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Datta S, Rahman MA, Koka S, Boini KM. High Mobility Group Box 1 (HMGB1): Molecular Signaling and Potential Therapeutic Strategies. Cells 2024; 13:1946. [PMID: 39682695 PMCID: PMC11639863 DOI: 10.3390/cells13231946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/19/2024] [Accepted: 11/21/2024] [Indexed: 12/18/2024] Open
Abstract
High Mobility Group Box 1 (HMGB1) is a highly conserved non-histone chromatin-associated protein across species, primarily recognized for its regulatory impact on vital cellular processes, like autophagy, cell survival, and apoptosis. HMGB1 exhibits dual functionality based on its localization: both as a non-histone protein in the nucleus and as an inducer of inflammatory cytokines upon extracellular release. Pathophysiological insights reveal that HMGB1 plays a significant role in the onset and progression of a vast array of diseases, viz., atherosclerosis, kidney damage, cancer, and neurodegeneration. However, a clear mechanistic understanding of HMGB1 release, translocation, and associated signaling cascades in mediating such physiological dysfunctions remains obscure. This review presents a detailed outline of HMGB1 structure-function relationship and its regulatory role in disease onset and progression from a signaling perspective. This review also presents an insight into the status of HMGB1 druggability, potential limitations in understanding HMGB1 pathophysiology, and future perspective of studies that can be undertaken to address the existing scientific gap. Based on existing paradigm of various studies, HMGB1 is a critical regulator of inflammatory cascades and drives the onset and progression of a broad spectrum of dysfunctions. Studies focusing on HMGB1 druggability have enabled the development of biologics with potential clinical benefits. However, deeper understanding of post-translational modifications, redox states, translocation mechanisms, and mitochondrial interactions can potentially enable the development of better courses of therapy against HMGB1-mediated physiological dysfunctions.
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Affiliation(s)
- Sayantap Datta
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Mohammad Atiqur Rahman
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Saisudha Koka
- Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA;
| | - Krishna M. Boini
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
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Foelsch K, Pelczar P, Zierz E, Kondratowicz S, Qi M, Mueller C, Alawi M, Huebener S, Clauditz T, Gagliani N, Huber S, Huebener P. Intestinal Epithelia and Myeloid Immune Cells Shape Colitis Severity and Colorectal Carcinogenesis via High-mobility Group Box Protein 1. J Crohns Colitis 2024; 18:1122-1133. [PMID: 38285546 DOI: 10.1093/ecco-jcc/jjae017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 01/11/2024] [Accepted: 01/27/2024] [Indexed: 01/31/2024]
Abstract
BACKGROUND High-mobility group box protein 1 [HMGB1] is a ubiquitous nucleoprotein with immune-regulatory properties following cellular secretion or release in sterile and in infectious inflammation. Stool and serum HMGB1 levels correlate with colitis severity and colorectal cancer [CRC] progression, yet recent reports indicate that HMGB1 mainly operates as an intracellular determinant of enterocyte fate during colitis, and investigations into the roles of HMGB1 in CRC are lacking. METHODS Using mice with conditional HMGB1-knockout in enterocytes [Hmgb1ΔIEC] and myeloid cells [Hmgb1ΔLysM], respectively, we explored functions of HMGB1 in pathogenetically diverse contexts of colitis and colitis-associated CRC. RESULTS HMGB1 is overexpressed in human inflammatory bowel disease and gastrointestinal cancers, and HMGB1 protein localises in enterocytes and stromal cells in colitis and CRC specimens from humans and rodents. As previously described, enterocyte HMGB1 deficiency aggravates severe chemical-induced intestinal injury, but not Citrobacter rodentium or T cell transfer colitis in mice. HMGB1-deficient enterocytes and organoids do not exhibit deviant apoptotic or autophagic activity, altered proliferative or migratory capacity, abnormal intestinal permeability, or aberrant DSS-induced organoid inflammation in vitro. Instead, we observed altered in vivo reprogramming of both intestinal epithelia and infiltrating myeloid cells in Hmgb1ΔIEC early during colitis, suggesting HMGB1-mediated paracrine injury signalling. Hmgb1ΔIEC had higher CRC burden than wild types in the Apc+/min model, whereas inflammatory CRC was attenuated in Hmgb1ΔLysM. Cellular and molecular phenotyping of Hmgb1ΔIEC and Hmgb1ΔLysM cancers indicates context-dependent transcriptional modulation of immune signalling and extracellular matrix remodelling via HMGB1. CONCLUSION Enterocytes and myeloid cells context-dependently regulate host responses to severe colitis and maladaptive intestinal wound healing via HMGB1.
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Affiliation(s)
- Katharina Foelsch
- Department of Internal Medicine, I. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Penelope Pelczar
- Department of Internal Medicine, I. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Elisabeth Zierz
- Department of Internal Medicine, I. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stephanie Kondratowicz
- Department of Internal Medicine, I. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Minyue Qi
- Bioinformatics Core Facility, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Mueller
- Bioinformatics Core Facility, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Malik Alawi
- Bioinformatics Core Facility, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sina Huebener
- Department of Internal Medicine, I. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nicola Gagliani
- Department of Internal Medicine, I. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Samuel Huber
- Department of Internal Medicine, I. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Peter Huebener
- Department of Internal Medicine, I. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Boonyaleka K, Okano T, Iida T, Leewananthawet A, Sasai M, Yamamoto M, Ashida H, Suzuki T. Fusobacterium nucleatum infection activates the noncanonical inflammasome and exacerbates inflammatory response in DSS-induced colitis. Eur J Immunol 2023; 53:e2350455. [PMID: 37471504 DOI: 10.1002/eji.202350455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 07/18/2023] [Accepted: 07/19/2023] [Indexed: 07/22/2023]
Abstract
Caspase activation results in pyroptosis, an inflammatory cell death that contributes to several inflammatory diseases by releasing inflammatory cytokines and cellular contents. Fusobacterium nucleatum is a periodontal pathogen frequently detected in human cancer and inflammatory bowel diseases. Studies have reported that F. nucleatum infection leads to NLRP3 activation and pyroptosis, but the precise activation process and disease association remain poorly understood. This study demonstrated that F. nucleatum infection exacerbates acute colitis in mice and activates pyroptosis through caspase-11-mediated gasdermin D cleavage in macrophages. Furthermore, F. nucleatum infection in colitis mice induces the enhancement of IL-1⍺ secretion from the colon, affecting weight loss and severe disease activities. Neutralization of IL-1⍺ protects F. nucleatum infected mice from severe colitis. Therefore, F. nucleatum infection facilitates inflammation in acute colitis with IL-1⍺ from colon tissue by activating noncanonical inflammasome through gasdermin D cleavage.
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Affiliation(s)
- Kotchakorn Boonyaleka
- Department of Bacterial pathogenesis, Infection, and Host Response, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tokuju Okano
- Department of Bacterial pathogenesis, Infection, and Host Response, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tamako Iida
- Department of Bacterial pathogenesis, Infection, and Host Response, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Anongwee Leewananthawet
- Department of Restorative Dentistry and Periodontology, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
- Department of Restorative Dentistry and Periodontology, Specialized Dental Center of Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
| | - Miwa Sasai
- Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Masahiro Yamamoto
- Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Hiroshi Ashida
- Department of Bacterial pathogenesis, Infection, and Host Response, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshihiko Suzuki
- Department of Bacterial pathogenesis, Infection, and Host Response, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
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Casciaro M, Vincelli D, Ferraro M, Mirabile G, Pace E, Martino B, Tonacci A, Gangemi S, Pioggia G, Allegra A. The role of High-mobility group box-1 and Psoriasin in multiple myeloma: Analysis of a population affected by monoclonal gammopathies and review of the literature. Pathol Res Pract 2023; 247:154562. [PMID: 37216746 DOI: 10.1016/j.prp.2023.154562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 05/18/2023] [Indexed: 05/24/2023]
Abstract
Multiple myeloma (MM) is a plasma cells neoplasm which is often preceded by a preneoplastic condition called monoclonal gammopathy of unknown significance (MGUS). A protein called High-mobility group box-1 (HMGB-1) controls transcription and genomic stability. Both pro- and anti-tumor properties of HMGB1 have been described during tumor growth. The S100 protein family includes a protein known as psoriasin. Poorer prognosis and survival were linked to higher psoriasin expression in cancer patients. The goal of the current investigation was to compare the plasma levels of HMGB-1 and psoriasin in patients with MM and MGUS significance, as well as in a group of healthy controls. According to our research, patients with MGUS have higher HMGHB-1 concentrations than healthy controls (846.7 ± 287.6 pg/ml vs. 176.9 ± 204.8 pg/ml for controls, p < 0.001). Similarly, we found a huge difference in HMGB-1 levels for MM patients with respect to controls (928.0 ± 551.4 pg/ml vs. 176.9 ± 204.8 pg/ml; p = 0.001). No difference was found as for the Psoriasin levels in the three groups considered. Additionally, we tried to evaluate the knowledge already present in the literature about putative mechanisms of action for these molecules in the onset and development of these disorders.
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Affiliation(s)
- Marco Casciaro
- Allergy and Clinical Immunology Unit, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
| | - Donatella Vincelli
- Division of Hematology, Azienda Ospedaliera "Bianchi Melacrino Morelli", 89133 Reggio Calabria, Italy
| | - Maria Ferraro
- Institute of Traslational Pharmacology (IFT), National Research Council of Italy (CNR), 90146 Palermo, Italy
| | - Giuseppe Mirabile
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, 98125 Messina, Italy
| | - Elisabetta Pace
- Institute of Traslational Pharmacology (IFT), National Research Council of Italy (CNR), 90146 Palermo, Italy
| | - Bruno Martino
- Division of Hematology, Azienda Ospedaliera "Bianchi Melacrino Morelli", 89133 Reggio Calabria, Italy
| | - Alessandro Tonacci
- Institute of Clinical Physiology, National Research Council of Italy (IFC-CNR), Via G. Moruzzi 1, 56124 Pisa, Italy
| | - Sebastiano Gangemi
- Allergy and Clinical Immunology Unit, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
| | - Giovanni Pioggia
- Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), 98164 Messina, Italy
| | - Alessandro Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, 98125 Messina, Italy.
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Smith AP, Creagh EM. Caspase-4 and -5 Biology in the Pathogenesis of Inflammatory Bowel Disease. Front Pharmacol 2022; 13:919567. [PMID: 35712726 PMCID: PMC9194562 DOI: 10.3389/fphar.2022.919567] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 05/11/2022] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the gastrointestinal tract, associated with high levels of inflammatory cytokine production. Human caspases-4 and -5, and their murine ortholog caspase-11, are essential components of the innate immune pathway, capable of sensing and responding to intracellular lipopolysaccharide (LPS), a component of Gram-negative bacteria. Following their activation by LPS, these caspases initiate potent inflammation by causing pyroptosis, a lytic form of cell death. While this pathway is essential for host defence against bacterial infection, it is also negatively associated with inflammatory pathologies. Caspases-4/-5/-11 display increased intestinal expression during IBD and have been implicated in chronic IBD inflammation. This review discusses the current literature in this area, identifying links between inflammatory caspase activity and IBD in both human and murine models. Differences in the expression and functions of caspases-4, -5 and -11 are discussed, in addition to mechanisms of their activation, function and regulation, and how these mechanisms may contribute to the pathogenesis of IBD.
