic microorganisms, but excessive pyroptosis can lead to persistent inflammatory responses, and cause tissue damage. In recent years, pyroptosis has emerged as a crucial contributor to the development of chronic inflammatory respiratory diseases, such as asthma. The present study reviews the involvement of pyroptosis in the development of asthma, in terms of its role in different inflammatory phenotypes of the disease, and its influence on various immune and non-immune cells in the airway. In addition, the potential therapeutic value of targeting pyroptosis for the treatment of specific phenotypes of asthma is discussed.
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Affiliation(s)
- Yuqiu Hao
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Wenrui Wang
- Department of Hepatopancreatobiliary Medicine, Digestive Diseases Center, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Lin Zhang
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Wei Li
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
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2
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Aggeletopoulou I, Kalafateli M, Tsounis EP, Triantos C. Exploring the role of IL-1β in inflammatory bowel disease pathogenesis. Front Med (Lausanne) 2024; 11:1307394. [PMID: 38323035 PMCID: PMC10845338 DOI: 10.3389/fmed.2024.1307394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 01/11/2024] [Indexed: 02/08/2024] Open
Abstract
Interleukin 1β (IL-1β) is a significant mediator of inflammation and tissue damage in IBD. The balance between IL-1β and its endogenous inhibitor-IL-1Ra-, plays a critical role in both initiation and regulation of inflammation. However, the precise role of IL-1β as a causative factor in IBD or simply a consequence of inflammation remains unclear. This review summarizes current knowledge on the molecular and cellular characteristics of IL-1β, describes the existing evidence on the role of this cytokine as a modulator of intestinal homeostasis and an activator of inflammatory responses, and also discusses the role of microRNAs in the regulation of IL-1β-related inflammatory responses in IBD. Current evidence indicates that IL-1β is involved in several aspects during IBD as it greatly contributes to the induction of pro-inflammatory responses through the recruitment and activation of immune cells to the gut mucosa. In parallel, IL-1β is involved in the intestinal barrier disruption and modulates the differentiation and function of T helper (Th) cells by activating the Th17 cell differentiation, known to be involved in the pathogenesis of IBD. Dysbiosis in the gut can also stimulate immune cells to release IL-1β, which, in turn, promotes inflammation. Lastly, increasing evidence pinpoints the central role of miRNAs involvement in IL-1β-related signaling during IBD, particularly in the maintenance of homeostasis within the intestinal epithelium. In conclusion, given the crucial role of IL-1β in the promotion of inflammation and immune responses in IBD, the targeting of this cytokine or its receptors represents a promising therapeutic approach. Further research into the IL-1β-associated post-transcriptional modifications may elucidate the intricate role of this cytokine in immunomodulation.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Maria Kalafateli
- Department of Gastroenterology, General Hospital of Patras, Patras, Greece
| | - Efthymios P. Tsounis
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
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3
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Keri D, Walker M, Singh I, Nishikawa K, Garces F. Next generation of multispecific antibody engineering. Antib Ther 2024; 7:37-52. [PMID: 38235376 PMCID: PMC10791046 DOI: 10.1093/abt/tbad027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/16/2023] [Accepted: 11/15/2023] [Indexed: 01/19/2024] Open
Abstract
Multispecific antibodies recognize two or more epitopes located on the same or distinct targets. This added capability through protein design allows these man-made molecules to address unmet medical needs that are no longer possible with single targeting such as with monoclonal antibodies or cytokines alone. However, the approach to the development of these multispecific molecules has been met with numerous road bumps, which suggests that a new workflow for multispecific molecules is required. The investigation of the molecular basis that mediates the successful assembly of the building blocks into non-native quaternary structures will lead to the writing of a playbook for multispecifics. This is a must do if we are to design workflows that we can control and in turn predict success. Here, we reflect on the current state-of-the-art of therapeutic biologics and look at the building blocks, in terms of proteins, and tools that can be used to build the foundations of such a next-generation workflow.
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Affiliation(s)
- Daniel Keri
- Department of Protein Therapeutics, Research, Gilead Research, 324 Lakeside Dr, Foster City, CA 94404, USA
| | - Matt Walker
- Department of Protein Therapeutics, Research, Gilead Research, 324 Lakeside Dr, Foster City, CA 94404, USA
| | - Isha Singh
- Department of Protein Therapeutics, Research, Gilead Research, 324 Lakeside Dr, Foster City, CA 94404, USA
| | - Kyle Nishikawa
- Department of Protein Therapeutics, Research, Gilead Research, 324 Lakeside Dr, Foster City, CA 94404, USA
| | - Fernando Garces
- Department of Protein Therapeutics, Research, Gilead Research, 324 Lakeside Dr, Foster City, CA 94404, USA
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De Luca G, Lev PR, Camacho MF, Goette NP, Sackmann F, Castro Ríos MA, Moiraghi B, Cortes Guerrieri V, Bendek G, Carricondo E, Enrico A, Vallejo V, Varela A, Khoury M, Gutierrez M, Larripa IB, Marta RF, Glembotsky AC, Heller PG. High cell-free DNA is associated with disease progression, inflammasome activation and elevated levels of inflammasome-related cytokine IL-18 in patients with myelofibrosis. Front Immunol 2023; 14:1161832. [PMID: 38035089 PMCID: PMC10687201 DOI: 10.3389/fimmu.2023.1161832] [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: 02/08/2023] [Accepted: 10/25/2023] [Indexed: 12/02/2023] Open
Abstract
Myelofibrosis (MF) is a clonal hematopoietic stem cell disorder classified among chronic myeloproliferative neoplasms, characterized by exacerbated myeloid and megakaryocytic proliferation and bone marrow fibrosis. It is induced by driver (JAK2/CALR/MPL) and high molecular risk mutations coupled to a sustained inflammatory state that contributes to disease pathogenesis. Patient outcome is determined by stratification into risk groups and refinement of current prognostic systems may help individualize treatment decisions. Circulating cell-free (cf)DNA comprises short fragments of double-stranded DNA, which promotes inflammation by stimulating several pathways, including inflammasome activation, which is responsible for IL-1β and IL-18 maturation and release. In this work, we assessed the contribution of cfDNA as a marker of disease progression and mediator of inflammation in MF. cfDNA was increased in MF patients and higher levels were associated with adverse clinical outcome, a high-risk molecular profile, advanced disease stages and inferior overall survival, indicating its potential value as a prognostic marker. Cell-free DNA levels correlated with tumor burden parameters and markers of systemic inflammation. To mimic the effects of cfDNA, monocytes were stimulated with poly(dA:dT), a synthetic double-stranded DNA. Following stimulation, patient monocytes released higher amounts of inflammasome-processed cytokine, IL-18 to the culture supernatant, reflecting enhanced inflammasome function. Despite overexpression of cytosolic DNA inflammasome sensor AIM2, IL-18 release from MF monocytes was shown to rely mainly on the NLRP3 inflammasome, as it was prevented by NLRP3-specific inhibitor MCC950. Circulating IL-18 levels were increased in MF plasma, reflecting in vivo inflammasome activation, and highlighting the previously unrecognized involvement of this cytokine in MF cytokine network. Monocyte counts were higher in patients and showed a trend towards correlation with IL-18 levels, suggesting monocytes represent a source of circulating IL-18. The close correlation shown between IL-18 and cfDNA levels, together with the finding of enhanced DNA-triggered IL-18 release from monocytes, suggest that cfDNA promotes inflammation, at least in part, through inflammasome activation. This work highlights cfDNA, the inflammasome and IL-18 as additional players in the complex inflammatory circuit that fosters MF progression, potentially providing new therapeutic targets.
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Affiliation(s)
- Geraldine De Luca
- División Hematología Investigación, Instituto de Investigaciones Médicas Dr. Alfredo Lanari, Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
- Instituto de Investigaciones Médicas (IDIM), UBA-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Paola R. Lev
- División Hematología Investigación, Instituto de Investigaciones Médicas Dr. Alfredo Lanari, Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
- Instituto de Investigaciones Médicas (IDIM), UBA-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Maria F. Camacho
- Laboratorio de Genética Hematológica, Instituto de Medicina Experimental, IMEX-CONICET/Academia Nacional de Medicina, Buenos Aires, Argentina
| | - Nora P. Goette
- División Hematología Investigación, Instituto de Investigaciones Médicas Dr. Alfredo Lanari, Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
| | | | | | - Beatriz Moiraghi
- Departamento de Hematología, Hospital Ramos Mejía, Buenos Aires, Argentina
| | - Veronica Cortes Guerrieri
- División Hematología Clínica, IDIM Dr. Alfredo Lanari, Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
| | - Georgina Bendek
- Departamento de Hematología, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Emiliano Carricondo
- Departamento de Hematología, Hospital Universitario Austral, Buenos Aires, Argentina
| | - Alicia Enrico
- Departamento de Hematología, Hospital Italiano de La Plata, Buenos Aires, Argentina
| | - Veronica Vallejo
- Departamento de Hematología, Instituto Cardiovascular de Buenos Aires, Buenos Aires, Argentina
| | - Ana Varela
- Departamento de Hematología, Hospital Ramos Mejía, Buenos Aires, Argentina
| | - Marina Khoury
- Departamento de Docencia e Investigación, IDIM Dr. Alfredo Lanari, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Marina Gutierrez
- Unidad Genómica, Laboratorio Stamboulian, Buenos Aires, Argentina
| | - Irene B. Larripa
- Laboratorio de Genética Hematológica, Instituto de Medicina Experimental, IMEX-CONICET/Academia Nacional de Medicina, Buenos Aires, Argentina
| | - Rosana F. Marta
- División Hematología Investigación, Instituto de Investigaciones Médicas Dr. Alfredo Lanari, Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
- Instituto de Investigaciones Médicas (IDIM), UBA-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Ana C. Glembotsky
- División Hematología Investigación, Instituto de Investigaciones Médicas Dr. Alfredo Lanari, Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
- Instituto de Investigaciones Médicas (IDIM), UBA-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Paula G. Heller
- División Hematología Investigación, Instituto de Investigaciones Médicas Dr. Alfredo Lanari, Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
- Instituto de Investigaciones Médicas (IDIM), UBA-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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5
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Sullivan GP, Davidovich P, Muñoz-Wolf N, Ward RW, Hernandez Santana YE, Clancy DM, Gorman A, Najda Z, Turk B, Walsh PT, Lavelle EC, Martin SJ. Myeloid cell-derived proteases produce a proinflammatory form of IL-37 that signals via IL-36 receptor engagement. Sci Immunol 2022; 7:eade5728. [PMID: 36525507 DOI: 10.1126/sciimmunol.ade5728] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Interleukin-1 (IL-1) family cytokines are key barrier cytokines that are typically expressed as inactive, or partially active, precursors that require proteolysis within their amino termini for activation. IL-37 is an enigmatic member of the IL-1 family that has been proposed to be activated by caspase-1 and to exert anti-inflammatory activity through engagement of the IL-18R and SIGIRR. However, here we show that the longest IL-37 isoform, IL-37b, exhibits robust proinflammatory activity upon amino-terminal proteolysis by neutrophil elastase or cathepsin S. In sharp contrast, caspase-1 failed to process or activate IL-37 at concentrations that robustly activated its canonical substrate, IL-1β. IL-37 and IL-36 exhibit high structural homology, and, consistent with this, a K53-truncated form of IL-37, mimicking the cathepsin S-processed form of this cytokine, was found to exert its proinflammatory effects via IL-36 receptor engagement and produced an inflammatory signature practically identical to IL-36. Administration of K53-truncated IL-37b intraperitoneally into wild-type mice also elicited an inflammatory response that was attenuated in IL-36R-/- animals. These data demonstrate that, in common with other IL-1 family members, mature IL-37 can also elicit proinflammatory effects upon processing by specific proteases.
