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1
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Na YR, Jung D, Song J, Park JW, Hong JJ, Seok SH. Pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages. J Mol Cell Biol 2021; 12:543-555. [PMID: 31900478 PMCID: PMC7493030 DOI: 10.1093/jmcb/mjz113] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 09/11/2019] [Accepted: 11/09/2019] [Indexed: 02/07/2023] Open
Abstract
Interleukin-10 (IL-10) is the most potent anti-inflammatory cytokine in the body and plays an essential role in determining outcomes of many inflammatory diseases. Cellular metabolism is a critical determinant of immune cell function; however, it is currently unclear whether metabolic processes are specifically involved in IL-10 production. In this study, we aimed to find the central metabolic molecule regulating IL-10 production of macrophages, which are the main producers of IL-10. Transcriptomic analysis identified that metabolic changes were predominantly enriched in Kupffer cells at the early inflammatory phase of a mouse endotoxemia model. Among them, pyruvate dehydrogenase kinase (PDK)-dependent acute glycolysis was negatively involved in IL-10 production. Inhibition or knockdown of PDK selectively increased macrophage IL-10 expression. Mechanistically, PDK inhibition increased IL-10 production via profound phosphorylation of adenosine monophosphate (AMP)-activated protein kinase alpha 1 (AMPKα1) by restricting glucose uptake in lipopolysaccharide-stimulated macrophages. AMPKα1 consequently activated p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and cyclic AMP-responsive element-binding protein to regulate IL-10 production. Our study uncovers a previously unknown regulatory mechanism of IL-10 in activated macrophages involving an immunometabolic function of PDK.
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Affiliation(s)
- Yi Rang Na
- Macrophage Lab, Department of Microbiology and Immunology and Institute of Endemic Disease, Seoul National University College of Medicine, Chongno-gu, Seoul 03080, Republic of Korea
| | - Daun Jung
- Macrophage Lab, Department of Microbiology and Immunology and Institute of Endemic Disease, Seoul National University College of Medicine, Chongno-gu, Seoul 03080, Republic of Korea
| | - Juha Song
- Macrophage Lab, Department of Microbiology and Immunology and Institute of Endemic Disease, Seoul National University College of Medicine, Chongno-gu, Seoul 03080, Republic of Korea
| | - Jong-Wan Park
- Department of Biomedical Science, BK21-Plus Education Program, Seoul National University College of Medicine, Jongno-gu, Seoul 03080, Republic of Korea.,Department of Pharmacology, Seoul National University College of Medicine, Jongno-gu, Seoul 03080, Republic of Korea.,Cancer Research Institute and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Jongno-gu, Seoul 03080, Republic of Korea
| | - Jung Joo Hong
- National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea
| | - Seung Hyeok Seok
- Macrophage Lab, Department of Microbiology and Immunology and Institute of Endemic Disease, Seoul National University College of Medicine, Chongno-gu, Seoul 03080, Republic of Korea
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2
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Zwicker C, Bujko A, Scott CL. Hepatic Macrophage Responses in Inflammation, a Function of Plasticity, Heterogeneity or Both? Front Immunol 2021; 12:690813. [PMID: 34177948 PMCID: PMC8220199 DOI: 10.3389/fimmu.2021.690813] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Accepted: 05/21/2021] [Indexed: 12/12/2022] Open
Abstract
With the increasing availability and accessibility of single cell technologies, much attention has been given to delineating the specific populations of cells present in any given tissue. In recent years, hepatic macrophage heterogeneity has also begun to be examined using these strategies. While previously any macrophage in the liver was considered to be a Kupffer cell (KC), several studies have recently revealed the presence of distinct subsets of hepatic macrophages, including those distinct from KCs both under homeostatic and non-homeostatic conditions. This heterogeneity has brought the concept of macrophage plasticity into question. Are KCs really as plastic as once thought, being capable of responding efficiently and specifically to any given stimuli? Or are the differential responses observed from hepatic macrophages in distinct settings due to the presence of multiple subsets of these cells? With these questions in mind, here we examine what is currently understood regarding hepatic macrophage heterogeneity in mouse and human and examine the role of heterogeneity vs plasticity in regards to hepatic macrophage responses in settings of both pathogen-induced and sterile inflammation.