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Affiliation(s)
| | - Emma M. Creagh
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
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Caravaca AS, Levine YA, Drake A, Eberhardson M, Olofsson PS. Vagus Nerve Stimulation Reduces Indomethacin-Induced Small Bowel Inflammation. Front Neurosci 2022; 15:730407. [PMID: 35095387 PMCID: PMC8789651 DOI: 10.3389/fnins.2021.730407] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 12/16/2021] [Indexed: 12/11/2022] Open
Abstract
Crohn's disease is a chronic, idiopathic condition characterized by intestinal inflammation and debilitating gastrointestinal symptomatology. Previous studies of inflammatory bowel disease (IBD), primarily in colitis, have shown reduced inflammation after electrical or pharmacological activation of the vagus nerve, but the scope and kinetics of this effect are incompletely understood. To investigate this, we studied the effect of electrical vagus nerve stimulation (VNS) in a rat model of indomethacin-induced small intestinal inflammation. 1 min of VNS significantly reduced small bowel total inflammatory lesion area [(mean ± SEM) sham: 124 ± 14 mm2, VNS: 62 ± 14 mm2, p = 0.002], intestinal peroxidation and chlorination rates, and intestinal and systemic pro-inflammatory cytokine levels as compared with sham-treated animals after 24 h following indomethacin administration. It was not known whether this observed reduction of inflammation after VNS in intestinal inflammation was mediated by direct innervation of the gut or if the signals are relayed through the spleen. To investigate this, we studied the VNS effect on the small bowel lesions of splenectomized rats and splenic nerve stimulation (SNS) in intact rats. We observed that VNS reduced small bowel inflammation also in splenectomized rats but SNS alone failed to significantly reduce small bowel lesion area. Interestingly, VNS significantly reduced small bowel lesion area for 48 h when indomethacin administration was delayed. Thus, 1 min of electrical activation of the vagus nerve reduced indomethacin-induced intestinal lesion area by a spleen-independent mechanism. The surprisingly long-lasting and spleen-independent effect of VNS on the intestinal response to indomethacin challenge has important implications on our understanding of neural control of intestinal inflammation and its potential translation to improved therapies for IBD.
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Affiliation(s)
- April S. Caravaca
- Laboratory of Immunobiology, Department of Medicine, Karolinska University Hospital, Solna, Sweden
- MedTechLabs, BioClinicum, Stockholm Center for Bioelectronic Medicine, Karolinska University Hospital, Solna, Sweden
- SetPoint Medical, Inc., Valencia, CA, United States
| | - Yaakov A. Levine
- Laboratory of Immunobiology, Department of Medicine, Karolinska University Hospital, Solna, Sweden
- MedTechLabs, BioClinicum, Stockholm Center for Bioelectronic Medicine, Karolinska University Hospital, Solna, Sweden
- SetPoint Medical, Inc., Valencia, CA, United States
- Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, New York, NY, United States
| | - Anna Drake
- SetPoint Medical, Inc., Valencia, CA, United States
| | - Michael Eberhardson
- Laboratory of Immunobiology, Department of Medicine, Karolinska University Hospital, Solna, Sweden
- MedTechLabs, BioClinicum, Stockholm Center for Bioelectronic Medicine, Karolinska University Hospital, Solna, Sweden
- Department of Gastroenterology and Hepatology, University Hospital of Linköping, Linköping, Sweden
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Peder S. Olofsson
- Laboratory of Immunobiology, Department of Medicine, Karolinska University Hospital, Solna, Sweden
- MedTechLabs, BioClinicum, Stockholm Center for Bioelectronic Medicine, Karolinska University Hospital, Solna, Sweden
- Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, New York, NY, United States
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Dai Q, Xie D, Zhang C, Zhu L, Xu Y, Li K, Hao W, Yin H. Osthole Blocks HMGB1 Release From the Nucleus and Confers Protective Effects Against Renal Ischemia-Reperfusion Injury. Front Physiol 2022; 12:735425. [PMID: 35002751 PMCID: PMC8727455 DOI: 10.3389/fphys.2021.735425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 10/20/2021] [Indexed: 11/13/2022] Open
Abstract
Renal ischemia-reperfusion (IR) is one of the main causes of renal injury. In severe cases with serious consequences, IR-related renal damage progresses rapidly and can even lead to acute renal failure. Its clinical treatment is currently difficult. According to various studies at home and abroad, HMGB1 is released from the nucleus into the cytoplasm or extracellular space by damaged parenchymal cells during ischemia and hypoxia, and this plays an important role in the initiation of reperfusion injury as an early inflammatory factor and is closely related to the occurrence and development of renal diseases. In recent years, the protective effect of osthole on IR of tissues and organs has been a key topic among clinical researchers. Osthole can inhibit the inflammatory response, reduce cell apoptosis the progression, and improve the prognosis of IR, thus protecting the kidney. During the development of renal IR, finding a mechanism through which the osthole blocks the release of HMGB1 from the nucleus would be helpful in detecting targets for clinical treatment.
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Affiliation(s)
- Qing Dai
- Department of Nephrology, The Second People's Hospital of Yibin, Yibin, China.,North Sichuan Medical College, Nanchong, China
| | - Deqiong Xie
- Department of Nephrology, The Second People's Hospital of Yibin, Yibin, China
| | - Chenli Zhang
- Department of Nephrology, The Second People's Hospital of Yibin, Yibin, China
| | - Lei Zhu
- Department of Nephrology, The Second People's Hospital of Yibin, Yibin, China
| | - Ying Xu
- Department of Nephrology, The Second People's Hospital of Yibin, Yibin, China
| | - Kui Li
- Department of Nephrology, The Second People's Hospital of Yibin, Yibin, China
| | - Wen Hao
- Department of Nephrology, The Second People's Hospital of Yibin, Yibin, China
| | - Hefei Yin
- Department of Nephrology, The Second People's Hospital of Yibin, Yibin, China
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Ethyl pyruvate, a versatile protector in inflammation and autoimmunity. Inflamm Res 2022; 71:169-182. [PMID: 34999919 PMCID: PMC8742706 DOI: 10.1007/s00011-021-01529-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/26/2021] [Accepted: 11/27/2021] [Indexed: 12/18/2022] Open
Abstract
Ethyl pyruvate (EP) has potent influence on redox processes, cellular metabolism, and inflammation. It has been intensively studied in numerous animal models of systemic and organ-specific disorders whose pathogenesis involves a strong immune component. Here, basic chemical and biological properties of EP are discussed, with an emphasis on its redox and metabolic activity. Further, its influence on myeloid and T cells is considered, as well as on intracellular signaling beyond its effect on immune cells. Also, the effects of EP on animal models of chronic inflammatory and autoimmune disorders are presented. Finally, a possibility to apply EP as a treatment for such diseases in humans is discussed. Scientific papers cited in this review were identified using the PubMed search engine that relies on the MEDLINE database. The reference list covers the most important findings in the field in the past twenty years.
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Liu XC, Guo L, Ling KR, Hu XY, Shen YJ, Li LQ. Serum Relmβ combined with abdominal signs may predict surgical timing in neonates with NEC: A cohort study. Front Pediatr 2022; 10:943320. [PMID: 36147817 PMCID: PMC9485553 DOI: 10.3389/fped.2022.943320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
AIMS To examine the predictive value of serum biomarkers combined with other indicators for necrotizing enterocolitis (NEC) surgery decision-making. METHODS Clinical data, including baseline information, clinical features, imaging presentation and serum assessment, of the infants enrolled were collected, and the serum concentrations of HBD2, HMGB-1, Claudin-3 and Relmβ were determined. Student's t test, the Mann-Whitney U test, the chi-square test and logistic regression analysis were used. Receiver operating characteristic (ROC) curves were also generated. RESULTS Forty-nine infants were enrolled, with 23 in the surgical NEC group and 26 in the medical NEC group. There were no differences in the baseline clinical information, including birth weight, gestational age, admission age and risk factors, during pregnancy and before enrollment (P > 0.05). Peritonitis, intestinal adhesion and sepsis were more common in the surgical group (P < 0.05). The incidences of abdominal distention, abdominal wall tenseness, abdominal tenderness and absent bowel sounds in the surgical group were significantly higher when NEC occurred (P < 0.05). There were no differences between the two groups in the imaging presentation (P > 0.05). The concentration of Relmβ {[8.66 (4.29, 19.28) vs. 20.65 (9.51, 44.65)]} in the surgical group was significantly higher (P < 0.05). Abdominal wall tenseness, abdominal tenderness and a Relmβ concentration > 19.7 μmol/L were included in the predictive model, and the AUC of the predictive score was 0.943 (95% CI: 0.891-1.000) (P < 0.05). CONCLUSION Serum Relmβ concentration combined with abdominal wall tenseness and abdominal tenderness may be useful in determining surgical timing in neonates with NEC.
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Affiliation(s)
- Xiao-Chen Liu
- Neonatal Diagnosis and Treatment Centre of Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Lu Guo
- Neonatal Diagnosis and Treatment Centre of Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Ke-Ran Ling
- Neonatal Diagnosis and Treatment Centre of Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Xiao-Yu Hu
- Neonatal Diagnosis and Treatment Centre of Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Yu-Jie Shen
- Neonatal Diagnosis and Treatment Centre of Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Lu-Quan Li
- Neonatal Diagnosis and Treatment Centre of Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
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Gajić D, Despotović S, Koprivica I, Miljković Đ, Saksida T. Ethyl Pyruvate Ameliorates Experimental Autoimmune Myocarditis. Biomolecules 2021; 11:biom11121768. [PMID: 34944410 PMCID: PMC8698267 DOI: 10.3390/biom11121768] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/17/2021] [Accepted: 11/23/2021] [Indexed: 02/07/2023] Open
Abstract
Ethyl pyruvate (EP) has profound anti-inflammatory and immunomodulatory properties. Here, its effects were determined on experimental autoimmune myocarditis (EAM) induced in mice by heart-specific myosin-alpha heavy chain peptide immunization. EP was applied intraperitoneally, daily, starting with the immunization. Severity of EAM was determined by histological assessment of immune cell infiltrates into the heart. Cells were phenotypically characterized by flow cytometry. Concentration of cytokines in cell culture supernatants and sera was determined by ELISA. EP reduced the infiltration of immune cells into the heart and lessened heart inflammation. Smaller number of total immune cells, as well as of CD11b+ and CD11c+ cells were isolated from the hearts of EP-treated mice. A reduced number of antigen-presenting cells, detected by anti-CD11c, MHC class II and CD86 antibodies, as well as of T helper (Th)1 and Th17 cells, detected by anti-CD4, IFN-γ and IL-17 antibodies, was determined in mediastinal lymph nodes draining the heart, in parallel. In the spleen, only the number of CD11c+ cells were reduced, but not of the other examined populations, thus implying limited systemic effect of EP. Reduced production of IFN-γ and IL-17 by myosin-alpha heavy chain peptide-restimulated cells of the lymph nodes draining the site of immunization was observed in EP-treated mice. Our results clearly imply that EP restrains autoimmunity in EAM. Therapeutic application of EP in the treatment of myocarditis in humans should be addressed in the forthcoming studies.
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Affiliation(s)
- Dragica Gajić
- Department of Immunology, Institute for Biological Research “Siniša Stanković”—National Institute of Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, 11000 Belgrade, Serbia; (D.G.); (I.K.); (T.S.)
| | - Sanja Despotović
- Faculty of Medicine, Institute of Histology and Embryology, University of Belgrade, Dr Subotića 9, 11000 Belgrade, Serbia;
| | - Ivan Koprivica
- Department of Immunology, Institute for Biological Research “Siniša Stanković”—National Institute of Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, 11000 Belgrade, Serbia; (D.G.); (I.K.); (T.S.)
| | - Đorđe Miljković
- Department of Immunology, Institute for Biological Research “Siniša Stanković”—National Institute of Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, 11000 Belgrade, Serbia; (D.G.); (I.K.); (T.S.)
- Correspondence: ; Tel.: +381-11-2078390
| | - Tamara Saksida
- Department of Immunology, Institute for Biological Research “Siniša Stanković”—National Institute of Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, 11000 Belgrade, Serbia; (D.G.); (I.K.); (T.S.)
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11
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Investigation of H 2S Donor Treatment on Neutrophil Extracellular Traps in Experimental Colitis. Int J Mol Sci 2021; 22:ijms222312729. [PMID: 34884536 PMCID: PMC8657984 DOI: 10.3390/ijms222312729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/18/2021] [Accepted: 11/22/2021] [Indexed: 11/17/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic, immune-mediated disorders, which affect the gastrointestinal tract with intermittent ulceration. It is increasingly clear that neutrophil extracellular traps (NETs) seem to have a role in IBD; however, the associated pathogenesis is still not known. Furthermore, several conventional therapies are available against IBD, although these might have side effects. Our current study aimed to investigate the effects of hydrogen sulfide (H2S) treatment on NETs formation and on the expression of inflammatory mediators in experimental rat colitis. To model IBD, 2,4,6-trinitrobenzenesulfonic acid (TNBS) was administered intracolonically (i.c.) to Wistar-Harlan male rats. Animals were treated (2 times/day) with H2S donor Lawesson's reagent per os. Our results showed that H2S treatment significantly decreased the extent of colonic lesions. Furthermore, the expression of members of NETs formation: peptidyl arginine deiminase 4 (PAD4), citrullinated histone H3 (citH3), myeloperoxidase (MPO) and inflammatory regulators, such as nuclear transcription factor-kappa B (NF-κB) and high-mobility group box 1 (HMGB1) were reduced in H2S treated group compared to TNBS. Additionally, H2S donor administration elevated the expression of ubiquitin C-terminal hydroxylase L1 (UCHL-1), a potential anti-inflammatory mediator. Taken together, our results showed that H2S may exert anti-inflammatory effect through the inhibition of NETs formation, which suggests a new therapeutic approach against IBD.