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Affiliation(s)
- Graeme P Sullivan
- Molecular Cell Biology Laboratory, Department of Genetics, Smurfit Institute, Trinity College, Dublin 2, Ireland
| | - Pavel Davidovich
- Molecular Cell Biology Laboratory, Department of Genetics, Smurfit Institute, Trinity College, Dublin 2, Ireland
| | - Natalia Muñoz-Wolf
- Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland.,4National Children's Research Centre, CHI-Crumlin, Dublin, Ireland
| | - Ross W Ward
- Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland
| | | | - Danielle M Clancy
- Molecular Cell Biology Laboratory, Department of Genetics, Smurfit Institute, Trinity College, Dublin 2, Ireland
| | - Aoife Gorman
- Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland
| | - Zaneta Najda
- Molecular Cell Biology Laboratory, Department of Genetics, Smurfit Institute, Trinity College, Dublin 2, Ireland
| | - Boris Turk
- Department of Biochemistry, Molecular and Structural Biology, Jožef Stefan Institute, Ljubljana, Slovenia
| | - Patrick T Walsh
- Department of Clinical Medicine, School of Medicine, Trinity College, Dublin 2, Ireland.,Department of Biochemistry, Molecular and Structural Biology, Jožef Stefan Institute, Ljubljana, Slovenia
| | - Ed C Lavelle
- Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland
| | - Seamus J Martin
- Molecular Cell Biology Laboratory, Department of Genetics, Smurfit Institute, Trinity College, Dublin 2, Ireland
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6
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Lei S, Jin J, Zhao X, Zhou L, Qi G, Yang J. The role of IL-33/ST2 signaling in the tumor microenvironment and Treg immunotherapy. Exp Biol Med (Maywood) 2022; 247:1810-1818. [PMID: 35733343 PMCID: PMC9679353 DOI: 10.1177/15353702221102094] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Interleukin (IL)-33 is a tissue-derived nuclear cytokine belonging to the IL-1 family. Stimulation-2 (ST2) is the only known IL-33 receptor. ST2 signals mostly on immune cells found within tissues, such as regulatory T cells (Treg cells), CD8+ T cells, and natural killer (NK) cells. Therefore, the IL-33/ST2 signaling pathway is important in the immune system. IL-33 deficiency impairs Treg cell function. ST2 signaling is also increased in active Treg cells, providing a new approach for Treg-related immunotherapy. The IL-33/ST2 signaling pathway regulates multiple immune-related cells by activating various intracellular kinases and factors in the tumor microenvironment (TME). Here, we review the latest studies on the role of the IL-33/ST2 signaling pathway in TME and Treg immunotherapy.
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Affiliation(s)
- Shangbo Lei
- Department of Immunology, Guilin Medical University, Guilin 541199, Guangxi, China,Department of Pathophysiology, Guilin Medical University, Guilin 541199, Guangxi, China,Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Jiamin Jin
- Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Xiangfeng Zhao
- Department of Immunology, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Lihua Zhou
- Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Guangying Qi
- Department of Pathophysiology, Guilin Medical University, Guilin 541199, Guangxi, China,Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Jinfeng Yang
- Department of Immunology, Guilin Medical University, Guilin 541199, Guangxi, China,Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, Guangxi, China,Jinfeng Yang.
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Guo Y, Mei Z, Li D, Banerjee A, Khalil MA, Burke A, Ritter J, Lau C, Kreisel D, Gelman AE, Jacobsen E, Luzina IG, Atamas SP, Krupnick AS. Ischemia reperfusion injury facilitates lung allograft acceptance through IL-33-mediated activation of donor-derived IL-5 producing group 2 innate lymphoid cells. Am J Transplant 2022; 22:1963-1975. [PMID: 35510760 PMCID: PMC9357103 DOI: 10.1111/ajt.17084] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 04/11/2022] [Accepted: 04/30/2022] [Indexed: 01/25/2023]
Abstract
Pathways regulating lung alloimmune responses differ from most other solid organs and remain poorly explored. Based on our recent work identifying the unique role of eosinophils in downregulating lung alloimmunity, we sought to define pathways contributing to eosinophil migration and homeostasis. Using a murine lung transplant model, we have uncovered that immunosuppression increases eosinophil infiltration into the allograft in an IL-5-dependent manner. IL-5 production depends on immunosuppression-mediated preservation of donor-derived group 2 innate lymphoid cells (ILC2). We further describe that ischemia reperfusion injury upregulates the expression of IL-33, which functions as the dominant and nonredundant mediator of IL-5 production by graft-resident ILC2. Our work thus identifies unique cellular mechanisms that contribute to lung allograft acceptance. Notably, ischemia reperfusion injury, widely considered to be solely deleterious to allograft survival, can also downregulate alloimmune responses by initiating unique pathways that promote IL-33/IL-5/eosinophil-mediated tolerance.
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Affiliation(s)
- Yizhan Guo
- Department of Surgery, University of Maryland, Baltimore Maryland
| | - Zhongcheng Mei
- Department of Surgery, University of Maryland, Baltimore Maryland
| | - Dongge Li
- Department of Surgery, University of Maryland, Baltimore Maryland
| | - Anirban Banerjee
- Department of Surgery, University of Maryland, Baltimore Maryland
| | - May A. Khalil
- Department of Surgery, University of Maryland, Baltimore Maryland
| | - Allen Burke
- Department of Pathology, University of Maryland, Baltimore Maryland
| | - Jon Ritter
- Department of Pathology & Immunology, Washington University in St. Louis, St. Louis Missouri
| | - Christine Lau
- Department of Surgery, University of Maryland, Baltimore Maryland
| | - Daniel Kreisel
- Department of Pathology & Immunology, Washington University in St. Louis, St. Louis Missouri
- Department of Surgery, Washington University in St. Louis, St. Louis Missouri
| | - Andrew E. Gelman
- Department of Pathology & Immunology, Washington University in St. Louis, St. Louis Missouri
- Department of Surgery, Washington University in St. Louis, St. Louis Missouri
| | - Elizabeth Jacobsen
- Division of Allergy, Asthma and Clinical Immunology, Mayo Clinic, Scottsdale, Arizona
| | - Irina G. Luzina
- Department of Medicine, University of Maryland, Baltimore Maryland
| | - Sergei P. Atamas
- Department of Surgery, University of Maryland, Baltimore Maryland
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Ciavattone NG, Wu L, O'Neill R, Qiu J, Davila E, Cao X. MyD88 Costimulation in Donor CD8 + T Cells Enhances the Graft-versus-Tumor Effect in Murine Hematopoietic Cell Transplantation. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2021; 206:892-903. [PMID: 33408257 PMCID: PMC8691539 DOI: 10.4049/jimmunol.2000479] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 12/01/2020] [Indexed: 11/19/2022]
Abstract
Donor-derived lymphocytes from allogeneic hematopoietic cell transplantation (allo-HCT) or donor lymphocyte infusion can mediate eradication of host tumor cells in a process labeled the graft-versus-tumor (GVT) effect. Unfortunately, these treatments have produced limited results in various types of leukemia because of an insufficient GVT effect. In this context, molecular engineering of donor lymphocytes to increase the GVT effect may benefit cancer patients. Activating MyD88 signaling in CD8+ T cells via TLR enhances T cell activation and cytotoxicity. However, systemic administration of TLR ligands to stimulate MyD88 could induce hyperinflammation or elicit protumor effects. To circumvent this problem, we devised a synthetic molecule consisting of MyD88 linked to the ectopic domain of CD8a (CD8α:MyD88). We used this construct to test the hypothesis that MyD88 costimulation in donor CD8+ T cells increases tumor control following allo-HCT in mice by increasing T cell activation, function, and direct tumor cytotoxicity. Indeed, an increase in both in vitro and in vivo tumor control was observed with CD8α:MyD88 T cells. This increase in the GVT response was associated with increased T cell expansion, increased functional capacity, and an increase in direct cytotoxic killing of the tumor cells. However, MyD88 costimulation in donor CD8+ T cells was linked to increased yet nonlethal graft-versus-host disease in mice treated with these engineered CD8+ T cells. Given these observations, synthetic CD8α:MyD88 donor T cells may represent a unique and versatile approach to enhance the GVT response that merits further refinement to improve the effectiveness of allo-HCT.
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Affiliation(s)
- Nicholas G Ciavattone
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Baltimore, Baltimore, MD 21201
| | - Long Wu
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Baltimore, Baltimore, MD 21201
- Department of Microbiology and Immunology, School of Medicine, University of Maryland Baltimore, Baltimore, MD 21201
| | - Rachel O'Neill
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Baltimore, Baltimore, MD 21201
- Department of Microbiology and Immunology, School of Medicine, University of Maryland Baltimore, Baltimore, MD 21201
| | - Jingxin Qiu
- Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263; and
| | - Eduardo Davila
- Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Xuefang Cao
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Baltimore, Baltimore, MD 21201;
- Department of Microbiology and Immunology, School of Medicine, University of Maryland Baltimore, Baltimore, MD 21201
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9
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Topal FA, Zuberbier T, Makris MP, Hofmann M. The role of IL-17, IL-23 and IL-31, IL-33 in allergic skin diseases. Curr Opin Allergy Clin Immunol 2020; 20:367-373. [PMID: 32590505 DOI: 10.1097/aci.0000000000000658] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW Allergic skin diseases such as urticaria, atopic dermatitis and allergic contact dermatitis are among the most common skin diseases with severe socioeconomic consequences. The pathogenesis of allergic skin diseases is complex. This review provides an overview of cytocines IL-17, IL-23, IL-31 and IL-33. RECENT FINDINGS Current research results show a variety of immunological processes in the pathogenesis of the allergic skin diseases, including the role of cytokines. In addition to the Th1 and Th2 immune response, the immune response via Th17 is becoming increasingly important in allergic skin diseases but also the cytokines IL-23, IL-31 and IL-33 have been discussed in the literature recently. Different cytokines promote in a kind of orchestra the different symptoms seen in the different allergic skin diseases, including pruritus, dermatitis, mast cell mediator release and inflammation. SUMMARY We are still in the early stages of understanding pathophysiology of allergic skin diseases and the role of various cytokines in the immune system. With the development of targeted antibodies against the proinflammatory cytokines, the variety of normal therapeutic options can be expected to evolve.
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MESH Headings
- Animals
- Clinical Trials as Topic
- Dermatitis, Allergic Contact/drug therapy
- Dermatitis, Allergic Contact/immunology
- Dermatitis, Allergic Contact/pathology
- Dermatitis, Atopic/drug therapy
- Dermatitis, Atopic/immunology
- Dermatitis, Atopic/pathology
- Disease Models, Animal
- Humans
- Immunosuppressive Agents/pharmacology
- Immunosuppressive Agents/therapeutic use
- Interleukin-17/antagonists & inhibitors
- Interleukin-17/immunology
- Interleukin-17/metabolism
- Interleukin-23/immunology
- Interleukin-23/metabolism
- Interleukin-33/antagonists & inhibitors
- Interleukin-33/immunology
- Interleukin-33/metabolism
- Interleukins/antagonists & inhibitors
- Interleukins/immunology
- Interleukins/metabolism
- Signal Transduction/drug effects
- Signal Transduction/immunology
- Skin/drug effects
- Skin/immunology
- Skin/pathology
- T-Lymphocytes, Helper-Inducer/drug effects
- T-Lymphocytes, Helper-Inducer/immunology
- T-Lymphocytes, Helper-Inducer/metabolism
- Treatment Outcome
- Urticaria/drug therapy
- Urticaria/immunology
- Urticaria/pathology
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Affiliation(s)
- Fatih A Topal
- Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Campus Benjamin-Franklin, Berlin, Germany
| | - Torsten Zuberbier
- Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Campus Benjamin-Franklin, Berlin, Germany
| | - Michael P Makris
- Allergy Unit 'D. Kalogeromitros', 2nd Department of Dermatology and Venereology, National and Kapodistrian University of Athens, Medical School, University General Hospital 'ATTIKON', Athens, Greece
| | - Maja Hofmann
- Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Berlin, Germany
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10
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Tallon J, Browning B, Couenne F, Bordes C, Venet F, Nony P, Gueyffier F, Moucadel V, Monneret G, Tayakout-Fayolle M. Dynamical modeling of pro- and anti-inflammatory cytokines in the early stage of septic shock. In Silico Biol 2020; 14:101-121. [PMID: 32597796 PMCID: PMC7505012 DOI: 10.3233/isb-200474] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
A dynamical model of the pathophysiological behaviors of IL18 and IL10 cytokines with their receptors is tested against data for the case of early sepsis. The proposed approach considers the surroundings (organs and bone marrow) and the different subsystems (cells and cyctokines). The interactions between blood cells, cytokines and the surroundings are described via mass balances. Cytokines are adsorbed onto associated receptors at the cell surface. The adsorption is described by the Langmuir model and gives rise to the production of more cytokines and associated receptors inside the cell. The quantities of pro and anti-inflammatory cytokines present in the body are combined to give global information via an inflammation level function which describes the patient’s state. Data for parameter estimation comes from the Sepsis 48 H database. Comparisons between patient data and simulations are presented and are in good agreement. For the IL18/IL10 cytokine pair, 5 key parameters have been found. They are linked to pro-inflammatory IL18 cytokine and show that the early sepsis is driven by components of inflammatory character.