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Affiliation(s)
- Christian Zwicker
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium
| | - Anna Bujko
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium
| | - Charlotte L. Scott
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium
- Department of Chemical Sciences, Bernal Institute, University of Limerick, Limerick, Ireland
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3
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Lehmann C, Aali M, Zhou J, Holbein B. Comparison of Treatment Effects of Different Iron Chelators in Experimental Models of Sepsis. Life (Basel) 2021; 11:life11010057. [PMID: 33466819 PMCID: PMC7830599 DOI: 10.3390/life11010057] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/09/2021] [Accepted: 01/11/2021] [Indexed: 01/19/2023] Open
Abstract
Growing evidence indicates that dysregulated iron metabolism with altered and excess iron availability in some body compartments plays a significant role in the course of infection and sepsis in humans. Given that all bacterial pathogens require iron for growth, that iron withdrawal is a normal component of innate host defenses and that bacterial pathogens have acquired increasing levels of antibiotic resistance, targeting infection and sepsis through use of appropriate iron chelators has potential to provide new therapeutics. We have directly compared the effects of three Food and Drug Administration (FDA)-approved chelators (deferoxamine—DFO; deferiprone—DFP; and deferasirox—DFX), as were developed for treating hematological iron overload conditions, to DIBI, a novel purpose-designed, anti-infective and anti-inflammatory water-soluble hydroxypyridinone containing iron-selective copolymers. Two murine sepsis models, endotoxemia and polymicrobial abdominal sepsis, were utilized to help differentiate anti-inflammatory versus anti-infective activities of the chelators. Leukocyte adhesion, as measured by intravital microscopy, was observed in both models, with DIBI providing the most effective reduction and DFX the poorest. Inflammation in the abdominal sepsis model, assessed by cytokine measurements, indicated exacerbation by DFX and DFO for plasma Interleukin (IL)-6 and reductions to near-control levels for DIBI and DFP. Peritoneal infection burden was reduced 10-fold by DIBI while DFX and DFP provided no reductions. Overall, the results, together with those from other studies, revealed serious limitations for each of the three hematological chelators, i.e., as potentially repurposed for treating infection/sepsis. In contrast, DIBI provided therapeutic benefits, consistent with various in vitro and in vivo results from other studies, supporting the potential for its use in treating sepsis.
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Affiliation(s)
- Christian Lehmann
- Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada;
- Correspondence:
| | - Maral Aali
- Department of Physiology and Biophysics, Dalhousie University, Halifax, NS B3H 4R2, Canada;
| | - Juan Zhou
- Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada;
| | - Bruce Holbein
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada;
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Kim TH, Yang K, Kim M, Kim HS, Kang JL. Apoptosis inhibitor of macrophage (AIM) contributes to IL-10-induced anti-inflammatory response through inhibition of inflammasome activation. Cell Death Dis 2021; 12:19. [PMID: 33414479 PMCID: PMC7791024 DOI: 10.1038/s41419-020-03332-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 12/08/2020] [Accepted: 12/10/2020] [Indexed: 01/29/2023]
Abstract
Apoptosis inhibitor of macrophage (AIM) modulates the signaling in inflammatory responses, including infection, cancer, or other immune diseases. Recent studies suggest that like interleukin-10 (IL-10), AIM is involved in alternatively activated (M2) macrophage polarization. We aimed to understand whether and how AIM is involved in IL-10-induced inhibition of inflammasome activation and resolution of inflammation. First, we demonstrated that IL-10 induced increases in mRNA and protein expression of AIM in murine bone marrow-derived macrophages (BMDM). In addition, genetic and pharmacologic inhibition of STAT3 (signal transducer and activator of transcription 3) reduced IL-10-induced AIM expression. We also found that IL-10-induced STAT3 activity enhanced the AIM promoter activity by directly binding the promoter of the AIM gene. Additionally, reduction of LPS/adenosine triphosphate (ATP)-induced IL-1β production and caspase-1 activation by IL-10 was reversed in BMDM from AIM-/- mice. Treatment of BMDM from both wild type (WT) and IL-10-/- mice with recombinant AIM showed the inhibitory effects on IL-1β and IL-18 production and caspase-1 activation. Endogenous and exogenous AIM inhibited apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) speck formation. In LPS-induced acute peritonitis, inhibition of IL-1β and IL-18 production in peritoneal lavage fluid (PLF) and serum, reduction of caspase-1 activation in peritoneal macrophages, and reduction of numbers of neutrophils and peritoneal macrophages in PLF by administration of IL-10 were not evident in AIM-/- mice. Our in vitro and in vivo data reveal a novel role of AIM in the inhibition of inflammasome-mediated caspase-1 activation and IL-1β and IL-18 production.