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12
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Tan G, Huang C, Chen J, Chen B, Zhi F. Gasdermin-E-mediated pyroptosis participates in the pathogenesis of Crohn's disease by promoting intestinal inflammation. Cell Rep 2021; 35:109265. [PMID: 34133932 DOI: 10.1016/j.celrep.2021.109265] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 11/01/2020] [Accepted: 05/26/2021] [Indexed: 11/23/2022] Open
Abstract
Crohn's disease (CD) is a kind of refractory intestinal inflammatory diseases. Pyroptosis was recently identified as a gasdermin-mediated proinflammatory cell death. However, it is unclear whether gasdermin-mediated pyroptosis participates in the pathogenesis of CD. Here, we show that the pyroptosis-inducing fragment GSDME N-terminal is obviously detected in the inflamed colonic mucosa but not in the uninflamed mucosa of patients with CD, suggesting that GSDME-mediated pyroptosis may be correlated with intestinal mucosal inflammation in CD. To investigate the role of GSDME in colitis development, Gsdme-/- mice and wild-type (WT) littermate controls were treated with 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce colitis. We found that Gsdme-/- mice exhibit less-severe intestinal inflammation than WT controls do. Furthermore, our results indicate that GSDME-mediated epithelial-cell pyroptosis induces intestinal inflammation through the release of proinflammatory intracellular contents. In summary, we show that GSDME participates in the pathogenesis of CD through GSDME-mediated pyroptosis to release proinflammatory cytokines.
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Affiliation(s)
- Gao Tan
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Chongyang Huang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jiaye Chen
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Bingxia Chen
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Fachao Zhi
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
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13
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Kvivik I, Grimstad T, Jonsson G, Kvaløy JT, Omdal R. Anti-HMGB1 auto-Abs influence fatigue in patients with Crohn's disease. Innate Immun 2021; 27:286-293. [PMID: 33940970 PMCID: PMC8186155 DOI: 10.1177/17534259211014252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Fatigue is common in all chronic inflammatory and autoimmune diseases. A conceptual model for understanding the biological basis of fatigue describes it as being a part of the sickness behaviour response generated by pro-inflammatory cytokines and other mediators. We hypothesised that the pro-inflammatory high mobility group box 1 (HMGB1) protein is a fatigue-inducing molecule and that auto-Abs against HMGB1 reduce fatigue. We measured Abs against disulphide (ds) HMGB1 and fully reduced (fr) HMGB1 in plasma from 57 patients with Crohn’s disease. Fatigue was rated using the fatigue visual analogue scale (fVAS) and disease activity with faecal calprotectin, C-reactive protein and the Simple Endoscopic Score for Crohn’s disease. Multivariable regression models identified anti-dsHMGB1 and anti-frHMGB1 Abs as the strongest contributing factors for fVAS scores (B = −29.10 (P = 0.01), R2 = 0.17, and B = −17.77 (P = 0.01), R2 = 0.17, respectively). Results indicate that anti-HMGB1 auto-Abs alleviate fatigue possibly by down-regulating HMGB1-induced sickness behaviour.
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Affiliation(s)
| | - Tore Grimstad
- Unit of Gastroenterology, Department of Internal Medicine, Stavanger University Hospital, Norway.,Department of Clinical Science, Faculty of Medicine, University of Bergen, Norway
| | - Grete Jonsson
- Department of Medical Biochemistry, Stavanger University Hospital, Norway.,Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Norway
| | - Jan T Kvaløy
- Research Department, Stavanger University Hospital, Norway.,Department of Mathematics and Physics, University of Stavanger, Norway
| | - Roald Omdal
- Department of Clinical Science, Faculty of Medicine, University of Bergen, Norway.,Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Norway
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14
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Tan G, Huang C, Chen J, Zhi F. HMGB1 released from GSDME-mediated pyroptotic epithelial cells participates in the tumorigenesis of colitis-associated colorectal cancer through the ERK1/2 pathway. J Hematol Oncol 2020; 13:149. [PMID: 33160389 PMCID: PMC7648939 DOI: 10.1186/s13045-020-00985-0] [Citation(s) in RCA: 176] [Impact Index Per Article: 35.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 10/28/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Pyroptosis is a form of proinflammatory gasdermin-mediated programmed cell death. Abnormal mucosal inflammation in the intestine is a critical risk factor for colitis-associated colorectal cancer (CAC). However, it is unknown whether pyroptosis participates in the development of CAC. METHODS To investigate the role of gasdermin E (GSDME)-mediated pyroptosis in the development of CAC, Gsdme-/- mice and their wild-type (WT) littermate controls were challenged with azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce a CAC model. Neutralizing antibodies against high-mobility group box protein 1 (HMGB1) were used to determine the role of HMGB1 in CAC. To identify the role of ERK1/2 in HMGB1-induced colon cancer cell proliferation, we performed western blotting and CCK8 assays using the ERK1/2-specific inhibitor U0126 in CT26 colon cancer cells. RESULTS In the CAC model, Gsdme-/- mice exhibited reduced weight loss and colon shortening, attenuated rectal prolapse, and reduced tumor numbers and sizes compared to WT littermates. Furthermore, treatment with neutralizing anti-HMGB1 antibodies decreased the numbers and sizes of tumors, ERK1/2 activation and proliferating cell nuclear antigen (PCNA) expression in AOM/DSS-challenged WT mice. In addition, our in vitro experiments demonstrated that HMGB1 induced proliferation and PCNA expression in CT26 colon cancer cells through the ERK1/2 pathway. CONCLUSION GSDME-mediated pyroptosis promotes the development of CAC by releasing HMGB1, which induces tumor cell proliferation and PCNA expression through the ERK1/2 pathway. This finding reveals a previously unrecognized link between pyroptosis and CAC tumorigenesis and offers new insight into CAC pathogenesis.
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Affiliation(s)
- Gao Tan
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Chongyang Huang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jiaye Chen
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Fachao Zhi
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
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15
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Chen L, Li J, Ye Z, Sun B, Wang L, Chen Y, Han J, Yu M, Wang Y, Zhou Q, Seidler U, Tian D, Xiao F. Anti-High Mobility Group Box 1 Neutralizing-Antibody Ameliorates Dextran Sodium Sulfate Colitis in Mice. Front Immunol 2020; 11:585094. [PMID: 33193406 PMCID: PMC7661783 DOI: 10.3389/fimmu.2020.585094] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Accepted: 10/12/2020] [Indexed: 12/16/2022] Open
Abstract
High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein in mammals. When released into the extracellular space, it acts as a damage-associated molecular pattern. This study investigates whether increased HMGB1 levels are found in the intestinal mucosa of ulcerative colitis (UC) patients, and whether an anti-HMGB1 neutralizing-antibody (HnAb) can inhibit the intestinal inflammation elicited by dextran sulfate sodium (DSS) in mice. Because toll-like receptor 4 (TLR4) is implicated in HMGB1-mediated immune cell activation, DSS colitis was also elicited in TLR4-deficient mice in the presence and absence of HnAb. The expression of HMGB1 in UC patients was examined. HnAb was administered via intraperitoneal injection to TLR4 deficient mice and their wild-type littermates, both being induced to colitis with DSS. Finally, the protective effect of HnAb and TLR4 deficiency were evaluated. In UC patients, HMGB1 was up-regulated in the inflamed colon. When administered during DSS application, HnAb alleviated the severity of colitis with a lower disease activity index, limited histological damages, and reduced production of proinflammatory cytokines. This antibody also limited colonic barrier loss, decreased colonic lamina propria macrophages and partially reversed the DSS treatment-associated dysbiosis. The protective effect of this antibody was enhanced in TLR4-deficient mice in some aspects, indicating that both additional HMGB1-mediated as well as TLR4-mediated inflammatory signaling pathways were involved in the induction of colitis by DSS. HnAb ameliorated colitis via macrophages inhibition and colonic barrier protection. It may therefore be a novel treatment option in colitis.
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Affiliation(s)
- Liping Chen
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junhua Li
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhenghao Ye
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Binghua Sun
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lu Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China.,Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Yu Chen
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian Han
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Meiping Yu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Wang
- Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qi Zhou
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ursula Seidler
- Department of Gastroenterology, Hannover Medical School, Hannover, Germany
| | - De'an Tian
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fang Xiao
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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16
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Wang J, Fu L, Yang H, Cao K, Sun Q, Chen T. The Anti-inflammatory Effects of HMGB1 Blockades in a Mouse Model of Cutaneous Vasculitis. Front Immunol 2020; 11:2032. [PMID: 33133061 PMCID: PMC7550423 DOI: 10.3389/fimmu.2020.02032] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 07/27/2020] [Indexed: 11/19/2022] Open
Abstract
In our previous study, we have found increased serum levels of HMGB1 in patients with Henoch– Schonlein purpura (HSP), allergic vasculitis (AV), and urticarial vasculitis (UV) and altered HMGB1 distribution in lesional skin in patients with HSP. HMGB1 plays a pro-inflammatory role in the pathogenesis of HSP. To further investigate the role of HMGB1 in the pathogenic mechanism of vasculitis, we investigated the anti-inflammatory effects of HMGB1 blockades (including anti-HMGB1 mAb and glycyrrhizin) in a mouse model of a cutaneous reverse passive Arthus (RPA) reaction. A total of 36 balb/c mice were randomly divided into four groups: the control group, IC model group, HMGB1 monoclonal antibody (anti-HMGB1-mAb) group and the glycyrrhizin group, with nine mice in each group. A cutaneous RPA reaction mouse model was established by injections of the OVA antibody and the OVA antigen. Mice of the anti-HMGB1-mAb group and glycyrrhizin group were pre-treated with anti-HMGB1 mAb or glycyrrhizin, respectively, before the RPA reaction. Our results indicated that HMGB1 blockades (anti-HMGB1 mAb and glycyrrhizin) obviously extenuated the severity of vasculitis skin damage and improved the histological evolvement of inflammatory cells infiltration, vascular fibroid necrosis, and vasodilation in a cutaneous RPA reaction mouse model. In addition, HMGB1 blockades reduced the infiltration of neutrophils, DCs, and T cells and decreased the mRNA expression of IL-6 and CCL5 in skin lesions in the cutaneous RPA reaction mouse model. We suggest that HMGB1 blockades may represent a new direction for the treatment of cutaneous vasculitis.