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Affiliation(s)
- J Tallon
- Université Claude Bernard Lyon 1, CNRS, LAGEPP UMR 5007, Villeurbanne, France
| | - B Browning
- Université Claude Bernard Lyon 1, CNRS, LAGEPP UMR 5007, Villeurbanne, France
| | - F Couenne
- Université Claude Bernard Lyon 1, CNRS, LAGEPP UMR 5007, Villeurbanne, France
| | - C Bordes
- Université Claude Bernard Lyon 1, CNRS, LAGEPP UMR 5007, Villeurbanne, France
| | - F Venet
- Hospices Civils de Lyon, LYON Cedex 03 - France
| | - P Nony
- Université Claude Bernard Lyon 1, CNRS, LBBE UMR 5558, Lyon, France
| | - F Gueyffier
- Université Claude Bernard Lyon 1, CNRS, LBBE UMR 5558, Lyon, France
| | | | - G Monneret
- Hospices Civils de Lyon, LYON Cedex 03 - France
| | - M Tayakout-Fayolle
- Université Claude Bernard Lyon 1, CNRS, LAGEPP UMR 5007, Villeurbanne, France
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11
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Lo Verso L, Matte JJ, Lapointe J, Talbot G, Bissonnette N, Blais M, Guay F, Lessard M. Impact of birth weight and neonatal nutritional interventions with micronutrients and bovine colostrum on the development of piglet immune response during the peri-weaning period. Vet Immunol Immunopathol 2020; 226:110072. [PMID: 32540688 DOI: 10.1016/j.vetimm.2020.110072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 12/19/2019] [Accepted: 05/17/2020] [Indexed: 10/24/2022]
Abstract
Immune system development of piglets is influenced by birth weight and colostrum and milk intake. Moreover, the dam transfer to piglets of vitamins A and D and copper, which play important role in immunity, is limited during lactation. In this study, we evaluated the potential of maternal and neonatal supplementations with vitamins A and D and copper, with or without neonatal supplementation of bovine colostrum (BC), to modulate the immune system development of low birth weight (LBW) and high birth weight (HBW) piglets during the peri-weaning period. Litters from 23 control sows (CONT) were assigned to one of the following treatments: 1) control (C); 2) oral administration at 2 and 8 days (d) of age of retinol-acetate, 25-hydroxyvitamin D and CuSO4 and exposure to UVB light for 15 min every second day from d 5 to d 21 (ADCu); 3) oral administration of dehydrated BC (4 g/d) from d 5 to d 10 (BC); 4) ADCu + BC. This experimental design was repeated with 24 sows fed extra daily supplements of 25-hydroxyvitamin D (4,000 IU), β-carotene (30,000 IU) and Cu-yeast (equivalent 45 mg of Cu) from 90 d of gestation until weaning at d 21 (SUPPL). Within each litter, 2 LBW and 2 HBW piglets were euthanized at d 16 and d 23 in order to characterize leukocyte subsets in mesenteric lymph nodes (MLN) and blood by flow cytometry, and to measure gene expression in the MLN and jejunal mucosa by qPCR. At d 16, results revealed that the percentages of γδ and cytotoxic T lymphocytes were significantly reduced in LBW compared to HBW piglets. The jejunal expression of interleukin (IL) 22 was also up-regulated, along with MLN expression of C-C Motif Chemokine Ligand 23, bone morphogenetic protein 2 and secreted phosphoprotein 1 (SPP1), whereas jejunal expression of tumor necrosis factor α was decreased in LBW piglets. At d 23, LBW piglets showed lower amounts of γδ T lymphocytes, higher percentages of CD3- and CD3-CD8α+CD16+ leukocytes (which include Natural killer cells) and lower jejunal expression of IL18. Furthermore, supplementation with BC increased the blood percentage of CD3-CD16+ leukocytes and reduced jejunal IL5 and MLN IL15 expression whereas supplementation with ADCu + BC increased jejunal TNF superfamily 13B and MLN SPP1 expression. Our results suggest that immune system development after birth differed between LBW and HBW piglets and that early dietary supplementation with BC and ADCu has the potential to modulate development of immune functions.
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Affiliation(s)
- Luca Lo Verso
- Sherbrooke Research and Development Centre, Agriculture and Agri-Food Canada, 2000 College Street, Sherbrooke, QC, J1M 0C3 Canada; Faculté des Sciences de l'Agriculture et de l'Alimentation, Département des Sciences Animales, Université Laval, Québec, QC, G1V 0A6 Canada.
| | - J Jacques Matte
- Sherbrooke Research and Development Centre, Agriculture and Agri-Food Canada, 2000 College Street, Sherbrooke, QC, J1M 0C3 Canada
| | - Jérôme Lapointe
- Sherbrooke Research and Development Centre, Agriculture and Agri-Food Canada, 2000 College Street, Sherbrooke, QC, J1M 0C3 Canada
| | - Guylaine Talbot
- Sherbrooke Research and Development Centre, Agriculture and Agri-Food Canada, 2000 College Street, Sherbrooke, QC, J1M 0C3 Canada; Centre de recherche en infectiologie porcine et avicole (CRIPA-FQRNT), Faculté de médecine vétérinaire, Université de Montréal, St-Hyacinthe, QC, J2S 2M2 Canada
| | - Nathalie Bissonnette
- Sherbrooke Research and Development Centre, Agriculture and Agri-Food Canada, 2000 College Street, Sherbrooke, QC, J1M 0C3 Canada
| | - Mylène Blais
- Sherbrooke Research and Development Centre, Agriculture and Agri-Food Canada, 2000 College Street, Sherbrooke, QC, J1M 0C3 Canada; Centre de recherche en infectiologie porcine et avicole (CRIPA-FQRNT), Faculté de médecine vétérinaire, Université de Montréal, St-Hyacinthe, QC, J2S 2M2 Canada
| | - Frédéric Guay
- Faculté des Sciences de l'Agriculture et de l'Alimentation, Département des Sciences Animales, Université Laval, Québec, QC, G1V 0A6 Canada; Centre de recherche en infectiologie porcine et avicole (CRIPA-FQRNT), Faculté de médecine vétérinaire, Université de Montréal, St-Hyacinthe, QC, J2S 2M2 Canada
| | - Martin Lessard
- Sherbrooke Research and Development Centre, Agriculture and Agri-Food Canada, 2000 College Street, Sherbrooke, QC, J1M 0C3 Canada; Centre de recherche en infectiologie porcine et avicole (CRIPA-FQRNT), Faculté de médecine vétérinaire, Université de Montréal, St-Hyacinthe, QC, J2S 2M2 Canada
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12
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Luzardo-Ocampo I, Campos-Vega R, Gonzalez de Mejia E, Loarca-Piña G. Consumption of a baked corn and bean snack reduced chronic colitis inflammation in CD-1 mice via downregulation of IL-1 receptor, TLR, and TNF-α associated pathways. Food Res Int 2020; 132:109097. [PMID: 32331643 DOI: 10.1016/j.foodres.2020.109097] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 12/06/2019] [Accepted: 02/10/2020] [Indexed: 12/12/2022]
Abstract
Ulcerative colitis (UC) is a condition that has been rising in the number of cases around the world. Food products made from natural ingredients such as corn and common bean might serve as alternatives for the treatment of UC. This study aimed to assess the anti-inflammatory effect of the consumption of a baked corn and bean snack (CBS) in an in vivo model of UC using 2% dextran sodium sulfate (DSS) as inductor of colitis. CD-1 mice (45, n = 9/group) were randomly separated into 5 groups, treated for 6-weeks as follows: G1 (basal diet, BD), G2 (2% DSS), G3 (20 g CBS/body weight BW/day + BD), G4 (40 g CBS/BW/day + BD) and G5 (60 g CBS/BW/day + BD). BW, Disease Activity Index (DAI), and feces were collected throughout the treatment. After euthanasia, organs (spleen, liver, and colon) were excised and weighed. Feces were analyzed for β-glucuronidase (β-GLUC) activity and gas-chromatography. The colons were analyzed for histopathology, myeloperoxidase (MPO) activity, and gene analysis. At the end of treatments, among the DSS-induced groups, G3 exhibited the lowest BW losses (11.5%), MPO activity (10.4%) and β-GLUC (8.6%). G4 presented the lowest DAI (0.88), relative spleen weight, and histological inflammation score (p < 0.05). Compared to G2, CBS consumption significantly (p < 0.05) reduced serum TNF-α, IL-10, and MCP-1 levels. The fecal metabolome analysis ranked 9-decenoic acid, decane, and butyric acid as the main contributors of pathways associated with the β-oxidation of fatty acids. G4 showed the highest fecal/cecal contents of short-chain fatty acids among all the DSS-induced groups. For the gene expression, G4 was clustered with G1, showing a differential inhibition of the pro-inflammatory genes Il1r1, Il1a, Tlr4, Tlr2, and Tnfrsf1b. In conclusion, CBS consumption decreased the inflammatory state and reduced the expression of the IL-1 receptor, TLR, and TNF-α-associated pathways in DSS-induced UC in CD-1 mice.
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Affiliation(s)
- Ivan Luzardo-Ocampo
- Programa de Posgrado en Alimentos del Centro de la República (PROPAC), Research and Graduate Program in Food Science, School of Chemistry, Universidad Autónoma de Querétaro, 76010 Queretaro, Mexico; Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, 228-230 ERML, 1201 W. Gregory Dr., Urbana, IL 61801, United States.
| | - Rocio Campos-Vega
- Programa de Posgrado en Alimentos del Centro de la República (PROPAC), Research and Graduate Program in Food Science, School of Chemistry, Universidad Autónoma de Querétaro, 76010 Queretaro, Mexico.
| | - Elvira Gonzalez de Mejia
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, 228-230 ERML, 1201 W. Gregory Dr., Urbana, IL 61801, United States.
| | - Guadalupe Loarca-Piña
- Programa de Posgrado en Alimentos del Centro de la República (PROPAC), Research and Graduate Program in Food Science, School of Chemistry, Universidad Autónoma de Querétaro, 76010 Queretaro, Mexico.
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13
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Wang C, Yan B, Zhang L. The epithelium-derived inflammatory mediators of chronic rhinosinusitis with nasal polyps. Expert Rev Clin Immunol 2020; 16:293-310. [PMID: 31986923 DOI: 10.1080/1744666x.2020.1723417] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Chengshuo Wang
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China
| | - Bing Yan
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China
| | - Luo Zhang
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China
- Department of Allergy, Beijing TongRen Hospital, Capital Medical University, Beijing, China
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14
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Chen J, He Y, Tu L, Duan L. Dual immune functions of IL-33 in inflammatory bowel disease. Histol Histopathol 2019; 35:137-146. [PMID: 31294456 DOI: 10.14670/hh-18-149] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Interleukin-33 (IL-33) has emerged as a critical regulator in a variety of diseases, including inflammatory bowel disease (IBD). IL-33 can be produced by various tissues and cells, and typically induces Th2-type immune responses via binding to the receptor ST2. In addition, accumulated data have shown that IL-33 also plays a modulatory role in the function of regulatory T cells (Tregs), B cells, and innate immune cells such as macrophages and innate lymphoid cells (ILCs). IBD, including Crohn's disease and ulcerative colitis, are characterized by aberrant immunological responses leading to intestinal tissue injury and destruction. Although IL-33 expression is increased in IBD patients and correlates with the patients' disease activity index, mechanistic studies to date have demonstrated both pathogenic and protective roles in animal models of experimental colitis. In this review, we will summarize the roles and mechanisms of IL-33 in IBD, which is essential to understand the pathogenesis of IBD and determine potential therapies.