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Affiliation(s)
- Tae-Hyun Kim
- grid.255649.90000 0001 2171 7754Department of Physiology, College of Medicine, Ewha Womans University, Seoul, 07804 Korea
| | - Kyungwon Yang
- grid.255649.90000 0001 2171 7754Department of Physiology, College of Medicine, Ewha Womans University, Seoul, 07804 Korea ,grid.255649.90000 0001 2171 7754Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, Seoul, 07804 Korea
| | - Minsuk Kim
- grid.255649.90000 0001 2171 7754Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, Seoul, 07804 Korea ,grid.255649.90000 0001 2171 7754Department of Pharmacology, College of Medicine, Ewha Womans University, Seoul, 07804 Korea
| | - Hee-Sun Kim
- grid.255649.90000 0001 2171 7754Department of Molecular Medicine, College of Medicine, Ewha Womans University, Seoul, 07804 Korea
| | - Jihee Lee Kang
- grid.255649.90000 0001 2171 7754Department of Physiology, College of Medicine, Ewha Womans University, Seoul, 07804 Korea ,grid.255649.90000 0001 2171 7754Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, Seoul, 07804 Korea
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5
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Howe M, Bauer J, Schulze A, Kropp S, Locksley RM, Alferink J, Weighardt H, Scheu S. Production of IFNβ by Conventional Dendritic Cells after Stimulation with Viral Compounds and IFNβ-Independent IFNAR1-Signaling Pathways are Associated with Aggravation of Polymicrobial Sepsis. Int J Mol Sci 2019; 20:ijms20184410. [PMID: 31500303 PMCID: PMC6770674 DOI: 10.3390/ijms20184410] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 09/01/2019] [Accepted: 09/05/2019] [Indexed: 12/27/2022] Open
Abstract
Viral infections are associated with increased incidence of severe sepsis. Particularly during the early stages, type I interferons (IFNs) are known mediators of detrimental effects. However, the functional role of early interferon β (IFNβ) and its cellular source during sepsis in the context of preexisting viral infections has not been defined. Using the colon ascendens stent peritonitis (CASP) model, we demonstrate that IFNβ−/− and type I IFN receptor (IFNAR1)−/− mice were less susceptible to sepsis after pre-stimulation with the viral mimetic poly(I:C). Wild type (WT) mice treated with poly(I:C) exhibited altered expression patterns of TNF and IL-12p40 during CASP which were dependent on IFNβ or IFNAR1, suggesting a mechanism for the increased sepsis susceptibility of WT mice. Using a double cytokine reporter mouse model, we present novel data on the simultaneous expression of IFNβ and IL-12p40 on a single cell level during polymicrobial sepsis in vivo. Conventional dendritic cells (cDCs) were identified as primary source of IFNβ and the protective cytokine IL-12p40 after CASP surgery irrespective of poly(I:C) pre-stimulation. These data demonstrated that if polymicrobial sepsis is preceded by a viral infection, IFNβ and IL-12p40 are expressed by polyfunctional cDCs suggesting that these cells can play both detrimental and beneficial roles during sepsis development.