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Affiliation(s)
- Jin Wang
- Department of Dermatovenereology, Chengdu Second People's Hospital, Chengdu, China
| | - Lixin Fu
- Department of Dermatovenereology, Chengdu Second People's Hospital, Chengdu, China
| | - Hao Yang
- Department of Dermatovenereology, Chengdu Second People's Hospital, Chengdu, China
| | - Kai Cao
- Department of Dermatovenereology, Chengdu Second People's Hospital, Chengdu, China
| | - Qiaomei Sun
- Department of Dermatovenereology, Chengdu Second People's Hospital, Chengdu, China
| | - Tao Chen
- Department of Dermatovenereology, Chengdu Second People's Hospital, Chengdu, China
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17
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Zhang YG, Zhu X, Lu R, Messer JS, Xia Y, Chang EB, Sun J. Intestinal epithelial HMGB1 inhibits bacterial infection via STAT3 regulation of autophagy. Autophagy 2019; 15:1935-1953. [PMID: 30894054 PMCID: PMC6844505 DOI: 10.1080/15548627.2019.1596485] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Revised: 02/20/2019] [Accepted: 03/01/2019] [Indexed: 12/30/2022] Open
Abstract
Extracellular HMGB1 (high mobility group box 1) is considered as a damage-associated molecular pattern protein. However, little is known about its intracellular role. We studied the mechanism whereby intestinal epithelial HMGB1 contributes to host defense, using cell culture, colonoids, conditional intestinal epithelial HMGB1-knockout mice with Salmonella-colitis, il10-/- mice, and human samples. We report that intestinal HMGB1 is an important contributor to host protection from inflammation and infection. We identified a physical interaction between HMGB1 and STAT3. Lacking intestinal epithelial HMGB1 led to redistribution of STAT3 and activation of STAT3 post bacterial infection. Indeed, Salmonella-infected HMGB1-deficient cells exhibited less macroautophagy/autophagy due to decreased expression of autophagy proteins and transcriptional repression by activated STAT3. Then, increased p-STAT3 and extranuclear STAT3 reduced autophagic responses and increased inflammation. STAT3 inhibition restored autophagic responses and reduced bacterial invasion in vitro and in vivo. Moreover, low level of HMGB1 was correlated with reduced nuclear STAT3 and enhanced p-STAT3 in inflamed intestine of il10-/- mice and inflammatory bowel disease (IBD) patients. We revealed that colonic epithelial HMGB1 was directly involved in the suppression of STAT3 activation and the protection of intestine from bacterial infection and injury. Abbreviations: ATG16L1: autophagy-related 16-like 1 (S. cerevisiae); DAMP: damage-associated molecular pattern; HBSS: Hanks balanced salt solution; HMGB1: high mobility group box 1; IBD: inflammatory bowel disease; IL1B/Il-1β: interleukin 1 beta; IL10: interleukin 10; IL17/IL-17: interleukin 17; MEFs: mouse embryonic fibroblasts; STAT3: signal transducer and activator of transcription 3; TLR: toll-like receptor; TNF/TNF-α: tumor necrosis factor.
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Affiliation(s)
- Yong-Guo Zhang
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Xiaorong Zhu
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, IL, USA
| | - Rong Lu
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Jeannette S. Messer
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, IL, USA
| | - Yinglin Xia
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Eugene B. Chang
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, IL, USA
| | - Jun Sun
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
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18
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Cheng KJ, Alshawsh MA, Mejia Mohamed EH, Thavagnanam S, Sinniah A, Ibrahim ZA. HMGB1: an overview of its versatile roles in the pathogenesis of colorectal cancer. Cell Oncol (Dordr) 2019; 43:177-193. [PMID: 31677065 DOI: 10.1007/s13402-019-00477-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/20/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In recent years, the high mobility group box-1 (HMGB1) protein, a damage-associated molecular pattern (DAMP) molecule, has been found to play multifunctional roles in the pathogenesis of colorectal cancer. Although much attention has been given to the diagnostic and prognostic values of HMGB1 in colorectal cancer, the exact functional roles of the protein as well as the mechanistic pathways involved have remained poorly defined. This systematic review aims to discuss what is currently known about the roles of HMGB1 in colorectal cancer development, growth and progression, and to highlight critical areas for future investigations. To achieve this, the bibliographic databases Pubmed, Scopus, Web of Science and ScienceDirect were systematically screened for articles from inception till June 2018, which address associations of HMGB1 with colorectal cancer. CONCLUSIONS HMGB1 plays multiple roles in promoting the pathogenesis of colorectal cancer, despite a few contradicting studies. HMGB1 may differentially regulate disease-related processes, depending on the redox status of the protein in colorectal cancer. Binding of HMGB1 to various protein partners may alter the impact of HMGB1 on disease progression. As HMGB1 is heavily implicated in the pathogenesis of colorectal cancer, it is crucial to further improve our understanding of the functional roles of HMGB1 not only in colorectal cancer, but ultimately in all types of cancers.
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Affiliation(s)
- Kim Jun Cheng
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | | | | | - Surendran Thavagnanam
- Paediatric Department, Royal London Hospital, Whitechapel Road, Whitechapel, London, E1 1BB, UK
| | - Ajantha Sinniah
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Zaridatul Aini Ibrahim
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
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19
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Chen X, Fu Y, Wang L, Qian W, Zheng F, Hou X. Bifidobacterium longum and VSL#3 ® amelioration of TNBS-induced colitis associated with reduced HMGB1 and epithelial barrier impairment. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2019; 92:77-86. [PMID: 30227219 DOI: 10.1016/j.dci.2018.09.006] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 09/11/2018] [Accepted: 09/11/2018] [Indexed: 06/08/2023]
Abstract
Probiotics are a beneficial treatment for inflammatory bowel disease (IBD). However, studies comparing the effects of similar doses of single and mixed probiotics on IBD are scarce. High mobility group box 1 (HMGB1) is an important proinflammatory mediator involved IBD development. The present study assessed fecal HMGB1 levels in IBD patients and compared the effects of similar doses of Bifidobacterium longum (Bif) versus VSL#3® on HMGB1 levels in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced murine colitis. Twenty-four mice were divided into four treatment groups (n = 6 per group): ethanol (control), TNBS, TNBS + Bif, and TNBS + VSL#3®. Bif and VSL#3® (4 × 109 CFU/dose) were administered daily by intragastric gavage, beginning 3 d before TNBS treatment, for a total of 7 d. Fecal HMGB1 levels were higher in both active IBD patients and TNBS-induced colitis mice versus their respective controls. Both Bif and VSL#3® improved intestinal inflammation and fecal microbiota imbalance in TNBS-induced colitis mice. Both treatments also reduced serum and fecal HMGB1 levels as well as increased expression of zonula occludins-1, occludin, and claudin-1 in colon tissues. In Caco-2 cells, HMGB1 reduced transepithelial electrical resistance, zonula occludins-1 protein expression, and increased paracellular permeability of FITC-dextran; the opposite was found with both probiotic treatments. These findings suggest Bif and VSL#3® have similar beneficial effects on TNBS-induced colitis, possibly through inhibition of HMGB1 release and subsequent HMGB1-mediated gut barrier dysfunction. The present study provides novel insights into probiotic treatment of IBD.
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Affiliation(s)
- Xiaohong Chen
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Fu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lingli Wang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Qian
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fang Zheng
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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20
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van den Bosch MHJ. Inflammation in osteoarthritis: is it time to dampen the alarm(in) in this debilitating disease? Clin Exp Immunol 2018; 195:153-166. [PMID: 30421798 DOI: 10.1111/cei.13237] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/02/2018] [Indexed: 12/25/2022] Open
Abstract
Osteoarthritis (OA) is the most common joint disease that strongly reduces the quality of life in patients; However, no disease-modifying therapy is available. For a long time, OA was considered a non-inflammatory disease that was the result of 'wear-and-tear' and abnormal mechanics, and therefore many considered the term 'osteoarthritis' a misnomer. However, during the last decades the notion arose that inflammation is not only present in the majority of OA patients but, rather, actively involved in the progression of the disease. Influx of immune cells is observed in the synovium and a plethora of inflammatory mediators is present in tissues and fluids from OA patients. These mediators cause the production of degrading enzymes that break down the cartilage matrix, which is the main hallmark of OA. Alarmins, which belong to the group of danger signals, have been implicated in many inflammatory diseases. They are among the first factors to be released upon cell stress due to, for example, infection, damage and inflammation. They attract and activate cells of the immune system and therefore lie at the base of the inflammatory reaction. In this narrative review, an overview of the history of OA, the evolving concept of inflammation as important factor in the OA pathogenesis, and particularly the central role that alarmins play in the initiation and maintenance of the low-grade inflammatory response in OA, is provided. Moreover, the targeting of alarmins as a promising approach to dampen the inflammation in OA is highlighted.
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Affiliation(s)
- M H J van den Bosch
- Experimental Rheumatology, Radboud university medical center, Nijmegen, the Netherlands
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21
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Nanini HF, Bernardazzi C, Castro F, de Souza HSP. Damage-associated molecular patterns in inflammatory bowel disease: From biomarkers to therapeutic targets. World J Gastroenterol 2018; 24:4622-4634. [PMID: 30416310 PMCID: PMC6224468 DOI: 10.3748/wjg.v24.i41.4622] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 10/08/2018] [Accepted: 10/16/2018] [Indexed: 02/06/2023] Open
Abstract
The chronic inflammatory process underlying inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, derives from the interplay of several components in a genetically susceptible host. These components include environmental elements and gut microbiota a dysbiosis. For decades, immune abnormalities have been investigated as critically important in IBD pathogenesis, and attempts to develop effective therapies have predominantly targeted the immune system. Nevertheless, immune events represent only one of the constituents contributing to IBD pathogenesis within the context of the complex cellular and molecular network underlying chronic intestinal inflammation. These factors need to be appreciated within the milieu of non-immune components. Damage-associated molecular patterns (DAMPs), which are essentially endogenous stress proteins expressed or released as a result of cell or tissue damage, have been shown to act as direct pro-inflammatory mediators. Excessive or persistent signalling mediated by such molecules can underlie several chronic inflammatory disorders, including IBD. The release of endogenous DAMPs amplifies the inflammatory response driven by immune and non-immune cells and promotes epigenetic reprogramming in IBD. The effects determine pathologic changes, which may sustain chronic intestinal inflammation and also underlie specific disease phenotypes. In addition to highlighting the potential use of DAMPs such as calprotectin as biomarkers, research on DAMPs may reveal novel mechanistic associations in IBD pathogenesis and is expected to uncover putative therapeutic targets.
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Affiliation(s)
- Hayandra Ferreira Nanini
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
| | - Claudio Bernardazzi
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
| | - Fernando Castro
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
| | - Heitor Siffert Pereira de Souza
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
- D’Or Institute for Research and Education (IDOR), Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro, RJ 22281-100, Brazil
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22
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Kim WK, Kwon Y, Park M, Yun S, Kwon JY, Kim H. Identification of specifically activated angiogenic molecules in HMGB-1-induced angiogenesis. BMB Rep 2018; 50:590-595. [PMID: 29065965 PMCID: PMC5720474 DOI: 10.5483/bmbrep.2017.50.11.129] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Indexed: 01/13/2023] Open
Abstract
High-mobility group box-1 (HMGB-1) is expressed in almost all cells, and its dysregulated expression correlates with inflammatory diseases, ischemia, and cancer. Some of these conditions accompany HMGB-1-mediated abnormal angiogenesis. Thus far, the mechanism of HMGB-1-induced angiogenesis remains largely unknown. In this study, we performed time-dependent DNA microarray analysis of endothelial cells (ECs) after HMGB-1 or VEGF treatment. The pathway analysis of each gene set upregulated by HMGB-1 or VEGF showed that most HMGB-1-induced angiogenic pathways were also activated by VEGF, although the activation time and gene sets belonging to the pathways differed. In addition, HMGB-1 upregulated some VEGFR signaling-related angiogenic factors including EGR1 and, importantly, novel angiogenic factors, such as ABL2, CEACAM1, KIT, and VIPR1, which are reported to independently promote angiogenesis under physiological and pathological conditions. Our findings suggest that HMGB-1 independently induces angiogenesis by activating HMGB-1-specific angiogenic factors and also functions as an accelerator for VEGF-mediated conventional angiogenesis.
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Affiliation(s)
- Won Kyu Kim
- Department of Pathology and Brain Korea 21 PLUS Projects for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Yujin Kwon
- Department of Pathology and Brain Korea 21 PLUS Projects for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Minhee Park
- Department of Pathology and Brain Korea 21 PLUS Projects for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Seongju Yun
- Department of Pathology and Brain Korea 21 PLUS Projects for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Ja-Young Kwon
- Departments of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Hoguen Kim
- Department of Pathology and Brain Korea 21 PLUS Projects for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
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23
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Wang SL, Shao BZ, Zhao SB, Fang J, Gu L, Miao CY, Li ZS, Bai Y. Impact of Paneth Cell Autophagy on Inflammatory Bowel Disease. Front Immunol 2018; 9:693. [PMID: 29675025 PMCID: PMC5895641 DOI: 10.3389/fimmu.2018.00693] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 03/21/2018] [Indexed: 12/19/2022] Open
Abstract
Intestinal mucosal barrier, mainly consisting of the mucus layer and epithelium, functions in absorbing nutrition as well as prevention of the invasion of pathogenic microorganisms. Paneth cell, an important component of mucosal barrier, plays a vital role in maintaining the intestinal homeostasis by producing antimicrobial materials and controlling the host-commensal balance. Current evidence shows that the dysfunction of intestinal mucosal barrier, especially Paneth cell, participates in the onset and progression of inflammatory bowel disease (IBD). Autophagy, a cellular stress response, involves various physiological processes, such as secretion of proteins, production of antimicrobial peptides, and degradation of aberrant organelles or proteins. In the recent years, the roles of autophagy in the pathogenesis of IBD have been increasingly studied. Here in this review, we mainly focus on describing the roles of Paneth cell autophagy in IBD as well as several popular autophagy-related genetic variants in Penath cell and the related therapeutic strategies against IBD.