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Affiliation(s)
- Jie Chen
- Department of Scientific Research and Education, Jiangxi Provincial People's Hospital, Affiliated to Nanchang University, Nanchang, China
| | - Yan He
- Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Lei Tu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Lihua Duan
- Department of Rheumatology and Clinical Immunology, Jiangxi Provincial People's Hospital, Affiliated to Nanchang University, Nanchang, China.
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15
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McEntee CP, Finlay CM, Lavelle EC. Divergent Roles for the IL-1 Family in Gastrointestinal Homeostasis and Inflammation. Front Immunol 2019; 10:1266. [PMID: 31231388 PMCID: PMC6568214 DOI: 10.3389/fimmu.2019.01266] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 05/17/2019] [Indexed: 12/11/2022] Open
Abstract
Inflammatory disorders of the gastro-intestinal tract are a major cause of morbidity and significant burden from a health and economic perspective in industrialized countries. While the incidence of such conditions has a strong environmental component, in particular dietary composition, epidemiological studies have identified specific hereditary mutations which result in disequilibrium between pro- and anti-inflammatory factors. The IL-1 super-family of cytokines and receptors is highly pleiotropic and plays a fundamental role in the pathogenesis of several auto-inflammatory conditions including rheumatoid arthritis, multiple sclerosis and psoriasis. However, the role of this super-family in the etiology of inflammatory bowel diseases remains incompletely resolved despite extensive research. Herein, we highlight the currently accepted paradigms as they pertain to specific IL-1 family members and focus on some recently described non-classical roles for these pathways in the gastrointestinal tract. Finally, we address some of the shortcomings and sources of variance in the field which to date have yielded several conflicting results from similar studies and discuss the potential effect of these factors on data interpretation.
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Affiliation(s)
- Craig P McEntee
- Faculty of Biology, Medicine and Health, School of Biological Sciences, Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom.,Faculty of Biology, Medicine and Health, Manchester Collaborative Centre for Inflammation Research, School of Biological Sciences, University of Manchester, Manchester, United Kingdom
| | - Conor M Finlay
- Faculty of Biology, Medicine and Health, School of Biological Sciences, Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom.,Faculty of Biology, Medicine and Health, Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, University of Manchester, Manchester, United Kingdom
| | - Ed C Lavelle
- Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.,Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN), Advanced Materials and BioEngineering Research (AMBER), Trinity College Dublin, Dublin, Ireland
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16
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Chan BCL, Lam CWK, Tam LS, Wong CK. IL33: Roles in Allergic Inflammation and Therapeutic Perspectives. Front Immunol 2019; 10:364. [PMID: 30886621 PMCID: PMC6409346 DOI: 10.3389/fimmu.2019.00364] [Citation(s) in RCA: 202] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 02/12/2019] [Indexed: 12/29/2022] Open
Abstract
Interleukin (IL)-33 belongs to IL-1 cytokine family which is constitutively produced from the structural and lining cells including fibroblasts, endothelial cells, and epithelial cells of skin, gastrointestinal tract, and lungs that are exposed to the environment. Different from most cytokines that are actively secreted from cells, nuclear cytokine IL-33 is passively released during cell necrosis or when tissues are damaged, suggesting that it may function as an alarmin that alerts the immune system after endothelial or epithelial cell damage during infection, physical stress, or trauma. IL-33 plays important roles in type-2 innate immunity via activation of allergic inflammation-related eosinophils, basophils, mast cells, macrophages, and group 2 innate lymphoid cells (ILC2s) through its receptor ST2. In this review, we focus on the recent advances of the underlying intercellular and intracellular mechanisms by which IL-33 can regulate the allergic inflammation in various allergic diseases including allergic asthma and atopic dermatitis. The future pharmacological strategy and application of traditional Chinese medicines targeting the IL-33/ST2 axis for anti-inflammatory therapy of allergic diseases were also discussed.
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Affiliation(s)
- Ben C L Chan
- State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Christopher W K Lam
- State Key Laboratory of Quality Research in Chinese Medicines, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau
| | - Lai-Shan Tam
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Chun K Wong
- State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.,Department of Chemical Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong
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17
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Mei Y, Liu H. IL-37: An anti-inflammatory cytokine with antitumor functions. Cancer Rep (Hoboken) 2018; 2:e1151. [PMID: 32935478 DOI: 10.1002/cnr2.1151] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 10/26/2018] [Accepted: 10/26/2018] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND IL-37 is a newly identified IL-1 family cytokine. Unlike other members in IL-1 family, IL-37 has been demonstrated to be an anti-inflammatory cytokine in many inflammatory and autoimmune diseases. IL-37 is regarded as a dual-function cytokine as both the extracellular and intracellular IL-37 are biologically functional. Extracellular IL-37 can bind to IL-18Rα and IL-1R8 to form a triple complex, regulating the downstream STAT3 and PTEN signaling. Intracellular IL-37 can interact with Smad3, translocate into nucleus, and regulate downstream target gene expressions. Recently, the role of IL-37 in tumor development has been extensively studied. RECENT FINDINGS IL-37 has been found to play an antitumor role in various types of tumors, such as non-small cell lung cancer, hepatocellular carcinoma, and renal cell carcinoma. Many mechanism studies have been carried out to elaborate the possible effects of IL-37 on tumor growth, immune responses, and tumor angiogenesis. More importantly, the function of IL-37 may be dependent on its concentration and receptor expression. It can form dimers at high concentrations to be inactivated, thus inhibiting its anti-inflammatory function. We focused on the role of IL-37 in various tumor types and provided the hypothesis regarding the underlying mechanisms. CONCLUSION IL-37 may affect tumor development through multiple mechanisms: (1) IL-37 directly influences tumor cell viability; (2) IL-37 regulates the immune response to promote the antitumor immunity; and (3) IL-37 suppresses tumor angiogenesis in the tumor microenvironment. Future studies are warranted to further investigate the mechanisms of these multifaceted functions of IL-37 in animal models and cancer patients.
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Affiliation(s)
- Yu Mei
- Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, National University of Singapore, Singapore
| | - Haiyan Liu
- Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, National University of Singapore, Singapore
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18
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Neuroimmunomodulation in Major Depressive Disorder: Focus on Caspase 1, Inducible Nitric Oxide Synthase, and Interferon-Gamma. Mol Neurobiol 2018; 56:4288-4305. [PMID: 30306457 PMCID: PMC6505498 DOI: 10.1007/s12035-018-1359-3] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Accepted: 09/19/2018] [Indexed: 12/13/2022]
Abstract
Major depressive disorder (MDD) is one of the leading causes of disability worldwide, and its incidence is expected to increase. Despite tremendous efforts to understand its underlying biological mechanisms, MDD pathophysiology remains elusive and pharmacotherapy outcomes are still far from ideal. Low-grade chronic inflammation seems to play a key role in mediating the interface between psychological stress, depressive symptomatology, altered intestinal microbiology, and MDD onset. We review the available pre-clinical and clinical evidence of an involvement of pro-inflammatory pathways in the pathogenesis, treatment, and remission of MDD. We focus on caspase 1, inducible nitric oxide synthase, and interferon gamma, three inflammatory systems dysregulated in MDD. Treatment strategies aiming at targeting such pathways alone or in combination with classical therapies could prove valuable in MDD. Further studies are needed to assess the safety and efficacy of immune modulation in MDD and other psychiatric disorders with neuroinflammatory components.
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19
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Hong J, Kim S, Lin PC. Interleukin-33 and ST2 Signaling in Tumor Microenvironment. J Interferon Cytokine Res 2018; 39:61-71. [PMID: 30256696 DOI: 10.1089/jir.2018.0044] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Interleukin-33 (IL-33) is one of the members of the IL-1 family of cytokines and a ligand of ST2 and IL-1 receptor accessory protein (IL-1RAcP) that is known to affect Th2 inflammatory response with partial effects on Th1 responses. This cytokine is released by epithelial and smooth muscle cells of the airway system during their injury by several environmental stimuli, such as allergens, viruses, helminths, and pollutants. IL-33 is an alarmin that acts as an endogenous danger signal, and it has been known to affect various types of cells, such as mast cells, basophils, eosinophils, T cells, and specific subsets of innate lymphoid cells (ILCs). In recent findings, this cytokine is believed to have a critical role in several types of cancers, such as lung cancer, liver cancer, and head and neck squamous cell cancer. The expression of IL-33/ST2 in cancer tissues shows a close association with tumor growth and tumor progression in several types of cancer, suggesting the IL-33/ST2 pathway as a potential target for therapy.
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Affiliation(s)
- Jaewoo Hong
- 1 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland
| | - Soohyun Kim
- 2 Laboratory of Cytokine Immunology, Department of Biomedical Science and Technology, Konkuk University, Seoul, South Korea
| | - P Charles Lin
- 1 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland
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20
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Luo Q, Fan Y, Lin L, Wei J, Li Z, Li Y, Nakae S, Lin W, Chen Q. Interleukin-33 Protects Ischemic Brain Injury by Regulating Specific Microglial Activities. Neuroscience 2018; 385:75-89. [DOI: 10.1016/j.neuroscience.2018.05.047] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Revised: 05/29/2018] [Accepted: 05/31/2018] [Indexed: 12/11/2022]
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21
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Osipova ED, Semyachkina-Glushkovskaya OV, Morgun AV, Pisareva NV, Malinovskaya NA, Boitsova EB, Pozhilenkova EA, Belova OA, Salmin VV, Taranushenko TE, Noda M, Salmina AB. Gliotransmitters and cytokines in the control of blood-brain barrier permeability. Rev Neurosci 2018; 29:567-591. [DOI: 10.1515/revneuro-2017-0092] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 11/26/2017] [Indexed: 11/15/2022]
Abstract
AbstractThe contribution of astrocytes and microglia to the regulation of neuroplasticity or neurovascular unit (NVU) is based on the coordinated secretion of gliotransmitters and cytokines and the release and uptake of metabolites. Blood-brain barrier (BBB) integrity and angiogenesis are influenced by perivascular cells contacting with the abluminal side of brain microvessel endothelial cells (pericytes, astrocytes) or by immune cells existing (microglia) or invading the NVU (macrophages) under pathologic conditions. The release of gliotransmitters or cytokines by activated astroglial and microglial cells is provided by distinct mechanisms, affects intercellular communication, and results in the establishment of microenvironment controlling BBB permeability and neuroinflammation. Glial glutamate transporters and connexin and pannexin hemichannels working in the tight functional coupling with the purinergic system serve as promising molecular targets for manipulating the intercellular communications that control BBB permeability in brain pathologies associated with excessive angiogenesis, cerebrovascular remodeling, and BBB-mediated neuroinflammation. Substantial progress in deciphering the molecular mechanisms underlying the (patho)physiology of perivascular glia provides promising approaches to novel clinically relevant therapies for brain disorders. The present review summarizes the current understandings on the secretory machinery expressed in glial cells (glutamate transporters, connexin and pannexin hemichannels, exocytosis mechanisms, membrane-derived microvesicles, and inflammasomes) and the role of secreted gliotransmitters and cytokines in the regulation of NVU and BBB permeability in (patho)physiologic conditions.
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22
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Dai Q, Li Y, Yu H, Wang X. Suppression of Th1 and Th17 Responses and Induction of Treg Responses by IL-18-Expressing Plasmid Gene Combined with IL-4 on Collagen-Induced Arthritis. BIOMED RESEARCH INTERNATIONAL 2018; 2018:5164715. [PMID: 29854762 PMCID: PMC5964485 DOI: 10.1155/2018/5164715] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 02/22/2018] [Accepted: 03/29/2018] [Indexed: 01/04/2023]
Abstract
OBJECTIVES IL-18 is a proinflammatory cytokine with multiple immunoregulatory properties. We studied the effect of IL-18 gene therapy on the development of murine collagen-induced arthritis (CIA). METHODS Plasmid pCAGGS-IL-18 along or in combination with IL-10 or IL-4 was administered to CIA mice. The incidence and severity of arthritis of the paws were determined by a visual scale. Joint destruction was determined by histology. The levels of a panel of cytokines and transcription factors in the synovium were determined by reverse transcription polymerase chain reaction and quantitative RT-PCR. Quantitative RT-PCR was employed to detect the mRNA expression of TLRs and their pathway on the surface of DCs. RESULTS IL-18 gene therapy had no therapeutic effect on CIA mice. Additional coadministration with low dosage of recombinant IL-4 ameliorated the disease progression. Histopathological examination of the joints showed intact cartilage surface in IL-18 gene combined with IL-4-treated mice. The synovium of IL-18 gene combined with rIL4-treated mice had lower expression of TNF-α, IFN-γ, and IL-17 and higher expression of IL-10. The mechanism of this response appeared to involve modulation of transcription factors FoxP3 and GATA-3. The DCs in the spleen and lymph nodes of IL-18 gene combined with rIL4-treated mice had lower expression of TLR2, MyD88, and NF-kB. CONCLUSIONS Our findings indicate that pIL-18 gene combined with IL-4 ameliorates arthritis in the CIA mouse by suppression of Th1 and Th17 cytokines and increasing expression of FoxP3 and GATA-3. The plasmid backbone and multiple immunoregulatory properties of IL-18 appear to play a major role in the pIL-18 coadministration with rIL-4-mediated immunomodulation of arthritis through blocking the TLR2/MyD88/NF-kappa B signaling pathway.