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Affiliation(s)
- Magdalena Howe
- Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Jens Bauer
- Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Anja Schulze
- Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Sonja Kropp
- Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Richard M Locksley
- Howard Hughes Medical Institute and Departments of Medicine and Microbiology/Immunology, University of California, San Francisco, CA 94143, USA
| | - Judith Alferink
- Department of Psychiatry, University of Münster, 48149 Münster, Germany
- Cluster of Excellence EXC 1003, Cells in Motion, 48149 Münster, Germany
| | - Heike Weighardt
- Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany
| | - Stefanie Scheu
- Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
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6
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Li HM, Jang JH, Jung JS, Shin J, Park CO, Kim YJ, Ahn WG, Nam JS, Hong CW, Lee J, Jung YJ, Chen JF, Ravid K, Lee HT, Huh WK, Kabarowski JH, Song DK. G2A Protects Mice against Sepsis by Modulating Kupffer Cell Activation: Cooperativity with Adenosine Receptor 2b. THE JOURNAL OF IMMUNOLOGY 2018; 202:527-538. [PMID: 30530591 DOI: 10.4049/jimmunol.1700783] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 11/04/2018] [Indexed: 01/01/2023]
Abstract
G2A is a GPCR abundantly expressed in immune cells. G2A-/- mice showed higher lethality, higher plasma cytokines, and an impaired bacterial clearance in response to a murine model of sepsis (cecal ligation and puncture), which were blocked by GdCl3, an inhibitor of Kupffer cells. Anti-IL-10 Ab reversed the impaired bacterial clearance in G2A-/- mice. Indomethacin effectively blocked both the increased i.p. IL-10 levels and the impaired bacterial clearance, indicating that disturbed PG system is the proximal cause of these phenomena. Stimulation with LPS/C5a induced an increase in Escherichia coli phagocytosis and intracellular cAMP levels in G2A+/+ peritoneal macrophages but not G2A-/- cells, which showed more PGE2/nitrite release and intracellular reactive oxygen species levels. Heterologous coexpression of G2A and adenosine receptor type 2b (A2bAR) induced a synergistic increase in cAMP signaling in a ligand-independent manner, with the evidence of physical interaction of G2A with A2bAR. BAY 60-6583, a specific agonist for A2bAR, increased intracellular cAMP levels in Kupffer cells from G2A+/+ but not from G2A-/- mice. Both G2A and A2bAR were required for antiseptic action of lysophosphatidylcholine. These results show inappropriate activation of G2A-/- Kupffer cells to septic insults due to an impaired cAMP signaling possibly by lack of interaction with A2bAR.
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Affiliation(s)
- Hong-Mei Li
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, Chuncheon, Gangwon-do 24252, Republic of Korea
| | - Ji Hye Jang
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, Chuncheon, Gangwon-do 24252, Republic of Korea
| | - Jun-Sub Jung
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, Chuncheon, Gangwon-do 24252, Republic of Korea
| | - Jiseon Shin
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, Chuncheon, Gangwon-do 24252, Republic of Korea
| | - Chul O Park
- Department of Biological Sciences, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul 08826, Korea
| | - Yeon-Ja Kim
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, Chuncheon, Gangwon-do 24252, Republic of Korea
| | - Won-Gyun Ahn
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, Chuncheon, Gangwon-do 24252, Republic of Korea
| | - Ju-Suk Nam
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, Chuncheon, Gangwon-do 24252, Republic of Korea
| | - Chang-Won Hong
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, Chuncheon, Gangwon-do 24252, Republic of Korea
| | - Jongho Lee
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, Chuncheon, Gangwon-do 24252, Republic of Korea
| | - Yu-Jin Jung
- Department of Biological Sciences, Kangwon National University, Chuncheon, Gangwon-do 24341, Republic of Korea
| | - Jiang-Fan Chen
- Department of Neurology, Boston University School of Medicine, Boston, MA 02118
| | - Katya Ravid
- Departments of Medicine and Biochemistry, Boston University School of Medicine, Boston, MA 02118
| | - H Thomas Lee
- Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, NY 10032; and
| | - Won-Ki Huh
- Department of Biological Sciences, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul 08826, Korea
| | - Janusz H Kabarowski
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294
| | - Dong-Keun Song
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, Chuncheon, Gangwon-do 24252, Republic of Korea;
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7