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Affiliation(s)
- Shu-Ling Wang
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University and Naval Medical University, Shanghai, China
| | - Bo-Zong Shao
- Department of Pharmocology, Second Military Medical University and Naval Medical University, Shanghai, China
| | - Sheng-Bing Zhao
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University and Naval Medical University, Shanghai, China
| | - Jun Fang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Lun Gu
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University and Naval Medical University, Shanghai, China
| | - Chao-Yu Miao
- Department of Pharmocology, Second Military Medical University and Naval Medical University, Shanghai, China
| | - Zhao-Shen Li
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University and Naval Medical University, Shanghai, China
| | - Yu Bai
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University and Naval Medical University, Shanghai, China
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24
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Zheng X, Lv Y, Li S, Zhang Q, Zhang X, Hao Z. Adeno-associated virus-mediated colonic secretory expression of HMGB1 A box attenuates experimental colitis in mice. J Gene Med 2018; 18:261-272. [PMID: 27572454 DOI: 10.1002/jgm.2899] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Revised: 08/25/2016] [Accepted: 08/25/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Extracellular high mobility group box 1 (HMGB1) is crucially implicated in the pathogenesis of inflammatory bowel diseases (IBDs). A box domain of HMGB1 has been identified as a specific antagonist of HMGB1. In the present study, we tested the effects of adeno-associated virus (AAV)-mediated colonic secretory expression of HMGB1 A box on murine experimental colitis. METHODS Self-complementary AAV-2 carrying mouse immunoglobin Gκ leader-human HMGB1 A box (AAV-HMGB1 A box) was constructed. The effects of intracolonically administered AAV-HMGB1 A box on dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis were assessed by the disease activity index (DAI), colon length, macroscopic and histological scoring, myeloperoxidase (MPO) activity, and epithelial apoptosis and complementary proliferation. Colonic immune cell infiltrates, mucosal malondialdehyde content and superoxide dismutase activity, colonic tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-10 levels, serum HMGB1 concentration, and colonic HMGB1 release were determined to investigate the underlying mechanisms. RESULTS Intracolonically administered AAV-HMGB1 A box efficiently mediated secretory expression of HMGB1 A box and led to significant decreases in DAI, macroscopic and histological scores and colonic epithelial apoptosis in both DSS- and TNBS-treated mice. Modulating inflammation-associated cytokines, such as inhibiting colonic TNF-α and IL-1β expression, decreasing HMGB1 release, and restoring colonic IL-10 levels, and thereby inhibiting inflammatory cell infiltration and alleviating oxidant damage, might be the underlying mechanism. CONCLUSIONS Intracolonic application of AAV-HMGB1 A box is effective in alleviating murine colitis and has therapeutic potential in human IBDs.
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Affiliation(s)
- Xiaoyan Zheng
- Department of Rheumatology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Yifei Lv
- Department of Gastroenterology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi Province, People's Republic of China
| | - Shuang Li
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Qiannan Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Xueting Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Zhiming Hao
- Department of Rheumatology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China. .,Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China.
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25
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Komai K, Shichita T, Ito M, Kanamori M, Chikuma S, Yoshimura A. Role of scavenger receptors as damage-associated molecular pattern receptors in Toll-like receptor activation. Int Immunol 2017; 29:59-70. [PMID: 28338748 DOI: 10.1093/intimm/dxx010] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 02/22/2017] [Indexed: 12/22/2022] Open
Abstract
Damage-associated molecular patterns (DAMPs) have been implicated in sterile inflammation in various tissue injuries. High-mobility group box 1 (HMGB1) is a representative DAMP, and has been shown to transmit signals through receptors for advanced glycation end products (RAGEs) and TLRs, including TLR2 and TLR4. HMGB1 does not, however, bind to TLRs with high affinity; therefore, the mechanism of HMGB1-mediated TLR activation remains unclear. In this study, we found that fluorescently labeled HMGB1 was efficiently internalized into macrophages through class A scavenger receptors. Although both M1- and M2-type macrophages internalized HMGB1, only M1-type macrophages secreted cytokines in response to HMGB1. The pan-class A scavenger receptor competitive inhibitor, maleylated bovine serum albumin (M-BSA), inhibited HMGB1 internalization and reduced cytokine production from macrophages in response to HMGB1 but not to LPS. The C-terminal acidic domain of HMGB1 is responsible for scavenger receptor-mediated internalization and cytokine production. HMGB1 and TLR4 co-localized in macrophages, and this interaction was disrupted by M-BSA, suggesting that class A scavenger receptors function as co-receptors of HMGB1 for TLR activation. M-BSA ameliorated LPS-induced sepsis and dextran sulfate sodium (DSS)-induced colitis models in which HMGB1 has been shown to play progressive roles. These data suggest that scavenger receptors function as co-receptors along with TLRs for HMGB1 in M1-type inflammatory macrophages.
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Affiliation(s)
- Kyoko Komai
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Takashi Shichita
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Minako Ito
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Mitsuhiro Kanamori
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Shunsuke Chikuma
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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26
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Manti S, Cuppari C, Tardino L, Parisi G, Spina M, Salpietro C, Leonardi S. HMGB1 as a new biomarker of celiac disease in children: A multicenter study. Nutrition 2017; 37:18-21. [PMID: 28359357 DOI: 10.1016/j.nut.2016.12.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 12/03/2016] [Accepted: 12/17/2016] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Despite the availability of specific sierology and point-of-care tests, the phenotypic heterogeneity and the symptoms fluctuation as well as the "open-window" existing among the late and silent forms cause often a delayed celiac disease (CD) diagnosis. Recently, it has been reported that high mobility group box 1 (HMGB1) mediates inflammation and gastrointestinal barrier failure. The aim of this study was to detect serum HMGB1 levels at CD diagnosis and to evaluate the relationship between serum HMGB1 levels and clinical and histologic phenotypes. METHODS 49 CD children and 44 healthy children were enrolled. Specific antitissue transglutaminase type 2, antideaminated form of gliadin antibodies, serum HMGB1 levels, and typical histopathological changes in duodenal mucosa were performed in all patients. Mucosal lesions were classified according to Marsh classification. In relation to clinical presentation, we classified patients into: typical, atypical and silent forms. RESULTS Serum HMGB1 levels were significantly higher in those with CD than those in the healthy control group (P < 0.001). Significant differences in serum HMGB1 levels were detected in children with typical CD form compared to both children with atypical CD form (P < 0.001) and children with silent CD form (P < 0.001). By using the Marsh classification, significant differences were found between subjects with grade 3 B-B1 and 3 C-B2 and villous atrophy, respectively (P < 0.05). On the contrary, no significant differences in serum HMGB1 levels in subgroups of children with grade 3 A compared to grade 3 B-B1 were detected. CONCLUSIONS HMGB1 is upregulated at diagnosis in all CD children, especially in typical form, and reflecting the histologic severity of disease.
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Affiliation(s)
- Sara Manti
- Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy
| | - Caterina Cuppari
- Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy
| | - Lucia Tardino
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Giuseppe Parisi
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Massimo Spina
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Carmelo Salpietro
- Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy
| | - Salvatore Leonardi
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
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27
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Ueda T, Higashiyama M, Narimatsu K, Yasutake Y, Kurihara C, Okada Y, Watanabe C, Yoshikawa K, Maruta K, Komoto S, Tomita K, Nagao S, Hokari R, Miura S. Recombinant Thrombomodulin Modulates Murine Colitis Possibly via High-Mobility Group Box 1 Protein Inhibition. Digestion 2017; 92:108-19. [PMID: 26302768 DOI: 10.1159/000438507] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 07/10/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIM Thrombomodulin (TM) is an anticoagulant cofactor protein. We hypothesized that its recombinant soluble TM (rhTM) form, widely used to treat disseminated intravascular coagulation, might have anti-inflammatory action in inflammatory bowel disease (IBD), possibly through its inhibition of high-mobility group box 1 protein (HMGB1). METHODS We investigated inflammatory effects of HMGB1 and anti-inflammatory effect of rhTM in dextran sulfate sodium (DSS)-treated mice, some cell lines and ulcerative colitis (UC) patients, particularly focusing on changes of vascular endothelial adhesion molecules. RESULTS Treatments with rhTM significantly attenuated DSS-treated mice clinically and histologically. The mRNA levels of proinflammatory cytokines and adhesion molecules were decreased by rhTM. Increased inflammatory cells in the colonic mucosa strongly expressed HMGB1 in the cytoplasm in the DSS-treated mice and UC patients' colonic mucosa, which were significantly decreased by rhTM in mice. In in vitro experiments, rhTM significantly decreased the mRNA levels of tumor necrosis factor-alpha (TNF-α) and adhesion molecules increased by endotoxin exposures in RAW 264.7 (macrophage cell line) and bEND.3 cells (endothelial cell line), suggesting the proinflammatory role of HMGB1 in TNF-α production from macrophages. CONCLUSIONS These findings suggest that rhTM may be useful for the treatment of IBD by attenuating inflammatory cytokine production and adhesion molecule expression, partly because of its inhibition of HMGB1.
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Affiliation(s)
- Toshihide Ueda
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
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Glycyrrhizin ameliorates experimental colitis through attenuating interleukin-17-producing T cell responses via regulating antigen-presenting cells. Immunol Res 2017; 65:666-680. [DOI: 10.1007/s12026-017-8894-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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29
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Ke P, Shao BZ, Xu ZQ, Chen XW, Liu C. Intestinal Autophagy and Its Pharmacological Control in Inflammatory Bowel Disease. Front Immunol 2017; 7:695. [PMID: 28119697 PMCID: PMC5220102 DOI: 10.3389/fimmu.2016.00695] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2016] [Accepted: 12/28/2016] [Indexed: 12/14/2022] Open
Abstract
Intestinal mucosal barrier, mainly composed of the intestinal mucus layer and the epithelium, plays a critical role in nutrient absorption as well as protection from pathogenic microorganisms. It is widely acknowledged that the damage of intestinal mucosal barrier or the disturbance of microorganism balance in the intestinal tract contributes greatly to the pathogenesis and progression of inflammatory bowel disease (IBD), which mainly includes Crohn’s disease and ulcerative colitis. Autophagy is an evolutionarily conserved catabolic process that involves degradation of protein aggregates and damaged organelles for recycling. The roles of autophagy in the pathogenesis and progression of IBD have been increasingly studied. This present review mainly describes the roles of autophagy of Paneth cells, macrophages, and goblet cells in IBD, and finally, several potential therapeutic strategies for IBD taking advantage of autophagy.