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Affiliation(s)
- Qiaomei Dai
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Pathology, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yang Li
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Haiyue Yu
- Department of Rheumatology, Qiqihar First Hospital, Qiqihar, China
| | - Xiaoyan Wang
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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23
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Rea IM, Gibson DS, McGilligan V, McNerlan SE, Alexander HD, Ross OA. Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines. Front Immunol 2018; 9:586. [PMID: 29686666 PMCID: PMC5900450 DOI: 10.3389/fimmu.2018.00586] [Citation(s) in RCA: 817] [Impact Index Per Article: 116.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Accepted: 03/08/2018] [Indexed: 12/11/2022] Open
Abstract
Cytokine dysregulation is believed to play a key role in the remodeling of the immune system at older age, with evidence pointing to an inability to fine-control systemic inflammation, which seems to be a marker of unsuccessful aging. This reshaping of cytokine expression pattern, with a progressive tendency toward a pro-inflammatory phenotype has been called "inflamm-aging." Despite research there is no clear understanding about the causes of "inflamm-aging" that underpin most major age-related diseases, including atherosclerosis, diabetes, Alzheimer's disease, rheumatoid arthritis, cancer, and aging itself. While inflammation is part of the normal repair response for healing, and essential in keeping us safe from bacterial and viral infections and noxious environmental agents, not all inflammation is good. When inflammation becomes prolonged and persists, it can become damaging and destructive. Several common molecular pathways have been identified that are associated with both aging and low-grade inflammation. The age-related change in redox balance, the increase in age-related senescent cells, the senescence-associated secretory phenotype (SASP) and the decline in effective autophagy that can trigger the inflammasome, suggest that it may be possible to delay age-related diseases and aging itself by suppressing pro-inflammatory molecular mechanisms or improving the timely resolution of inflammation. Conversely there may be learning from molecular or genetic pathways from long-lived cohorts who exemplify good quality aging. Here, we will discuss some of the current ideas and highlight molecular pathways that appear to contribute to the immune imbalance and the cytokine dysregulation, which is associated with "inflammageing" or parainflammation. Evidence of these findings will be drawn from research in cardiovascular disease, cancer, neurological inflammation and rheumatoid arthritis.
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Affiliation(s)
- Irene Maeve Rea
- School of Medicine, Dentistry and Biomedical Science, Queens University Belfast, Belfast, United Kingdom
- Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute, University of Ulster, C-TRIC Building, Altnagelvin Area Hospital, Londonderry, United Kingdom
- Care of Elderly Medicine, Belfast Health and Social Care Trust, Belfast, United Kingdom
| | - David S. Gibson
- Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute, University of Ulster, C-TRIC Building, Altnagelvin Area Hospital, Londonderry, United Kingdom
| | - Victoria McGilligan
- Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute, University of Ulster, C-TRIC Building, Altnagelvin Area Hospital, Londonderry, United Kingdom
| | - Susan E. McNerlan
- Regional Genetics Service, Belfast Health and Social Care Trust, Belfast, United Kingdom
| | - H. Denis Alexander
- Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute, University of Ulster, C-TRIC Building, Altnagelvin Area Hospital, Londonderry, United Kingdom
| | - Owen A. Ross
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, United States
- School of Medicine and Medical Science, University College Dublin, Dublin, Ireland
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24
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Wang L, Quan Y, Yue Y, Heng X, Che F. Interleukin-37: A crucial cytokine with multiple roles in disease and potentially clinical therapy. Oncol Lett 2018; 15:4711-4719. [PMID: 29552110 DOI: 10.3892/ol.2018.7982] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 10/19/2017] [Indexed: 12/26/2022] Open
Abstract
Interleukin (IL)-37, a new IL-1 family member, has received increasing attention in recent years. In the past decade, it has been determined that IL-37 is expressed in various normal cells and tissues and is regulated by inflammatory stimuli and pro-cytokines via different signal transduction pathways. Recently, it has been found that IL-37 is expressed in a variety of cancers, chronic inflammatory and autoimmune disorders, and exerts anti-inflammatory effects. Moreover, a growing body of literature demonstrates that IL-37 plays a vital role in inhibiting both innate and adaptive immune responses as well as inflammatory reactions. In addition, IL-37 may prove to be a new and potentially useful target for effective cytokine therapy. Further evidence is needed to clarify in more detail the effects of IL-37 in experimental and clinical studies. Based on an extensive summary of published data, the aim of this review is to outline the current knowledge of IL-37, including the location, structure, expression, regulation and function, as well as the potential clinical applications of this cytokine.
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Affiliation(s)
- Lijuan Wang
- Central Laboratory, Hematology Laboratory, Linyi People's Hospital, Shandong University, Linyi, Shandong 276000, P.R. China.,Department of Hematology, Hematology Laboratory, Linyi People's Hospital, Shandong University, Linyi, Shandong 276000, P.R. China
| | - Yanchun Quan
- Central Laboratory, Hematology Laboratory, Linyi People's Hospital, Shandong University, Linyi, Shandong 276000, P.R. China
| | - Yongfang Yue
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Xueyuan Heng
- Department of Neurosurgery, Linyi People's Hospital, Shandong University, Linyi, Shandong 276000, P.R. China
| | - Fengyuan Che
- Central Laboratory, Hematology Laboratory, Linyi People's Hospital, Shandong University, Linyi, Shandong 276000, P.R. China
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25
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Loxham M, Davies DE. Phenotypic and genetic aspects of epithelial barrier function in asthmatic patients. J Allergy Clin Immunol 2017; 139:1736-1751. [PMID: 28583446 PMCID: PMC5457128 DOI: 10.1016/j.jaci.2017.04.005] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 04/13/2017] [Accepted: 04/14/2017] [Indexed: 12/22/2022]
Abstract
The bronchial epithelium is continuously exposed to a multitude of noxious challenges in inhaled air. Cellular contact with most damaging agents is reduced by the action of the mucociliary apparatus and by formation of a physical barrier that controls passage of ions and macromolecules. In conjunction with these defensive barrier functions, immunomodulatory cross-talk between the bronchial epithelium and tissue-resident immune cells controls the tissue microenvironment and barrier homeostasis. This is achieved by expression of an array of sensors that detect a wide variety of viral, bacterial, and nonmicrobial (toxins and irritants) agents, resulting in production of many different soluble and cell-surface molecules that signal to cells of the immune system. The ability of the bronchial epithelium to control the balance of inhibitory and activating signals is essential for orchestrating appropriate inflammatory and immune responses and for temporally modulating these responses to limit tissue injury and control the resolution of inflammation during tissue repair. In asthmatic patients abnormalities in many aspects of epithelial barrier function have been identified. We postulate that such abnormalities play a causal role in immune dysregulation in the airways by translating gene-environment interactions that underpin disease pathogenesis and exacerbation.
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Affiliation(s)
- Matthew Loxham
- Clinical and Experimental Sciences and the Southampton NIHR Respiratory Biomedical Research Unit, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, University Hospital Southampton, Southampton, United Kingdom
| | - Donna E Davies
- Clinical and Experimental Sciences and the Southampton NIHR Respiratory Biomedical Research Unit, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, University Hospital Southampton, Southampton, United Kingdom.
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26
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Vargas TR, Martin F, Apetoh L. Role of interleukin-1-family cytokines on effector CD4 T cell differentiation. World J Immunol 2017; 7:24-31. [DOI: 10.5411/wji.v7.i2.24] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 03/30/2017] [Accepted: 04/17/2017] [Indexed: 02/05/2023] Open
Abstract
The ability of CD4 T cells to differentiate into various effector or regulatory T cell subsets explains the successful adaptation of immune responses to different types of infectious pathogens. Immune responses in the context of cancer are also shaped by CD4 T cells, which can directly affect cancer prognosis in patients. While the proinflammatory mediator interleukin (IL)-1β was initially shown to enhance Th2 cell responses, recent findings support a predominant role of two other members of the IL-1 family, IL-18 and IL-33, on the production of Th1 and Th2-derived cytokines. In addition, IL-1β was found to profoundly affect the biology of two recently identified CD4 T cell subsets, Th17 and Th9 cells. IL-1β is critical for Th17 cell differentiation and it enhances the production of IL-9 and IL-21 by Th9 cells, thus increasing their anticancer properties. We will here review the mechanisms accounting for the ability of IL-1 cytokines to affect the differentiation of CD4 effector T cells with a focus on Th17 and Th9 cells. The physiopathological relevance of IL-1-driven effects on CD4 T cells will also be discussed.
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27
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Abstract
The objective of the study is to investigate the role and specific molecular mechanism of interleukin-33 (IL-33) acted on acute lung injury (ALI) induced by lipopolysaccharide (LPS). C57BL/6 mice intratracheally instilled LPS to induce ALI model. The mice were randomly divided into three groups: the sham operation group (Sham), ALI group (ALI), and pretreatment with IL-33 of ALI group (IL-33). By observing the survival rate, inflammatory cytokines in bronchoalveolar lavage fluid (BALF), myeloperoxidase (MPO) levels in lung tissue, lung histopathological examination, pulmonary capillary leakage, lung wet/dry (W/D) weight ratio, fibrosis levels in lung tissue, and associated pathways changes among the different groups, comparing to explore the role of IL-33 pretreatment on ALI mice and the possible molecular mechanisms. IL-33 pretreatment overall decreased the survival rate of ALI mice. IL-33 aggravated inflammation reaction showing as increasing the release of proinflammatory cytokines TNF-α and IL-6, increasing MPO levels in lung tissue, and aggravating lung pathology injury. In addition, IL-33 pretreatment further destroyed adherens junctions (AJs) by increasing the phosphorylation of VE-cadherin, resulting in the concomitantly pulmonary capillary barrier damage and pulmonary edema. During this process, mitogen-activated protein kinase (MAPK) pathways further activated. However, IL-33 pretreatment had no significant impact on collagen content of lung tissue. Our results indicated that IL-33 aggravated inflammatory reaction and increased microvascular permeability, but had little effect on pulmonary fibrosis, associated with the further activation of MAPK family proteins in the process. To sum up, IL-33 decreased survival rate and aggravated LPS-induced ALI.
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28
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Sato S, Yanagawa Y, Hiraide S, Iizuka K. Cyclic AMP signaling enhances lipopolysaccharide sensitivity and interleukin-33 production in RAW264.7 macrophages. Microbiol Immunol 2017; 60:382-9. [PMID: 27059942 DOI: 10.1111/1348-0421.12381] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 03/17/2016] [Accepted: 04/01/2016] [Indexed: 12/28/2022]
Abstract
While it has been suggested that IL-33 plays pathogenic roles in various disorders, the factors that stimulate IL-33 production are poorly characterized. In the present study, the effect of cyclic adenosine monophosphate (cAMP) signaling on IL-33 production in RAW264.7 macrophages in response to various doses of LPS was examined. High-dose LPS treatment induced IL-33 and TNF protein production in RAW264.7 macrophages. In contrast, low-dose LPS failed to induce IL-33 production while significantly inducing TNF production. In the presence of the membrane-permeable cAMP analog 8-Br-cAMP, low-dose LPS induced vigorous IL-33 production. This phenomenon was consistent with amounts of mRNA. Similarly, the cAMP-increasing agent adrenaline also enhanced the sensitivity of RAW264.7 macrophages to LPS as demonstrated by IL-33 production. The protein kinase A (PKA) inhibitor H89 blocked the effects of 8-Br-cAMP and adrenaline on IL-33 production, suggesting that PKA is involved in IL-33 induction. Taken together, cAMP-mediated signaling pathway appears to enhance the sensitivity of RAW264.7 macrophages to LPS with respect to IL-33 production. Our findings suggest that stress events and the subsequent secretion of adrenaline enhance macrophage production via IL-33; this process may be associated with the pathogenesis of various disorders involving IL-33.