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Smirnov A, Pohlmann S, Nehring M, Ali S, Mann-Nüttel R, Scheu S, Antoni AC, Hansen W, Büettner M, Gardiasch MJ, Westendorf AM, Wirsdörfer F, Pastille E, Dudda M, Flohé SB. Sphingosine 1-Phosphate- and C-C Chemokine Receptor 2-Dependent Activation of CD4 + Plasmacytoid Dendritic Cells in the Bone Marrow Contributes to Signs of Sepsis-Induced Immunosuppression. Front Immunol 2017; 8:1622. [PMID: 29218051 PMCID: PMC5703700 DOI: 10.3389/fimmu.2017.01622] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 11/08/2017] [Indexed: 12/24/2022] Open
Abstract
Sepsis is the dysregulated response of the host to systemic, mostly bacterial infection, and is associated with an enhanced susceptibility to life-threatening opportunistic infections. During polymicrobial sepsis, dendritic cells (DCs) secrete enhanced levels of interleukin (IL) 10 due to an altered differentiation in the bone marrow and contribute to the development of immunosuppression. We investigated the origin of the altered DC differentiation using murine cecal ligation and puncture (CLP), a model for human polymicrobial sepsis. Bone marrow cells (BMC) were isolated after sham or CLP operation, the cellular composition was analyzed, and bone marrow-derived DCs (BMDCs) were generated in vitro. From 24 h on after CLP, BMC gave rise to BMDC that released enhanced levels of IL-10. In parallel, a population of CD11chiMHCII+CD4+ DCs expanded in the bone marrow in a MyD88-dependent manner. Prior depletion of the CD11chiMHCII+CD4+ DCs from BMC in vitro reversed the increased IL-10 secretion of subsequently differentiating BMDC. The expansion of the CD11chiMHCII+CD4+ DC population in the bone marrow after CLP required the function of sphingosine 1-phosphate receptors and C-C chemokine receptor (CCR) 2, the receptor for C-C chemokine ligand (CCL) 2, but was not associated with monocyte mobilization. CD11chiMHCII+CD4+ DCs were identified as plasmacytoid DCs (pDCs) that had acquired an activated phenotype according to their increased expression of MHC class II and CD86. A redistribution of CD4+ pDCs from MHC class II− to MHC class II+ cells concomitant with enhanced expression of CD11c finally led to the rise in the number of CD11chiMHCII+CD4+ DCs. Enhanced levels of CCL2 were found in the bone marrow of septic mice and the inhibition of CCR2 dampened the expression of CD86 on CD4+ pDCs after CLP in vitro. Depletion of pDCs reversed the bias of splenic DCs toward increased IL-10 synthesis after CLP in vivo. Thus, during polymicrobial sepsis, CD4+ pDCs are activated in the bone marrow and induce functional reprogramming of differentiating BMDC toward an immunosuppressive phenotype.
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Affiliation(s)
- Anna Smirnov
- Department of Orthopedics and Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Stephanie Pohlmann
- Department of Orthopedics and Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Melanie Nehring
- Department of Orthopedics and Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Shafaqat Ali
- Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany.,Cells in Motion, Cluster of Excellence, University of Münster, Münster, Germany
| | - Ritu Mann-Nüttel
- Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany
| | - Stefanie Scheu
- Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany
| | - Anne-Charlotte Antoni
- Department of Orthopedics and Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Wiebke Hansen
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Manuela Büettner
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
| | - Miriam J Gardiasch
- Department of Orthopedics and Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Astrid M Westendorf
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Florian Wirsdörfer
- Medical Faculty, Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany
| | - Eva Pastille
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Marcel Dudda
- Department of Orthopedics and Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Stefanie B Flohé
- Department of Orthopedics and Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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8
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Bala S, Csak T, Kodys K, Catalano D, Ambade A, Furi I, Lowe P, Cho Y, Iracheta-Vellve A, Szabo G. Alcohol-induced miR-155 and HDAC11 inhibit negative regulators of the TLR4 pathway and lead to increased LPS responsiveness of Kupffer cells in alcoholic liver disease. J Leukoc Biol 2017; 102:487-498. [PMID: 28584078 PMCID: PMC6608073 DOI: 10.1189/jlb.3a0716-310r] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 04/11/2017] [Accepted: 05/04/2017] [Indexed: 12/13/2022] Open
Abstract