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Affiliation(s)
- Ping Ke
- Department of Pharmacology, Second Military Medical University , Shanghai , China
| | - Bo-Zong Shao
- Department of Pharmacology, Second Military Medical University , Shanghai , China
| | - Zhe-Qi Xu
- Department of Pharmacology, Second Military Medical University , Shanghai , China
| | - Xiong-Wen Chen
- Department of Pharmacology, Second Military Medical University , Shanghai , China
| | - Chong Liu
- Department of Pharmacology, Second Military Medical University , Shanghai , China
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30
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A. Richard S, Min W, Su Z, Xu HX. Epochal neuroinflammatory role of high mobility group box 1 in central nervous system diseases. AIMS MOLECULAR SCIENCE 2017. [DOI: 10.3934/molsci.2017.2.185] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
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31
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Cheng Y, Wang D, Wang B, Li H, Xiong J, Xu S, Chen Q, Tao K, Yang X, Zhu Y, He S. HMGB1 translocation and release mediate cigarette smoke-induced pulmonary inflammation in mice through a TLR4/MyD88-dependent signaling pathway. Mol Biol Cell 2016; 28:201-209. [PMID: 27807045 PMCID: PMC5221624 DOI: 10.1091/mbc.e16-02-0126] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 10/20/2016] [Accepted: 10/26/2016] [Indexed: 02/05/2023] Open
Abstract
Cigarette smoke (CS) increases up-regulation of TLR4-mediated signaling and induces TLR4-dependent inflammation in lungs. CS exposure–induced HMGB1 translocation and release of HMGB1 controls CS-induced inflammatory response. MGB1 induces TLR4-mediated proinflammatory cytokine production and activates NF-κB and JNK/p38 pathways. We performed studies to determine the role of high-mobility group box 1 (HMGB1) in cigarette smoke (CS)–induced pulmonary inflammation. After mice were exposed to five cigarettes four times a day for 3 d, toll-like receptor 4 (TLR4) expression and TLR4-mediated signaling were significantly up-regulated, and HMGB1 had translocated from the nucleus to the cytoplasm in lung epithelial cells and then been released into the extracellular lung space. On CS exposure, inflammatory cell recruitment and proinflammatory cytokine production were significantly increased in lung tissue and bronchoalveolar lavage, and these effects depended on the TLR4 signaling pathway. HMGB1 inhibition decreased the CS-induced inflammatory response, whereas treatment with exogenous HMGB1 aggravated the damage and increased the phosphorylation of JNK, p38, and IκBα in the lungs of wild-type mice but not in TLR4-knockout mice. Blockade of TLR4 action or TLR4 knockout significantly inhibited HMGB1-induced proinflammatory cytokine production in mouse tracheal epithelial (MTE) cells and lung tissues. In addition, a MyD88 deficiency inhibited JNK, p38, and IκBα phosphorylation, and this effect was associated with the suppressed production of TNF-α and IL-1β in MTE cells and lung tissues in response to CS stimulation. Thus HMGB1 activates the NF-κB and JNK/p38 pathways through TLR4/MyD88-dependent signaling and induces an inflammatory response in lungs exposed to CS.
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Affiliation(s)
- Yao Cheng
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chong-qing 400016, China.,Department of Hepatobiliary Surgery, Second Affiliated Hospital, Chongqing Medical University, Chong-qing 400016, China
| | - Dan Wang
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chong-qing 400016, China.,Department of Respiration Medicine, Sichuan University, Chengdu, Sichuan 610041, China
| | - Bin Wang
- Institute of Life Science, Chongqing Medical University, Chong-qing 400016, China
| | - Huanan Li
- College of Biomedical Engineering, Chongqing Medical University, Chong-qing 400016, China
| | - Junjie Xiong
- Department of General Surgery, Sichuan University, Chengdu, Sichuan 610041, China
| | - Shuyun Xu
- Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Quan Chen
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chong-qing 400016, China
| | - Kun Tao
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chong-qing 400016, China
| | - Xiaoyan Yang
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chong-qing 400016, China
| | - Yu Zhu
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chong-qing 400016, China
| | - Sirong He
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chong-qing 400016, China
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Chen X, Li L, Khan MN, Shi L, Wang Z, Zheng F, Gong F, Fang M. HMGB1 exacerbates experimental mouse colitis by enhancing innate lymphoid cells 3 inflammatory responses via promoted IL-23 production. Innate Immun 2016; 22:696-705. [PMID: 27670944 DOI: 10.1177/1753425916669862] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2023] Open
Abstract
In inflammatory bowel diseases (IBD), high mobility group box 1 (HMGB1), as an endogenous inflammatory molecule, can promote inflammatory cytokines secretion by acting on TLR2/4 resulting in tissue damage. The underlying mechanisms remain unclear. Here we report a novel role of HMGB1 in controlling the maintenance and function of intestine-resident group-3 innate lymphoid cells (ILC3s) that are important innate effector cells implicated in mucosal homeostasis and IBD pathogenesis. We showed that mice treated with anti-HMGB1 Ab, or genetically deficient for TLR2-/- or TLR4-/- mice, displayed reduced intestinal inflammation. In these mice, the numbers of colonic ILC3s were significantly reduced, and the levels of IL-17 and IL-22 that can be secreted by ILC3s were also decreased in the colon tissues. Furthermore, HMGB1 promoted DCs via TLR2/4 signaling to produce IL-23, activating ILC3s to produce IL-17 and IL-22. Our data thus indicated that the HMGB1-TLR2/4-DCs-IL-23 cascade pathway enhances the functions of ILC3s to produce IL-17 and IL-22, and this signal way might play a vital role in the development of IBD.
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Affiliation(s)
- Xiangyu Chen
- 1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, P. R. China
| | - Lingyun Li
- 1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, P. R. China
| | | | - Lifeng Shi
- 1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, P. R. China
| | - Zhongyan Wang
- 1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, P. R. China
| | - Fang Zheng
- 1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, P. R. China
| | - Feili Gong
- 1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, P. R. China
| | - Min Fang
- 1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, P. R. China
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Gebremeskel S, Johnston B. Concepts and mechanisms underlying chemotherapy induced immunogenic cell death: impact on clinical studies and considerations for combined therapies. Oncotarget 2016; 6:41600-19. [PMID: 26486085 PMCID: PMC4747176 DOI: 10.18632/oncotarget.6113] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 09/22/2015] [Indexed: 01/12/2023] Open
Abstract
Chemotherapy has historically been thought to induce cancer cell death in an immunogenically silent manner. However, recent studies have demonstrated that therapeutic outcomes with specific chemotherapeutic agents (e.g. anthracyclines) correlate strongly with their ability to induce a process of immunogenic cell death (ICD) in cancer cells. This process generates a series of signals that stimulate the immune system to recognize and clear tumor cells. Extensive studies have revealed that chemotherapy-induced ICD occurs via the exposure/release of calreticulin (CALR), ATP, chemokine (C–X–C motif) ligand 10 (CXCL10) and high mobility group box 1 (HMGB1). This review provides an in-depth look into the concepts and mechanisms underlying CALR exposure, activation of the Toll-like receptor 3/IFN/CXCL10 axis, and the release of ATP and HMGB1 from dying cancer cells. Factors that influence the impact of ICD in clinical studies and the design of therapies combining chemotherapy with immunotherapy are also discussed.
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Affiliation(s)
- Simon Gebremeskel
- Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.,Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada
| | - Brent Johnston
- Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.,Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.,Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.,Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada
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34
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Reed KR, Song F, Young MA, Hassan N, Antoine DJ, Gemici NPB, Clarke AR, Jenkins JR. Secreted HMGB1 from Wnt activated intestinal cells is required to maintain a crypt progenitor phenotype. Oncotarget 2016; 7:51665-51673. [PMID: 27323825 PMCID: PMC5239505 DOI: 10.18632/oncotarget.10076] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 05/29/2016] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND AND AIMS Colorectal cancer (CRC) arises via multiple genetic changes. Mutation of the tumour suppressor gene APC, a key regulator of Wnt signalling, is recognised as a frequent early driving mutation in CRC. We have previously shown that conditional loss of Apc within the murine small intestine (Apcfloxmice) results in acute Wnt signalling activation, altered crypt-villus architecture and many hallmarks of neoplasia. Our transctipomic profiling (Affymetrix Microarrays) and proteomic profiling (iTRAQ-QSTAR) of Apc-deficient intestine inferred the involvement of High Mobility Group Box 1 (Hmgb1) in CRC pathogenesis. Here we assess the contribution of HMGB1 to the crypt progenitor phenotype seen following Apc loss. RESULTS Elevated HMGB1 was confirmed in intestinal epithelia and serum following conditional loss of Apc. Treatment of Apcflox mice with anti-HMGB1 neutralising antibody significantly reduced many of the crypt progenitor phenotypes associated with Apc loss; proliferation and apoptosis levels were reduced, cell differentiation was restored and the expansion of stem cell marker expression was eradicated. METHODS Hmgb1 levels in intestinal epithelia and serum in Apcflox and ApcMin mice were assessed using qRT-PCR, Western blot and ELISA assays. The functional importance of elevated extracellular Hmgb1 was assessed using an anti-HMGB1 neutralising antibody in Apcflox mice. CONCLUSIONS HMGB1 is expressed and secreted from intestinal epithelial cells in response to Wnt signalling activation. This secreted HMGB1 is required to maintain nearly all aspects of the crypt progenitor phenotype observed following Apc loss and add to the body of accumulating evidence indicating that targeting HMGB1 may be a viable novel therapeutic approach.
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Affiliation(s)
- Karen R. Reed
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, CF24 4HQ, UK
| | - Fei Song
- Infrafrontier GmbH, Neuherberg / München, 85764, Germany
- Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, UK
| | - Maddy A. Young
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, CF24 4HQ, UK
| | - Nurudeen Hassan
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, CF24 4HQ, UK
- Cardiff School of Health Sciences at Cardiff Metropolitan University, Cardiff, CF5 2YB, UK
| | - Daniel J. Antoine
- Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, UK
| | - Nesibe-Princess B. Gemici
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, CF24 4HQ, UK
| | - Alan R. Clarke
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, CF24 4HQ, UK
| | - John R. Jenkins
- Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, UK
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Venereau E, De Leo F, Mezzapelle R, Careccia G, Musco G, Bianchi ME. HMGB1 as biomarker and drug target. Pharmacol Res 2016; 111:534-544. [PMID: 27378565 DOI: 10.1016/j.phrs.2016.06.031] [Citation(s) in RCA: 187] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 06/29/2016] [Accepted: 06/30/2016] [Indexed: 12/27/2022]
Abstract
High Mobility Group Box 1 protein was discovered as a nuclear protein, but it has a "second life" outside the cell where it acts as a damage-associated molecular pattern. HMGB1 is passively released or actively secreted in a number of diseases, including trauma, chronic inflammatory disorders, autoimmune diseases and cancer. Extracellular HMGB1 triggers and sustains the inflammatory response by inducing cytokine release and by recruiting leucocytes. These characteristics make extracellular HMGB1 a key molecular target in multiple diseases. A number of strategies have been used to prevent HMGB1 release or to inhibit its activities. Current pharmacological strategies include antibodies, peptides, decoy receptors and small molecules. Noteworthy, salicylic acid, a metabolite of aspirin, has been recently found to inhibit HMGB1. HMGB1 undergoes extensive post-translational modifications, in particular acetylation and oxidation, which modulate its functions. Notably, high levels of serum HMGB1, in particular of the hyper-acetylated and disulfide isoforms, are sensitive disease biomarkers and are associated with different disease stages. In the future, the development of isoform-specific HMGB1 inhibitors may potentiate and fine-tune the pharmacological control of inflammation. We review here the current therapeutic strategies targeting HMGB1, in particular the emerging and relatively unexplored small molecules-based approach.
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Affiliation(s)
- Emilie Venereau
- Chromatin Dynamics Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; HMGBiotech s.r.l., Milan, Italy
| | - Federica De Leo
- Biomolecular NMR Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Rosanna Mezzapelle
- Chromatin Dynamics Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giorgia Careccia
- Chromatin Dynamics Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; University of Milano Bicocca, Milan, Italy
| | - Giovanna Musco
- Biomolecular NMR Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Marco E Bianchi
- Chromatin Dynamics Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; San Raffaele University, Milan, Italy.
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Boyapati RK, Rossi AG, Satsangi J, Ho GT. Gut mucosal DAMPs in IBD: from mechanisms to therapeutic implications. Mucosal Immunol 2016; 9:567-82. [PMID: 26931062 DOI: 10.1038/mi.2016.14] [Citation(s) in RCA: 113] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 12/31/2015] [Indexed: 02/06/2023]
Abstract
Endogenous damage-associated molecular patterns (DAMPs) are released during tissue damage and have increasingly recognized roles in the etiology of many human diseases. The inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn's disease (CD), are immune-mediated conditions where high levels of DAMPs are observed. DAMPs such as calprotectin (S100A8/9) have an established clinical role as a biomarker in IBD. In this review, we use IBD as an archetypal common chronic inflammatory disease to focus on the conceptual and evidential importance of DAMPs in pathogenesis and why DAMPs represent an entirely new class of targets for clinical translation.