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Affiliation(s)
- Shizuka Sato
- Department of Pharmacology, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Kanazawa 1757, Ishikari-Tobetsu 061-0293, Japan
| | - Yoshiki Yanagawa
- Department of Pharmacology, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Kanazawa 1757, Ishikari-Tobetsu 061-0293, Japan
| | - Sachiko Hiraide
- Department of Pharmacology, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Kanazawa 1757, Ishikari-Tobetsu 061-0293, Japan
| | - Kenji Iizuka
- Department of Pharmacology, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Kanazawa 1757, Ishikari-Tobetsu 061-0293, Japan
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29
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Alsahebfosoul F, Rahimmanesh I, Shajarian M, Etemadifar M, Sedaghat N, Hejazi Z, Naderi S. Interleukin-33 plasma levels in patients with relapsing-remitting multiple sclerosis. Biomol Concepts 2017; 8:55-60. [PMID: 28107165 DOI: 10.1515/bmc-2016-0026] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 11/25/2016] [Indexed: 02/08/2023] Open
Abstract
Cytokines are implicated in the immunopathogenesis of multiple sclerosis (MS). Interleukin (IL)-33, one of the recently discovered members of the IL-1 superfamily, is a dual functional cytokine involved in various autoimmune disorders. In a case-control study, venous blood was collected from healthy subjects categorized as control group (n=44) and MS patients (n=44). All recruited patients were clinically diagnosed with relapsing-remitting MS (RRMS), including patients without treatment (new identified cases, n=16) and those treated with interferon beta (IFN-β) (n=28). The plasma levels of IL-33 in subjects were measured with ELISA. Significantly elevated IL-33 plasma levels were observed in RRMS patients (p=0.005). Furthermore, IFN-β-treated MS patients had lower levels of IL-33 compared to the untreated patients (p<0.001). Increased IL-33 plasma levels in the patient group might be associated with development of MS. These results could contribute to our better understanding about the role of IL-33 in the immunopathogenesis of MS.
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Affiliation(s)
- Fereshteh Alsahebfosoul
- Isfahan Research Center of Multiple Sclerosis, Isfahan, Iran.,Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ilnaz Rahimmanesh
- Isfahan Research Center of Multiple Sclerosis, Isfahan, Iran.,Departments of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mansour Shajarian
- Isfahan Research Center of Multiple Sclerosis, Isfahan, Iran.,Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Masoud Etemadifar
- Isfahan Research Center of Multiple Sclerosis, Isfahan, Iran.,Department of Neurology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nahid Sedaghat
- Isfahan Research Center of Multiple Sclerosis, Isfahan, Iran.,Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zahra Hejazi
- Isfahan Research Center of Multiple Sclerosis, Isfahan, Iran.,Departments of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shamsi Naderi
- Isfahan Research Center of Multiple Sclerosis, Isfahan, Iran.,Departments of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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30
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Ellisdon AM, Nold-Petry CA, D’Andrea L, Cho SX, Lao JC, Rudloff I, Ngo D, Lo CY, Soares da Costa TP, Perugini MA, Conroy PJ, Whisstock JC, Nold MF. Homodimerization attenuates the anti-inflammatory activity of interleukin-37. Sci Immunol 2017; 2:2/8/eaaj1548. [DOI: 10.1126/sciimmunol.aaj1548] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2016] [Revised: 11/29/2016] [Accepted: 01/19/2017] [Indexed: 12/14/2022]
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31
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Booker CS, Grattan DR. IL1R9Is Evolutionarily Related toIL18BPand May Function as an IL-18 Receptor. THE JOURNAL OF IMMUNOLOGY 2016; 198:270-278. [DOI: 10.4049/jimmunol.1500648] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 11/02/2016] [Indexed: 12/14/2022]
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32
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Zhao X, Zhang X, Lv Y, Xu Y, Li M, Pan Q, Chu Y, Liu N, Zhang GX, Zhu L. Matrine downregulates IL-33/ST2 expression in the central nervous system of rats with experimental autoimmune encephalomyelitis. Immunol Lett 2016; 178:97-104. [PMID: 27562326 DOI: 10.1016/j.imlet.2016.08.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 08/08/2016] [Accepted: 08/17/2016] [Indexed: 01/30/2023]
Abstract
Interleukin (IL)-33 is a recently described member of the IL-1 family and functions as a ligand for ST2, a member of the IL-1 receptor family. The role of IL-33/ST2 axis in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS), remains controversial. Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been recently found to suppress clinical EAE and CNS inflammation. However, the underlying immunoregulatory mechanisms have not been fully elucidated, and whether this effect of MAT is through inhibiting the function of the IL-33/ST2 axis is not known. In this study, we investigated the relationship between the therapeutic effects of MAT and IL-33/ST2 expression. MAT treatment successfully attenuated severe clinical deficit and histopathological changes, compared to untreated controls. While IL-33/ST2 mRNA expression was largely increased in spinal cord of EAE rats compared to naïve rats, this expression was significantly inhibited in rats treated with MAT. These results were further confirmed by their protein levels tested with immunohistochemistry. Together, our study demonstrates that MAT treatment regulates the inflammatory IL-33/ST2 axis, thus being a novel mechanism underlying the effect of MAT.
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MESH Headings
- Alkaloids/pharmacology
- Animals
- Anthelmintics/pharmacology
- Central Nervous System/metabolism
- Disease Models, Animal
- Down-Regulation
- Encephalomyelitis, Autoimmune, Experimental/genetics
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Encephalomyelitis, Autoimmune, Experimental/pathology
- Female
- Gene Expression Regulation/drug effects
- Immunohistochemistry
- Interleukin-33/genetics
- Interleukin-33/metabolism
- Multiple Sclerosis/genetics
- Multiple Sclerosis/immunology
- Multiple Sclerosis/metabolism
- Quinolizines/pharmacology
- Rats
- Receptors, Interleukin-1/genetics
- Receptors, Interleukin-1/metabolism
- Spinal Cord/immunology
- Spinal Cord/metabolism
- Spinal Cord/pathology
- Matrines
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Affiliation(s)
- Xiaoyu Zhao
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Xiaojian Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Ying Lv
- Department of Nutriology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Yuming Xu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Menglong Li
- Department of Neurosurgery, Nanshi Affiliated Hospital of Henan University, Nanyang 473000, Henan, China
| | - Qingxia Pan
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Yaojuan Chu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Nan Liu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Guang-Xian Zhang
- Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
| | - Lin Zhu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
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33
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The modern interleukin-1 superfamily: Divergent roles in obesity. Semin Immunol 2016; 28:441-449. [DOI: 10.1016/j.smim.2016.10.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 10/03/2016] [Accepted: 10/03/2016] [Indexed: 11/20/2022]
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34
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Kamradt T, Drube S. A complicated liaison: IL-33 and IL-33R in arthritis pathogenesis. Arthritis Res Ther 2016; 15:115. [PMID: 23638884 PMCID: PMC3672742 DOI: 10.1186/ar4209] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Interruption of cytokine signaling, by targeting either the cytokine itself or its cellular receptor, is a mainstay in the therapy for patients with rheumatic diseases. Interleukin (IL)-33, a member of the IL-1 cytokine family, has emerged as an important mediator of inflammatory responses. In a side-by-side examination of IL-33-deficient and IL-33 receptor (IL-33R)-deficient mice in the K/BxN serum transfer model, arthritis was ameliorated in the IL-33R knockout (KO) mice but not in the IL-33 KO mice. These findings complement previous knowledge on IL-33R signaling, demonstrating that the IL-33R cross-activates other signaling pathways in addition to IL-33-mediated signals. The results reported by Martin and colleagues in a previous issue of Arthritis Research & Therapy underline the clinical relevance of IL-33R cross-signaling and further illustrate that targeting a cytokine receptor (IL-33R) can have completely different clinical outcomes than targeting the respective cytokine.
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35
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Elsherbiny NM, Al-Gayyar MMH. The role of IL-18 in type 1 diabetic nephropathy: The problem and future treatment. Cytokine 2016; 81:15-22. [PMID: 26836949 DOI: 10.1016/j.cyto.2016.01.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 01/21/2016] [Accepted: 01/24/2016] [Indexed: 12/18/2022]
Abstract
Diabetic vascular complication is a leading cause of diabetic nephropathy, a progressive increase in urinary albumin excretion coupled with elevated blood pressure leading to declined glomerular filtration and eventually end stage renal failure. There is growing evidence that activated inflammation is contributing factor to the pathogenesis of diabetic nephropathy. Meanwhile, IL-18, a member of the IL-1 family of inflammatory cytokines, is involved in the development and progression of diabetic nephropathy. However, the benefits derived from the current therapeutics for diabetic nephropathy strategies still provide imperfect protection against renal progression. This imperfection points to the need for newer therapeutic agents that have potential to affect primary mechanisms contributing to the pathogenesis of diabetic nephropathy. Therefore, the recognition of IL-18 as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.
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Affiliation(s)
- Nehal M Elsherbiny
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt
| | - Mohammed M H Al-Gayyar
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia.
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36
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Affiliation(s)
- S Roth
- Clinic for Infectiology and Microbiology, University of Lübeck, Ratzeburger Allee 160, Lübeck 23562, Germany
| | - W Solbach
- Institute for Medical Microbiology and Hygiene, University of Lübeck, Ratzeburger Allee 160, Lübeck 23562, Germany
| | - T Laskay
- Clinic for Infectiology and Microbiology, University of Lübeck, Ratzeburger Allee 160, Lübeck 23562, Germany
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37
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Hristova M, Habibovic A, Veith C, Janssen-Heininger YMW, Dixon AE, Geiszt M, van der Vliet A. Airway epithelial dual oxidase 1 mediates allergen-induced IL-33 secretion and activation of type 2 immune responses. J Allergy Clin Immunol 2015; 137:1545-1556.e11. [PMID: 26597162 DOI: 10.1016/j.jaci.2015.10.003] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 09/23/2015] [Accepted: 10/02/2015] [Indexed: 11/16/2022]
Abstract
BACKGROUND The IL-1 family member IL-33 plays a critical role in type 2 innate immune responses to allergens and is an important mediator of allergic asthma. The mechanisms by which allergens provoke epithelial IL-33 secretion are still poorly understood. OBJECTIVE Based on previous findings indicating involvement of the NADPH oxidase dual oxidase 1 (DUOX1) in epithelial wound responses, we explored the potential involvement of DUOX1 in allergen-induced IL-33 secretion and potential alterations in airways of asthmatic patients. METHODS Cultured human or murine airway epithelial cells or mice were subjected to acute challenge with Alternaria alternata or house dust mite, and secretion of IL-33 and activation of subsequent type 2 responses were determined. The role of DUOX1 was explored by using small interfering RNA approaches and DUOX1-deficient mice. Cultured nasal epithelial cells from healthy subjects or asthmatic patients were evaluated for DUOX1 expression and allergen-induced responses. RESULTS In vitro or in vivo allergen challenge resulted in rapid airway epithelial IL-33 secretion, which depended critically on DUOX1-mediated activation of epithelial epidermal growth factor receptor and the protease calpain-2 through a redox-dependent mechanism involving cysteine oxidation within epidermal growth factor receptor and the tyrosine kinase Src. Primary nasal epithelial cells from patients with allergic asthma were found to express increased DUOX1 and IL-33 levels and demonstrated enhanced IL-33 secretion in response to allergen challenge compared with values seen in nasal epithelial cells from nonasthmatic subjects. CONCLUSION Our findings implicate epithelial DUOX1 as a pivotal mediator of IL-33-dependent activation of innate airway type 2 immune responses to common airborne allergens and indicate that enhanced DUOX1 expression and IL-33 secretion might present important contributing features of allergic asthma.