Inflammation promotes the progression of alcoholic liver disease. Alcohol sensitizes KCs to gut-derived endotoxin (LPS); however, signaling pathways that perpetuate inflammation in alcoholic liver disease are only partially understood. We found that chronic alcohol feeding in mice induced miR-155, an inflammatory miRNA in isolated KCs. We hypothesized that miR-155 might increase the responsiveness of KCs to LPS via targeting the negative regulators of LPS signaling. Our results revealed that KCs that were isolated from alcohol-fed mice showed a decrease in IRAK-M, SHIP1, and PU.1, and an increase in TNF-α levels. This was specific to KCs, as no significant differences were observed in these genes in hepatocytes. We found a causal effect of miR-155 deficiency on LPS responsiveness, as KCs that were isolated from miR-155 KO mice showed a greater induction of IRAK-M, SHIP1, and suppressor of cytokine signaling 1 after LPS treatment. C/EBPβ, a validated miR-155 target, stimulates IL-10 transcription. We found a higher induction of C/EBPβ and IL-10 in KCs that were isolated from miR-155 KO mice after LPS treatment. Gain- and loss-of-function studies affirmed that alcohol-induced miR-155 directly regulates IRAK-M, SHIP1, suppressor of cytokine signaling 1, and C/EBPβ, as miR-155 inhibition increased and miR-155 overexpression decreased these genes in LPS or alcohol-pretreated wild-type KCs. HDAC11, a regulator of IL-10, was significantly increased and IL-10 was decreased in KCs that were isolated from alcohol-fed mice. Functionally, knockdown of HDAC11 with small interfering RNA resulted in an IL-10 increase in LPS or alcohol-pretreated Mϕ. We found that acetaldehyde and NF-κB pathways regulate HDAC11 levels. Collectively, our results indicate that the alcohol-induced responsiveness of KCs to LPS, in part, is governed by miR-155 and HDAC11.
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Affiliation(s)
- Shashi Bala
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Timea Csak
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Karen Kodys
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Donna Catalano
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Aditya Ambade
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Istvan Furi
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Patrick Lowe
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Yeonhee Cho
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Arvin Iracheta-Vellve
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
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9
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Cavaillon JM, Annane D. Invited review: Compartmentalization of the inflammatory response in sepsis and SIRS. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/09680519060120030301] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Sepsis and systemic inflammatory response syndrome (SIRS) are associated with an exacerbated production of both pro- and anti-inflammatory mediators that are mainly produced within tissues. Although a systemic process, the pathophysiological events differ from organ to organ, and from organ to peripheral blood, leading to the concept of compartmentalization. The nature of the insult ( e.g. burn, hemorrhage, trauma, peritonitis), the cellular composition of each compartment ( e.g . nature of phagocytes, nature of endothelial cells), and its micro-environment ( e.g. local presence of granulocyte-macrophage colony stimulating factor [GM-CSF] in the lungs, low levels of arginine in the liver, release of endotoxin from the gut), and leukocyte recruitment, have a great influence on local inflammation and on tissue injury. High levels of pro-inflammatory mediators ( e.g. interleukin-1 [IL-1], tumor necrosis factor [TNF], gamma interferon [IFN-γ], high mobility group protein-1 [HMGB1], macrophage migration inhibitory factor [MIF]) produced locally and released into the blood stream initiate remote organ injury as a consequence of an organ cross-talk. The inflammatory response within the tissues is greatly influenced by the local delivery of neuromediators by the cholinergic and sympathetic neurons. Acetylcholine and epinephrine contribute with IL-10 and other mediators to the anti-inflammatory compensatory response initiated to dampen the inflammatory process. Unfortunately, this regulatory response leads to an altered immune status of leukocytes that can increase the susceptibility to further infection. Again, the nature of the insult, the nature of the leukocytes, the presence of circulating microbial components, and the nature of the triggering agent employed to trigger cells, greatly influence the immune status of the leukocytes that may differ from one compartment to another. While anti-inflammatory mediators predominate within the blood stream to avoid igniting new inflammatory foci, their presence within tissues may not always be sufficient to prevent the initiation of a deleterious inflammatory response in the different compartments.