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Affiliation(s)
- R K Boyapati
- MRC Centre for Inflammation Research, Queens Medical Research Institute, Edinburgh, UK.,Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, UK
| | - A G Rossi
- MRC Centre for Inflammation Research, Queens Medical Research Institute, Edinburgh, UK
| | - J Satsangi
- Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, UK
| | - G-T Ho
- MRC Centre for Inflammation Research, Queens Medical Research Institute, Edinburgh, UK.,Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, UK
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Nguyen A, Bhavsar S, Riley E, Caponetti G, Agrawal D. Clinical Value of High Mobility Group Box 1 and the Receptor for Advanced Glycation End-products in Head and Neck Cancer: A Systematic Review. Int Arch Otorhinolaryngol 2016; 20:382-389. [PMID: 27746844 PMCID: PMC5063723 DOI: 10.1055/s-0036-1583168] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 02/28/2016] [Indexed: 01/04/2023] Open
Abstract
Introduction High mobility group box 1 is a versatile protein involved in gene transcription, extracellular signaling, and response to inflammation. Extracellularly, high mobility group box 1 binds to several receptors, notably the receptor for advanced glycation end-products. Expression of high mobility group box 1 and the receptor for advanced glycation end-products has been described in many cancers. Objectives To systematically review the available literature using PubMed and Web of Science to evaluate the clinical value of high mobility group box 1 and the receptor for advanced glycation end-products in head and neck squamous cell carcinomas. Data synthesis A total of eleven studies were included in this review. High mobility group box 1 overexpression is associated with poor prognosis and many clinical and pathological characteristics of head and neck squamous cell carcinomas patients. Additionally, the receptor for advanced glycation end-products demonstrates potential value as a clinical indicator of tumor angiogenesis and advanced staging. In diagnosis, high mobility group box 1 demonstrates low sensitivity. Conclusion High mobility group box 1 and the receptor for advanced glycation end-products are associated with clinical and pathological characteristics of head and neck squamous cell carcinomas. Further investigation of the prognostic and diagnostic value of these molecules is warranted.
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Affiliation(s)
- Austin Nguyen
- Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, Nebraska, United States
| | - Sheila Bhavsar
- Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, Nebraska, United States
| | - Erinn Riley
- Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, Nebraska, United States
| | - Gabriel Caponetti
- Department of Pathology, Creighton University School of Medicine, Omaha, Nebraska, United States
| | - Devendra Agrawal
- Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, Nebraska, United States
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Pandolfi F, Altamura S, Frosali S, Conti P. Key Role of DAMP in Inflammation, Cancer, and Tissue Repair. Clin Ther 2016; 38:1017-28. [PMID: 27021609 DOI: 10.1016/j.clinthera.2016.02.028] [Citation(s) in RCA: 126] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Revised: 02/29/2016] [Accepted: 02/29/2016] [Indexed: 12/30/2022]
Abstract
PURPOSE This review aimed to take stock of the current status of research on damage-associated molecular pattern (DAMP) protein. We discuss the Janus-faced role of DAMP molecules in inflammation, cancer, and tissue repair. The high-mobility group box (HMGB)-1 and adenosine triphosphate proteins are well-known DAMP molecules and have been primarily associated with inflammation. However, as we shall see, recent data have linked these molecules to tissue repair. HMGB1 is associated with cancer-related inflammation. It activates nuclear factor kB, which is involved in cancer regulation via its receptor for advanced glycation end-products (RAGE), Toll-like receptors 2 and 4. Proinflammatory activity and tissue repair may lead to pharmacologic intervention, by blocking DAMP RAGE and Toll like receptor 2 and 4 role in inflammation and by increasing their concentration in tissue repair, respectively. METHODS We conducted a MEDLINE search for articles pertaining to the various issues related to DAMP, and we discuss the most relevant articles especially (ie, not only those published in journals with a higher impact factor). FINDINGS A cluster of remarkable articles on DAMP have appeared in the literature in recent years. Regarding inflammation, several strategies have been proposed to target HMGB1, from antibodies to recombinant box A, which interacts with RAGE, competing with the full molecule. In tissue repair, it was reported that the overexpression of HMGB1 or the administration of exogenous HMGB1 significantly increased the number of vessels and promoted recovery in skin-wound, ischemic injury. IMPLICATIONS Due to the bivalent nature of DAMP, it is often difficult to explain the relative role of DAMP in inflammation versus its role in tissue repair. However, this point is crucial as DAMP-related treatments move into clinical practice.
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Affiliation(s)
- Franco Pandolfi
- Department of Internal Medicine, School of Medicine, Catholic University, Rome, Italy.
| | - Simona Altamura
- Department of Internal Medicine, School of Medicine, Catholic University, Rome, Italy
| | - Simona Frosali
- Department of Internal Medicine, School of Medicine, Catholic University, Rome, Italy
| | - Pio Conti
- Postgraduate Medical School, Chieti University, Chieti, Italy
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rhHMGB1 drives osteoblast migration in a TLR2/TLR4- and NF-κB-dependent manner. Biosci Rep 2016; 36:e00300. [PMID: 26744383 PMCID: PMC4759610 DOI: 10.1042/bsr20150239] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 01/06/2016] [Indexed: 02/02/2023] Open
Abstract
Osteoblast migration is significant in skeletal development. Recently, high mobility group box 1 protein (HMGB1) has been shown to highly expressed in cartilage to regulate endochondral ossification. Nevertheless, whether HMGB1 can modulate osteoblast proliferation and migration is poorly understood, as well as the intracellular signalling pathways that are involved in this process. Herein, we examined the effects of recombinant human HMGB1 (rhHMGB1) on the proliferation and migration of rat osteoblasts and investigated whether Toll-like receptor 2 (TLR2)- and TLR4-dependent signalling pathways are involved in the regulation of intracellular signalling. A transwell chamber assay was used to evaluate the migration of osteoblasts and the MTT assay was used to assess osteoblast proliferation. rhHMGB1 could significantly promote the migration of osteoblasts without inhibiting their proliferation. Meanwhile, rhHMGB1 can increase the nuclear translocation of nuclear factor-kappa B (NF-κB) p65. Specific siRNA constructs that target TLR2 or TLR4 could markedly inhibit HMGB1-induced migration of osteoblasts and HMGB1-enhanced activation of NF-κB. Collectively, HMGB1 could significantly enhance the migration of osteoblasts in vitro, and TLR2/TLR4-dependent NF-κB pathways are involved in HMGB1-induced osteoblast migration.
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Abstract
IBD is a chronic inflammatory condition of the gastrointestinal tract encompassing two main clinical entities: Crohn's disease and ulcerative colitis. Although Crohn's disease and ulcerative colitis have historically been studied together because they share common features (such as symptoms, structural damage and therapy), it is now clear that they represent two distinct pathophysiological entities. Both Crohn's disease and ulcerative colitis are associated with multiple pathogenic factors including environmental changes, an array of susceptibility gene variants, a qualitatively and quantitatively abnormal gut microbiota and a broadly dysregulated immune response. In spite of this realization and the identification of seemingly pertinent environmental, genetic, microbial and immune factors, a full understanding of IBD pathogenesis is still out of reach and, consequently, treatment is far from optimal. An important reason for this unsatisfactory situation is the currently limited comprehension of what are the truly relevant components of IBD immunopathogenesis. This article will comprehensively review current knowledge of the classic immune components and will expand the concept of IBD immunopathogenesis to include various cells, mediators and pathways that have not been traditionally associated with disease mechanisms, but that profoundly affect the overall intestinal inflammatory process.
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Affiliation(s)
- Heitor S P de Souza
- Department of Gastroenterology &Multidisciplinary Research Laboratory, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil
| | - Claudio Fiocchi
- Department of Pathobiology, Lerner Research Institute, Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
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Ethyl pyruvate ameliorates experimental colitis in mice by inhibiting the HMGB1-Th17 and Th1/Tc1 responses. Int Immunopharmacol 2015; 29:454-461. [DOI: 10.1016/j.intimp.2015.10.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 09/09/2015] [Accepted: 10/14/2015] [Indexed: 12/15/2022]
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HMGB1 induction of clusterin creates a chemoresistant niche in human prostate tumor cells. Sci Rep 2015; 5:15085. [PMID: 26469759 PMCID: PMC4606829 DOI: 10.1038/srep15085] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 09/10/2015] [Indexed: 02/07/2023] Open
Abstract
Development of chemoresistance, especially to docetaxel (DTX), is the primary barrier to the cure of castration-resistant prostate cancer but its mechanism is obscure. Here, we report a seminal crosstalk between dying and residual live tumor cells during treatment with DTX that can result in outgrowth of a chemoresistant population. Survival was due to the induction of secretory/cytoplasmic clusterin (sCLU), which is a potent anti-apoptotic protein known to bind and sequester Bax from mitochondria, to prevent caspase 3 activation. sCLU induction in live cells depended on HMGB1 release from dying cells. Supernatants from DTX-treated DU145 tumor cells, which were shown to contain HMGB1, effectively induced sCLU from newly-plated DU145 tumor cells and protected them from DTX toxicity. Addition of anti-HMBG1 to the supernatant or pretreatment of newly-plated DU145 tumor cells with anti-TLR4 or anti-RAGE markedly abrogated sCLU induction and protective effect of the supernatant. Mechanistically, HMGB1 activated NFκB to promote sCLU gene expression and prevented the translocation of activated Bax to mitochondria to block cell death. Importantly, multiple currently-used chemotherapeutic drugs could release HMGB1 from tumor cells. These results suggest that acquisition of chemoresistance may involve the HMGB1/TLR4-RAGE/sCLU pathway triggered by dying cells to provide survival advantage to remnant live tumor cells.
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Zhu X, Sun L, Wang Y. High mobility group box 1 (HMGB1) is upregulated by the Epstein-Barr virus infection and promotes the proliferation of human nasopharyngeal carcinoma cells. Acta Otolaryngol 2015; 136:87-94. [PMID: 26382001 DOI: 10.3109/00016489.2015.1082192] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
CONCLUSION The current study confirmed the significant high mobility group box 1 (HMGB1) was promoted in human nasopharyngeal carcinoma (NPC) tissues by Epstein-Barr virus (EBV) infection, in association with the malignant status of NPC, and promoted the proliferation NPC cells RAGE-dependently. OBJECTIVES The present study was to examine the association of HMGB1 over-expression in human NPC with the EBV-positivity and to determine the regulatory role of HMGB1 on the proliferation of NPC cells in vitro. METHODS Real-time PCR and Western blotting were utilized to examine the HMGB1 expression. EBV infection in CNE-2 cells was performed to investigate the HMGB1 promotion by EBV infection. RNA interference technology was utilized for the RAGE knockout. RESULTS It was demonstrated that HMGB1 was significantly higher in both mRNA and protein levels in the EBV-positive NPC tissues, in marked association with the malignant status of NPC, and with the LMP1 DNA level in EBV-positive NPC samples. In addition, the MTT assay, growth curve, and the colony forming assay confirmed the promotion by HMGB1 to the proliferation of CNE-2 cells, depending on RAGE.
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Affiliation(s)
- Xuewei Zhu
- a Department of Otolaryngology, Head & Neck Surgery , China-Japan Union Hospital, Jilin University , Changchun , PR China and
| | - Le Sun
- b Department of Otolaryngology, Head & Neck Surgery , First Hospital of Jilin University , Changchun , PR China
| | - Yusheng Wang
- b Department of Otolaryngology, Head & Neck Surgery , First Hospital of Jilin University , Changchun , PR China
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Yao L, Zhao H, Tang H, Song J, Dong H, Zou F, Cai S. Chicken IgY facilitates allergic airway inflammation in a chemical-induced murine asthma model by potentiating IL-4 release. Toxicol Lett 2015; 239:22-31. [PMID: 26341180 DOI: 10.1016/j.toxlet.2015.08.1108] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Revised: 08/25/2015] [Accepted: 08/29/2015] [Indexed: 10/23/2022]
Abstract
High mobility group box 1 (HMGB1) is a DNA-binding protein that is abundantly expressed in most tissues. Recently, HMGB1 has gained much attention for its regulation of immunity and inflammation. Yet its role in toluene diisocyanate (TDI)-induced asthma still remains poorly characterized. In this study, mice were sensitized and challenged with TDI to establish a TDI-induced asthma model. An IgY anti-HMGB1 antibody or isotype IgY was given intraperitoneally after each challenge. Airway reactivity to methacholine, airway inflammation, bronchial epithelial hyperplasia and shedding were unexpectedly aggravated after administration of the anti-HMGB1 antibody and was accompanied by increased pulmonary expression of HMGB1, especially in those mice treated with IgY. Levels of IL-4, IL-5, IL-13 and TNF-α were also elevated with TDI-induction. Primary lymphocytes from TDI sensitized and challenged mice demonstrated increased secretion of IL-4 after IgY stimulation. To confirm the effect of IgY, a cohort of mice exposed to TDI or vehicle was injected with IgY and the same results were observed after IgY treatment as in TDI asthmatic mice. Taken together, these results show that the IgY anti-HMGB1 antibody can facilitate TDI-induced allergic airway inflammation. Specifically, IgY, rather than anti-HMGB1, plays an important role in the process of exacerbated asthma, shedding light on an underappreciated role of avian IgY.