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Affiliation(s)
- Milena Hristova
- Department of Pathology and Laboratory Medicine, Vermont Lung Center, University of Vermont, Burlington, Vt
| | - Aida Habibovic
- Department of Pathology and Laboratory Medicine, Vermont Lung Center, University of Vermont, Burlington, Vt
| | - Carmen Veith
- Department of Pathology and Laboratory Medicine, Vermont Lung Center, University of Vermont, Burlington, Vt
| | | | - Anne E Dixon
- Department of Medicine, Vermont Lung Center, University of Vermont, Burlington, Vt
| | - Miklos Geiszt
- Department of Physiology and Lendület Peroxidase Enzyme Research Group, Semmelweis University, Budapest, Hungary
| | - Albert van der Vliet
- Department of Pathology and Laboratory Medicine, Vermont Lung Center, University of Vermont, Burlington, Vt.
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Jabir MS, Hopkins L, Ritchie ND, Ullah I, Bayes HK, Li D, Tourlomousis P, Lupton A, Puleston D, Simon AK, Bryant C, Evans TJ. Mitochondrial damage contributes to Pseudomonas aeruginosa activation of the inflammasome and is downregulated by autophagy. Autophagy 2015; 11:166-82. [PMID: 25700738 PMCID: PMC4502769 DOI: 10.4161/15548627.2014.981915] [Citation(s) in RCA: 137] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The nucleotide-binding domain, leucine-rich repeat containing family caspase recruitment domain containing 4 (NLRC4) inflammasome can be activated by pathogenic bacteria via products translocated through the microbial type III secretion apparatus (T3SS). Recent work has shown that activation of the NLRP3 inflammasome is downregulated by autophagy, but the influence of autophagy on NLRC4 activation is unclear. We set out to determine how autophagy might influence this process, using the bacterium Pseudomonas aeruginosa, which activates the NLRC4 inflammasome via its T3SS. Infection resulted in T3SS-dependent mitochondrial damage with increased production of reactive oxygen intermediates and release of mitochondrial DNA. Inhibiting mitochondrial reactive oxygen release or degrading intracellular mitochondrial DNA abrogated NLRC4 inflammasome activation. Moreover, macrophages lacking mitochondria failed to activate NLRC4 following infection. Removal of damaged mitochondria by autophagy significantly attenuated NLRC4 inflammasome activation. Mitochondrial DNA bound specifically to NLRC4 immunoprecipitates and transfection of mitochondrial DNA directly activated the NLRC4 inflammasome; oxidation of the DNA enhanced this effect. Manipulation of autophagy altered the degree of inflammasome activation and inflammation in an in vivo model of P. aeruginosa infection. Our results reveal a novel mechanism contributing to NLRC4 activation by P. aeruginosa via mitochondrial damage and release of mitochondrial DNA triggered by the bacterial T3SS that is downregulated by autophagy.
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Key Words
- AIM2, absent in melanoma 2
- ATG, autophagy related
- ATPIF1, ATPase inhibitory factor 1
- BID, BH3 interacting domain death agonist
- BMDM, bone marrow-derived macrophages
- BrdU, 5-bromo-2-deoxyuridine
- CASP, caspase
- DNA detection
- GFP, green fluorescent protein
- IL1B, interleukin 1, β
- LC3B, microtubule-associated protein 1 light chain 3 β
- LDH, lactate dehydrogenase
- LPS, lipopolysaccharide
- MT-CO1, mitochondrially encoded cytochrome c oxidase I
- Mito-TEMPO, (2-(2, 2, 6, 6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride
- NAC, N-acetylcysteine
- NAIP, NLR family apoptosis inhibitor
- NGS, normal goat serum
- NLR proteins
- NLR, nucleotide-binding domain, leucine-rich repeat containing
- NLRC4, NLR family, CARD domain containing 4
- NLRP3, NLR family, pyrin domain containing 3
- PBS, phosphate-buffered saline
- PINK1, PTEN induced putative kinase 1
- Rn18s, 18S rRNA
- T3SS, type III secretion system
- TNF, tumor necrosis factor
- TUBB5, tubulin, β 5 class I
- Three-MA, 3-methyladenine
- Vav, vav 1 oncogene
- infection
- mitophagy
- mtDNA, mitochondrial DNA
- type III secretion system
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Affiliation(s)
- Majid Sakhi Jabir
- a Institute of Immunity, Infection and Inflammation ; University of Glasgow ; UK
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Bourdiec A, Ahmad SF, Lachhab A, Akoum A. Regulation of inflammatory and angiogenesis mediators in a functional model of decidualized endometrial stromal cells. Reprod Biomed Online 2015; 32:85-95. [PMID: 26602943 DOI: 10.1016/j.rbmo.2015.09.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Revised: 09/11/2015] [Accepted: 09/15/2015] [Indexed: 01/02/2023]
Abstract
The mechanisms involving the expression of interleukin (IL) 1 family members in the process of preparing the endometrium to receive an embryo remain unclear. In this study, decidualization differentially skewed the balance of IL1 family receptor expression in a pattern that increases endometrial stromal cell receptivity to IL1, IL18 and IL33. Additionally, endometrial cells showed increased expression of homeobox HOXA10 and HOXA11 and LIFR, which are known to be involved in endometrial embryo receptivity. Further analyses of decidual endometrial cells revealed a significant increase in the release of potent proinflammatory, remodelling and angiogenic factors implicated in the embryo invasion process, such as VEGF (P = 0.0305), MMP9 (P = 0.0003), TIMP3 (P = 0.0001), RANTES (P = 0.0020), MCP1 (P = 0.0001) and MIF (P = 0.0068). No significant changes in endogenous IL1B secretion were observed. Decreased secretion of IL18 and decidualization increased secretion of IL33. These findings reveal a significant modulation of endometrial cell receptivity to IL1 family members during endometrial stromal cell decidualization, and suggest that the involvement of IL1 family members is important in physiological processes of endometrial receptivity, including adaptive immunology. This may be relevant to establishing a favourable uterine microenvironment for embryo implantation.
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Affiliation(s)
- Amélie Bourdiec
- Endocrinologie de la reproduction, Centre de recherche-Hôpital Saint-François d'Assise, Centre Hospitalier Universitaire de Québec, Faculté de médecine, Université Laval, Québec, Canada.
| | - Syed-Furquan Ahmad
- Endocrinologie de la reproduction, Centre de recherche-Hôpital Saint-François d'Assise, Centre Hospitalier Universitaire de Québec, Faculté de médecine, Université Laval, Québec, Canada
| | - Asmaa Lachhab
- Endocrinologie de la reproduction, Centre de recherche-Hôpital Saint-François d'Assise, Centre Hospitalier Universitaire de Québec, Faculté de médecine, Université Laval, Québec, Canada
| | - Ali Akoum
- Endocrinologie de la reproduction, Centre de recherche-Hôpital Saint-François d'Assise, Centre Hospitalier Universitaire de Québec, Faculté de médecine, Université Laval, Québec, Canada
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Decreased expression of IL-33 in immune thrombocytopenia. Int Immunopharmacol 2015; 28:420-4. [DOI: 10.1016/j.intimp.2015.06.035] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Revised: 06/22/2015] [Accepted: 06/23/2015] [Indexed: 12/27/2022]
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Molofsky AB, Savage AK, Locksley RM. Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation. Immunity 2015; 42:1005-19. [PMID: 26084021 DOI: 10.1016/j.immuni.2015.06.006] [Citation(s) in RCA: 491] [Impact Index Per Article: 49.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Indexed: 12/12/2022]
Abstract
Interleukin-33 (IL-33) is a nuclear-associated cytokine of the IL-1 family originally described as a potent inducer of allergic type 2 immunity. IL-33 signals via the receptor ST2, which is highly expressed on group 2 innate lymphoid cells (ILC2s) and T helper 2 (Th2) cells, thus underpinning its association with helminth infection and allergic pathology. Recent studies have revealed ST2 expression on subsets of regulatory T cells, and for a role for IL-33 in tissue homeostasis and repair that suggests previously unrecognized interactions within these cellular networks. IL-33 can participate in pathologic fibrotic reactions, or, in the setting of microbial invasion, can cooperate with inflammatory cytokines to promote responses by cytotoxic NK cells, Th1 cells, and CD8(+) T cells. Here, we highlight the regulation and function of IL-33 and ST2 and review their roles in homeostasis, damage, and inflammation, suggesting a conceptual framework for future studies.
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Affiliation(s)
- Ari B Molofsky
- Department of Microbiology & Immunology, University of California, San Francisco, 94143-0795, USA; Department of Laboratory Medicine, University of California, San Francisco, 94143-0795, USA
| | - Adam K Savage
- Howard Hughes Medical Institute, University of California, San Francisco, 94143-0795, USA; Department of Microbiology & Immunology, University of California, San Francisco, 94143-0795, USA
| | - Richard M Locksley
- Howard Hughes Medical Institute, University of California, San Francisco, 94143-0795, USA; Department of Medicine, University of California, San Francisco, 94143-0795, USA; Department of Microbiology & Immunology, University of California, San Francisco, 94143-0795, USA.
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Gao SJ, Zhang L, Lu W, Wang L, Chen L, Zhu Z, Zhu HH. Interleukin-18 genetic polymorphisms contribute differentially to the susceptibility to Crohn’s disease. World J Gastroenterol 2015; 21:8711-8722. [PMID: 26229413 PMCID: PMC4515852 DOI: 10.3748/wjg.v21.i28.8711] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 12/05/2014] [Accepted: 03/12/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the correlation between interleukin-18 (IL-18) gene polymorphisms and the risk of developing Crohn’s disease (CD).
METHODS: The PubMed, CISCOM, CINAHL, Web of Science, EBSCO, Cochrane Library, MEDLINE, EMBASE and CBM databases were searched without any language restrictions using combinations of keywords relating to CD and IL-18 for relevant articles published before November 1st, 2013. Screening of the published studies retrieved from searches was based on our stringent inclusion and exclusion criteria and resulted in seven eligible studies for meta-analysis. A meta-analysis was conducted using a random-effects model with STATA 12.0 software. Crude odds ratios (ORs) with 95% confidence intervals (95%CI) were calculated.
RESULTS: Seven case-control studies, with a total of 1930 CD cases and 1930 healthy subjects, met our inclusion criteria. The results of our meta-analysis indicated that the IL-18 rs1946518 A>C and rs187238 G>C polymorphisms may correlate with an increased risk of CD under five genetic models (all P < 0.05). Furthermore, we observed positive associations between the IL-18 rs360718 A>C polymorphism and CD risk under three genetic models (C allele vs A allele: OR = 2.03, 95%CI: 1.20-3.43, P = 0.008; CC vs AA+AC: OR = 2.39, 95%CI: 1.2-4.43, P = 0.006; CC vs AC: OR = 2.31, 95%CI: 1.22-4.38, P = 0.010). However, such associations were not found for the IL-18 rs917997 C>T, codon 35 A>C and rs1946519 G>T polymorphisms (all P > 0.05). A subgroup analysis was conducted to investigate the effect of ethnicity on an individual’s susceptibility to CD. Our results revealed positive correlations between IL-18 genetic polymorphisms and an increased risk of CD among Asians and Africans (all P < 0.05), but not among Caucasians (all P > 0.05).
CONCLUSION: This meta-analysis indicated that the IL-18 rs1946518 A>C, rs187238 G>C and rs360718 A>C polymorphisms may contribute to susceptibility to CD, especially among Asians and Africans. These polymorphisms are known to reduce IL-18 mRNA and protein levels.
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YE XIAOLEI, ZHAO YARONG, WENG GUOBIN, CHEN YICHEN, WEI XUENI, SHAO JINGPING, JI HUI. IL-33-induced JNK pathway activation confers gastric cancer chemotherapy resistance. Oncol Rep 2015; 33:2746-52. [DOI: 10.3892/or.2015.3898] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Accepted: 12/15/2014] [Indexed: 02/06/2023] Open
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The sterile inflammation in the exacerbation of HBV-associated liver injury. Mediators Inflamm 2015; 2015:508681. [PMID: 25892853 PMCID: PMC4393905 DOI: 10.1155/2015/508681] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Revised: 09/25/2014] [Accepted: 10/08/2014] [Indexed: 12/20/2022] Open
Abstract
Exacerbation of hepatitis B virus-associated liver injury is characterized by abnormal immune response which not only mobilizes specific antiviral effects but also poses a potentially lethal nonspecific sterile inflammation to the host. How nonspecific sterile inflammation is triggered after the preexisting injury caused by specific immune injury remains elusive. In the setting of sterile inflammation, endogenous damage-associated molecular patterns are released by stressed and dying hepatocytes, which alarm the immune system through their potential pattern recognition receptors and related signaling pathways, orchestrate the influx of diverse cytokines, and ultimately amplify liver destruction. This review highlights current knowledge about the sterile hepatic inflammation in the exacerbation of chronic hepatitis B.