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Affiliation(s)
- Lihong Yao
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Haijin Zhao
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Haixiong Tang
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jiafu Song
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Hangming Dong
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Fei Zou
- School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Shaoxi Cai
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
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Hu Z, Wang X, Gong L, Wu G, Peng X, Tang X. Role of high-mobility group box 1 protein in inflammatory bowel disease. Inflamm Res 2015; 64:557-63. [PMID: 26077468 DOI: 10.1007/s00011-015-0841-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Revised: 06/07/2015] [Accepted: 06/08/2015] [Indexed: 12/16/2022] Open
Abstract
High-mobility group box 1 (HMGB1) protein is a nuclear non-histone DNA-binding protein. It is released into the extracellular milieu and mediates inflammatory responses, which contribute to the pathogenesis of numerous inflammatory diseases, including inflammatory bowel disease (IBD). An online search was performed in PubMed and Web of Science databases for articles providing evidence on the role of HMGB1 in IBD. HMGB1 plays an important role in IBD pathogenesis. Application of HMGB1 antagonists reduced inflammatory reactions and ameliorated colitis in rodent models, which may provide new insights into the diagnosis and treatment of IBD.
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Affiliation(s)
- Zhen Hu
- Division of Gastroenterology, Wuxi No.2 Hospital Affiliated to Nanjing Medical University, Zhong Shan Road 68, Wuxi, Jiang Su, China
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Scarpa M, Kessler S, Sadler T, West G, Homer C, McDonald C, de la Motte C, Fiocchi C, Stylianou E. The epithelial danger signal IL-1α is a potent activator of fibroblasts and reactivator of intestinal inflammation. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:1624-37. [PMID: 25864926 DOI: 10.1016/j.ajpath.2015.02.018] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 01/26/2015] [Accepted: 02/03/2015] [Indexed: 12/19/2022]
Abstract
Intestinal epithelial cell (IEC) death is typical of inflammatory bowel disease (IBD). We investigated: i) whether IEC-released necrotic cell products (proinflammatory mediators) amplify mucosal inflammation, ii) the capacity of necrotic cell lysates from HT29 cells or human IECs to induce human intestinal fibroblasts' (HIF) production of IL-6 and IL-8, and iii) whether IL-1α, released by injured colonocytes, exacerbated experimental IBD. Necrotic cell lysates potently induced HIF IL-6 and IL-8 production independent of Toll-like receptors 2 and 4, receptor for advanced glycation end-products, high-mobility group box 1, uric acid, IL-33, or inflammasome activation. IL-1α was the key IEC-derived necrotic cell product involved in HIF cytokine production. IL-1α-positive cells were identified in the epithelium in human IBD and dextran sulfate sodium (DSS)-induced colitis. IL-1α was detected in the stool of colitic mice before IL-1β. IL-1α enemas reactivated inflammation after DSS colitis recovery, induced IL-1 receptor expression in subepithelial fibroblasts, and activated de novo inflammation even in mice without overt colitis, after the administration of low-dose DSS. IL-1α amplifies gut inflammation by inducing cytokine production by mesenchymal cells. IL-1α-mediated IEC-fibroblast interaction may be involved in amplifying and perpetuating inflammation, even without obvious intestinal damage. IL-1α may be a target for treating early IBD or preventing the reactivation of IBD.
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Affiliation(s)
- Melania Scarpa
- Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio
| | - Sean Kessler
- Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio
| | - Tammy Sadler
- Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio
| | - Gail West
- Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio
| | - Craig Homer
- Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio
| | - Christine McDonald
- Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Carol de la Motte
- Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio; Department of Gastroenterology & Hepatology, Digestive Disease Institute, Cleveland, Ohio
| | - Claudio Fiocchi
- Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio; Department of Gastroenterology & Hepatology, Digestive Disease Institute, Cleveland, Ohio
| | - Eleni Stylianou
- Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio; Department of Gastroenterology & Hepatology, Digestive Disease Institute, Cleveland, Ohio.
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Wang JL, Wu DW, Cheng ZZ, Han WZ, Xu SW, Sun NN. Expression of high mobility group box - B1 (HMGB-1) and matrix metalloproteinase-9 (MMP-9) in non-small cell lung cancer (NSCLC). Asian Pac J Cancer Prev 2015; 15:4865-9. [PMID: 24998555 DOI: 10.7314/apjcp.2014.15.12.4865] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE This study evaluated the expression level of high mobility group box-B1 (HMGB-1) and matrix metalloproteinase-9 (MMP-9) in non-small cell lung cancer (NSCLC) inmorder to reveal any relation with development and prognosis. METHODS NSCLC and normal tissues were selected from 30 patients at age of 30- 73, and used for RT-PCR and Western blot analyses of HMGB-1. A total of 100 paraffin embedded NSCLC tissues were also isolated from patients through surgical resection, and used for detection of HMGB-1 by immunohistochemistry. In addition, 50 samples were also applied for MMP-9 detection, and 30 normal tissues were considered as controls. Correlation analysis of HMGB-1 and MMP-9 was carried out by Pearsons correlation coefficient. RESULTS The average expression level of HMGB-1 in NSCLC patients was significantly higher than in normal lung tissues. In addition, patients in III-IV period exhibit significantly higher positive rate of HMGB- 1 when compared with I-II period cases. Furthermore, a positive correlation with HMGB-1 was found in the expression of MPP-9. CONCLUSION HMGB-1 was highly expressed in NSCLC, which may become a prognostic and predictive marker for NSCLC. Besides, MPP-9 was positively correlated with HMGB-1.
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Affiliation(s)
- Jing-Luan Wang
- Department of Critical Care Medicine, Qilu Hospital, Shandong University, Jinan, China E-mail :
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Abe A, Kuwata T, Yamauchi C, Higuchi Y, Ochiai A. High Mobility Group Box1 (HMGB1) released from cancer cells induces the expression of pro-inflammatory cytokines in peritoneal fibroblasts. Pathol Int 2015; 64:267-75. [PMID: 24965109 DOI: 10.1111/pin.12167] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Accepted: 04/13/2014] [Indexed: 11/28/2022]
Abstract
High Mobility Group Box1 protein (HMGB1), one of the mediators of inflammation, is associated with tumorigenesis. The HMGB1-Receptor for advanced glycation end-products (RAGE) in gastric adenocarcinoma tissues promoted gastric cancer growth, however, there are no reports concerning the relationship between the expression of HMGB1 in gastric cancer and cancer-related inflammation. Fibroblasts exist most abundantly on cancer tissue where inflammation occurs. So, we studied the effects of HMGB1 released from cancer cells on the fibroblasts. The expression of HMGB1 in cancer cells and nuclear factor-kappa B (NF-kB) in fibroblasts were evaluated immunohistochemically in human gastric cancer specimens. Cytoplasmic HMGB1 expression in the cancer cells and nuclear translocation of NF-kB in fibroblasts were detected at deeper invasion. To determine whether HMGB1 released from cancer cells induces the expression of pro-inflammatory cytokines in fibroblasts, we analyzed the activation of Toll-like receptor (TLR) signaling. Fibroblasts stimulated by recombinant HMGB1 and the HSC44PE-conditioned medium showed the phosphorylation of Interleukin-1 receptor associated-kinase 4 (IRAK4), nuclear translocation of NF-kB, and enhanced pro-inflammatory cytokine expression. Treatment with HSC44PE-conditioned-medium transfected with siRNA-HMGB1 reduced the expressions of pro-inflammatory cytokines in the fibroblasts. We propose that HMGB1 released from cancer cells induces the expression of pro-inflammatory cytokines in peritoneal fibroblasts through the HMGB1-TLR2/4 pathway.
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Affiliation(s)
- Anna Abe
- Laboratory of Cancer Biology, Department of Integrated Bioscience, Graduate School of Frontier Science, The University of Tokyo; Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
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Kang R, Chen R, Zhang Q, Hou W, Wu S, Cao L, Huang J, Yu Y, Fan XG, Yan Z, Sun X, Wang H, Wang Q, Tsung A, Billiar TR, Zeh HJ, Lotze MT, Tang D. HMGB1 in health and disease. Mol Aspects Med 2014; 40:1-116. [PMID: 25010388 PMCID: PMC4254084 DOI: 10.1016/j.mam.2014.05.001] [Citation(s) in RCA: 731] [Impact Index Per Article: 66.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 05/05/2014] [Indexed: 12/22/2022]
Abstract
Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed high-mobility group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhibitors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localization, structure, post-translational modification, and identification of additional partners will undoubtedly uncover additional secrets regarding HMGB1's multiple functions.
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Affiliation(s)
- Rui Kang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
| | - Ruochan Chen
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Qiuhong Zhang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Wen Hou
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Sha Wu
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Lizhi Cao
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Jin Huang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yan Yu
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xue-Gong Fan
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Zhengwen Yan
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA; Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Xiaofang Sun
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Experimental Department of Institute of Gynecology and Obstetrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China
| | - Haichao Wang
- Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA
| | - Qingde Wang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Allan Tsung
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Herbert J Zeh
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Michael T Lotze
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Daolin Tang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
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Ju Z, Chavan SS, Antoine DJ, Dancho M, Tsaava T, Li J, Lu B, Levine YA, Stiegler A, Tamari Y, Al-Abed Y, Roth J, Tracey KJ, Yang H. Sequestering HMGB1 via DNA-conjugated beads ameliorates murine colitis. PLoS One 2014; 9:e103992. [PMID: 25127031 PMCID: PMC4134190 DOI: 10.1371/journal.pone.0103992] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Accepted: 07/09/2014] [Indexed: 01/03/2023] Open
Abstract
Inflammatory bowel disease (IBD) is chronic inflammation of the gastrointestinal tract that affects millions of people worldwide. Although the etiology of IBD is not clear, it is known that products from stressed cells and enteric microbes promote intestinal inflammation. High mobility group box 1 (HMGB1), originally identified as a nuclear DNA binding protein, is a cytokine-like protein mediator implicated in infection, sterile injury, autoimmune disease, and IBD. Elevated levels of HMGB1 have been detected in inflamed human intestinal tissues and in feces of IBD patients and mouse models of colitis. Neutralizing HMGB1 activity by administration of anti-HMGB1 antibodies or HMGB1-specific antagonist improves clinical outcomes in animal models of colitis. Since HMGB1 binds to DNA with high affinity, here we developed a novel strategy to sequester HMGB1 using DNA immobilized on sepharose beads. Screening of DNA-bead constructs revealed that B2 beads, one linear form of DNA conjugated beads, bind HMGB1 with high affinity, capture HMGB1 ex vivo from endotoxin-stimulated RAW 264.7 cell supernatant and from feces of mice with colitis. Oral administration of B2 DNA beads significantly improved body weight, reduced colon injury, and suppressed colonic and circulating cytokine levels in mice with spontaneous colitis (IL-10 knockout) and with dextran sulfate sodium-induced colitis. Thus, DNA beads reduce inflammation by sequestering HMGB1 and may have therapeutic potential for the treatment of IBD.
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Affiliation(s)
- Zhongliang Ju
- Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Sangeeta S. Chavan
- Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Daniel J. Antoine
- MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Meghan Dancho
- Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Teá Tsaava
- Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Jianhua Li
- Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Ben Lu
- Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Yaakov A. Levine
- SetPoint Medical Corporation, Valencia, California, United States of America
| | - Andrew Stiegler
- Circulatory Technology Inc., Oyster Bay, New York, United States of America
| | - Yehuda Tamari
- Circulatory Technology Inc., Oyster Bay, New York, United States of America
| | - Yousef Al-Abed
- Medicinal Chemistry, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Jesse Roth
- Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Kevin J. Tracey
- Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Huan Yang
- Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
- * E-mail:
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