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The IL-33/ST2 axis augments effector T-cell responses during acute GVHD. Blood 2015; 125:3183-92. [PMID: 25814531 DOI: 10.1182/blood-2014-10-606830] [Citation(s) in RCA: 133] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Accepted: 03/11/2015] [Indexed: 12/19/2022] Open
Abstract
Interleukin (IL)-33 binding to the receptor suppression of tumorigenicity 2 (ST2) produces pro-inflammatory and anti-inflammatory effects. Increased levels of soluble ST2 (sST2) are a biomarker for steroid-refractory graft-versus-host disease (GVHD) and mortality. However, whether sST2 has a role as an immune modulator or only as a biomarker during GVHD was unclear. We show increased IL-33 production by nonhematopoietic cells in the gastrointestinal (GI) tract in mice post-conditioning and patients during GVHD. Exogenous IL-33 administration during the peak inflammatory response worsened GVHD. Conversely, GVHD lethality and tumor necrosis factor-α production was significantly reduced in il33(-/-) recipients. ST2 was upregulated on murine and human alloreactive T cells and sST2 increased as experimental GVHD progressed. Concordantly, st2(-/-) vs wild-type (WT) donor T cells had a marked reduction in GVHD lethality and GI histopathology. Alloantigen-induced IL-18 receptor upregulation was lower in st2(-/-) T cells, and linked to reduced interferon-γ production by st2(-/-) vs WT T cells during GVHD. Blockade of IL-33/ST2 interactions during allogeneic-hematopoietic cell transplantation by exogenous ST2-Fc infusions had a marked reduction in GVHD lethality, indicating a role of ST2 as a decoy receptor modulating GVHD. Together, these studies point to the IL-33/ST2 axis as a novel and potent target for GVHD therapy.
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Interleukin-18 increases TLR4 and mannose receptor expression and modulates cytokine production in human monocytes. Mediators Inflamm 2015; 2015:236839. [PMID: 25873755 PMCID: PMC4383410 DOI: 10.1155/2015/236839] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 09/02/2014] [Accepted: 09/03/2014] [Indexed: 12/13/2022] Open
Abstract
Interleukin-18 is a proinflammatory cytokine belonging to the interleukin-1 family of cytokines. This cytokine exerts many unique biological and immunological effects. To explore the role of IL-18 in inflammatory innate immune responses, we investigated its impact on expression of two toll-like receptors (TLR2 and TLR4) and mannose receptor (MR) by human peripheral blood monocytes and its effect on TNF-α, IL-12, IL-15, and IL-10 production. Monocytes from healthy donors were stimulated or not with IL-18 for 18 h, and then the TLR2, TLR4, and MR expression and intracellular TNF-α, IL-12, and IL-10 production were assessed by flow cytometry and the levels of TNF-α, IL-12, IL-15, and IL-10 in culture supernatants were measured by ELISA. IL-18 treatment was able to increase TLR4 and MR expression by monocytes. The production of TNF-α and IL-10 was also increased by cytokine treatment. However, IL-18 was unable to induce neither IL-12 nor IL-15 production by these cells. Taken together, these results show an important role of IL-18 on the early phase of inflammatory response by promoting the expression of some pattern recognition receptors (PRRs) that are important during the microbe recognition phase and by inducing some important cytokines such as TNF-α and IL-10.
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Rubin K, Janefeldt A, Andersson L, Berke Z, Grime K, Andersson TB. HepaRG cells as human-relevant in vitro model to study the effects of inflammatory stimuli on cytochrome P450 isoenzymes. Drug Metab Dispos 2015; 43:119-25. [PMID: 25371393 DOI: 10.1124/dmd.114.059246] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Abstract
The suppression of hepatic cytochrome P450 (P450) expression during inflammatory and infectious diseases and the relief of this suppression by successful disease treatment have been previously demonstrated to impact drug disposition. To address this clinically relevant phenomenon preclinically, the effect of proinflammatory cytokines on P450 isoenzymes in human hepatocytes has been examined by several researchers. In the present study we used the human hepatoma cell line (HepaRG) and cryopreserved primary human hepatocytes to investigate the effects of various inflammatory stimuli on P450 levels with the aim of further characterizing HepaRG cells as a useful surrogate for primary hepatocytes. In this study, HepaRG cells were exposed to bacterial lipopolysaccharide (LPS), interleukin-6 (IL-6), and interleukin-18 (IL-18) for 48 or 72 hours. The effects on CYP1A2, CYP2B6, and CYP3A4 mRNA and catalytic activity (phenacetin-O-deethylase, bupropion-hydroxylase, and midazolam-1'-hydroxylase) were measured. Cryopreserved pooled plateable hepatocytes were also exposed to IL-6 or IL-18 for 48 hours, and the effects on CYP1A2, CYP2B6, and CYP3A4 mRNA levels were measured. The exposure of HepaRG cells to IL-6 and LPS resulted in suppression of CYP1A2, CYP2B6, and CYP3A4 mRNA levels as well as their catalytic activities. However, no suppression of P450 activities or mRNA levels was observed after exposure to IL-18. Similar results on CYP1A2, CYP2B6, and CYP3A4 mRNA levels were observed with primary hepatocytes. The present study indicates that different proinflammatory mediators influence the expression of P450 differentially and that HepaRG cells may be used as an alternative to human hepatocytes for studies on cytokine-mediated suppression of drug-metabolizing enzymes.
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Affiliation(s)
- Katarina Rubin
- AstraZeneca R&D, Mölndal, Sweden; and Respiratory, Inflammation and Autoimmunity Innovative Medicines Drug Metabolism and Pharmacokinetics (K.R., K.G.), Cardiovascular and Metabolic Diseases Innovative Medicines (A.J., T.B.A.), Drug Safety and Metabolism Drug Metabolism and Pharmacokinetics (L.A.), Personalized Healthcare and Biomarkers (Z.B.), and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
| | - Annika Janefeldt
- AstraZeneca R&D, Mölndal, Sweden; and Respiratory, Inflammation and Autoimmunity Innovative Medicines Drug Metabolism and Pharmacokinetics (K.R., K.G.), Cardiovascular and Metabolic Diseases Innovative Medicines (A.J., T.B.A.), Drug Safety and Metabolism Drug Metabolism and Pharmacokinetics (L.A.), Personalized Healthcare and Biomarkers (Z.B.), and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
| | - Linda Andersson
- AstraZeneca R&D, Mölndal, Sweden; and Respiratory, Inflammation and Autoimmunity Innovative Medicines Drug Metabolism and Pharmacokinetics (K.R., K.G.), Cardiovascular and Metabolic Diseases Innovative Medicines (A.J., T.B.A.), Drug Safety and Metabolism Drug Metabolism and Pharmacokinetics (L.A.), Personalized Healthcare and Biomarkers (Z.B.), and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
| | - Zsofia Berke
- AstraZeneca R&D, Mölndal, Sweden; and Respiratory, Inflammation and Autoimmunity Innovative Medicines Drug Metabolism and Pharmacokinetics (K.R., K.G.), Cardiovascular and Metabolic Diseases Innovative Medicines (A.J., T.B.A.), Drug Safety and Metabolism Drug Metabolism and Pharmacokinetics (L.A.), Personalized Healthcare and Biomarkers (Z.B.), and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
| | - Ken Grime
- AstraZeneca R&D, Mölndal, Sweden; and Respiratory, Inflammation and Autoimmunity Innovative Medicines Drug Metabolism and Pharmacokinetics (K.R., K.G.), Cardiovascular and Metabolic Diseases Innovative Medicines (A.J., T.B.A.), Drug Safety and Metabolism Drug Metabolism and Pharmacokinetics (L.A.), Personalized Healthcare and Biomarkers (Z.B.), and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
| | - Tommy B Andersson
- AstraZeneca R&D, Mölndal, Sweden; and Respiratory, Inflammation and Autoimmunity Innovative Medicines Drug Metabolism and Pharmacokinetics (K.R., K.G.), Cardiovascular and Metabolic Diseases Innovative Medicines (A.J., T.B.A.), Drug Safety and Metabolism Drug Metabolism and Pharmacokinetics (L.A.), Personalized Healthcare and Biomarkers (Z.B.), and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
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Abstract
The airway epithelial cell barrier serves as the main site of replication for most of the common respiratory viruses and is thereby the first line of defense against these viruses. Host epithelial cells are specially enriched for pattern recognition receptors that activate immune response genes to limit viral replication. A prominently expressed set of these genes encodes cytokines that orchestrate key aspects of host defense, such as recruitment of immune cells and repair of epithelial cell damage. Under some circumstances, airway epithelial cells may be programmed to release cytokines (notably IL-33) that activate a type 2 immune response, which in excess might contribute to the development of chronic obstructive lung disease. Moreover, long-term epithelial progenitor cells with this capability may explain an ongoing susceptibility to lung disease in response to acute respiratory infection or other types of inhaled danger signals. The mucosal airway epithelial cell can thereby mediate a beneficial response for host defense and a detrimental response leading to inflammatory disease.
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Bedi B, McNair NN, Förster I, Mead JR. IL-18 Cytokine Levels Modulate Innate Immune Responses and Cryptosporidiosis in Mice. J Eukaryot Microbiol 2014; 62:44-50. [DOI: 10.1111/jeu.12164] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Revised: 06/09/2014] [Accepted: 07/11/2014] [Indexed: 02/03/2023]
Affiliation(s)
- Brahmchetna Bedi
- Atlanta VA Medical Center; Decatur Georgia USA
- Department of Pediatrics; Emory University; Atlanta Georgia USA
| | - Nina N. McNair
- Department of Pediatrics; Emory University; Atlanta Georgia USA
| | - Irmgard Förster
- Immunology and Environment; Life and Medical Sciences (LIMES) Institute; University of Bonn; Bonn Germany
| | - Jan R. Mead
- Atlanta VA Medical Center; Decatur Georgia USA
- Department of Pediatrics; Emory University; Atlanta Georgia USA
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Ekman AK, Verma D, Fredrikson M, Bivik C, Enerbäck C. Genetic variations of NLRP1: susceptibility in psoriasis. Br J Dermatol 2014; 171:1517-20. [PMID: 24909542 DOI: 10.1111/bjd.13178] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2014] [Indexed: 12/29/2022]
Abstract
BACKGROUND NACHT, LRR and PYD domain-containing protein (NLRP)1 is part of the inflammasome multiprotein complex involved in the production of interleukin (IL)-1β and IL-18, two cytokines strongly implicated in psoriasis pathogenesis. Genetic variations in NLRP1 are associated with a predisposition for chronic inflammatory conditions. OBJECTIVES The aim of the study was to investigate the role of genetic variation in the NLRP1 inflammasome in psoriasis susceptibility. MATERIAL AND METHODS Four haplotype-tagging single-nucleotide polymorphisms (SNPs) (rs6502867, rs8079034, rs878329 and rs12150220) were investigated by TaqMan allelic discrimination in a patient sample comprising 1847 individuals from 478 families and 802 healthy controls. RESULTS Using the transmission disequilibrium test, a significant increase in the transmission of the NLRP1 rs8079034C and rs878329C alleles to patients with psoriasis was demonstrated (P = 0·006 and P = 0·033, respectively). Furthermore, homozygosity for the rs878329C allele correlated with a younger age of onset. We also observed an increase in the expression of NLRP1 mRNA in the peripheral blood cells of patients with psoriasis. This was accompanied by a higher level of circulating IL-18 and appeared to be associated with the rs878329C allele. CONCLUSIONS Our data support the involvement of NLRP1 and the NLRP1 inflammasome in psoriasis susceptibility and further support the role of innate immunity in psoriasis.
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Affiliation(s)
- A-K Ekman
- Ingrid Asp Psoriasis Research Center, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-581 85, Linköping, Sweden
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