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Affiliation(s)
| | - Djillali Annane
- Service de Réanimation, Hôpital Raymond Poincaré, Assistance Publique - Hôpitaux de Paris, Faculté de Médecine Paris Ile de France Ouest, Université de Versailles Saint-Quentin-en-Yvelines, Garches, France
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Abstract
Sepsis is a serious clinical problem involving complex mechanisms which requires better understanding and insight. Animal models of sepsis have played a major role in providing insight into the complex pathophysiology of sepsis. There have been various animal models of sepsis with different paradigms. Endotoxin, bacterial infusion, cecal ligation and puncture, and colon ascendens stent peritonitis models are the commonly practiced methods at present. Each of these models has their own advantages and also confounding factors. We have discussed the underlying mechanisms regulating each of these models along with possible reasons why each model failed to translate into the clinic. In animal models, the timing of development of the hemodynamic phases and the varied cytokine patterns could not accurately resemble the progression of clinical sepsis. More often, the exuberant and transient pro-inflammatory cytokine response is only focused in most models. Immunosuppression and apoptosis in the later phase of sepsis have been found to cause more damage than the initial acute phase of sepsis. Likewise, better understanding of the existing models of sepsis could help us create a more relevant model which could provide solution to the currently failed clinical trials in sepsis.
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Differential contribution of complement receptor C5aR in myeloid and non-myeloid cells in chronic ethanol-induced liver injury in mice. Mol Immunol 2016; 75:122-32. [PMID: 27280845 DOI: 10.1016/j.molimm.2016.05.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Revised: 05/05/2016] [Accepted: 05/07/2016] [Indexed: 01/06/2023]
Abstract
BACKGROUND Complement is implicated in the development of alcoholic liver disease. C3 and C5 contribute to ethanol-induced liver injury; however, the role of C5a receptor (C5aR) on myeloid and non-myeloid cells to progression of injury is not known. METHODS C57BL/6 (WT), global C5aR-/-, myeloid-specific C5aR-/-, and non-myeloid-specific C5aR-/- mice were fed a Lieber-DeCarli diet (32%kcal EtOH) for 25 days. Cultured hepatocytes were challenged with ethanol, TNFα, and C5a. RESULTS Chronic ethanol feeding increased expression of pro-inflammatory mediators in livers of WT mice; this response was completely blunted in C5aR-/- mice. However, C5aR-/- mice were not protected from other measures of hepatocellular damage, including ethanol-induced increases in hepatic triglycerides, plasma alanine aminotransferase and hepatocyte apoptosis. CYP2E1 and 4-hydroxynonenal protein adducts were induced in WT and C5aR-/- mice. Myeloid-specific C5aR-/- mice were protected from ethanol-induced increases in hepatic TNFα, whereas non-myeloid-specific C5aR-/- displayed increased hepatocyte apoptosis and inflammation after chronic ethanol feeding. In cultured hepatocytes, cytotoxicity induced by challenge with ethanol and TNFα was completely eliminated by treatment with C5a in cells from WT, but not C5aR-/- mice. Further, treatment with C5a enhanced activation of pro-survival signal AKT in hepatocytes challenged with ethanol and TNFα. CONCLUSION Taken together, these data reveal a differential role for C5aR during ethanol-induced liver inflammation and injury, with C5aR on myeloid cells contributing to ethanol-induced inflammatory cytokine expression, while non-myeloid C5aR protects hepatocytes from death after chronic ethanol feeding.
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12
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Zhang Q, Deng C, Fu Y, Sun X, Gong T, Zhang Z. Repeated Administration of Hyaluronic Acid Coated Liposomes with Improved Pharmacokinetics and Reduced Immune Response. Mol Pharm 2016; 13:1800-8. [PMID: 27112287 DOI: 10.1021/acs.molpharmaceut.5b00952] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Quan Zhang
- Key
Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of
Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
- School
of Pharmacy, Chengdu Medical College, Chengdu 610083, China
| | - Caifeng Deng
- Key
Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of
Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yao Fu
- Key
Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of
Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Xun Sun
- Key
Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of
Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Tao Gong
- Key
Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of
Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Zhirong Zhang
- Key
Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of
Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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13
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Lauer S, Fischer LG, Van Aken HK, Nofer JR, Freise H. Gadolinium chloride modulates bradykinin-induced pulmonary vasoconstriction and hypoxic pulmonary vasoconstriction during polymicrobial abdominal sepsis in rats. Exp Lung Res 2016; 41:270-82. [PMID: 26052827 DOI: 10.3109/01902148.2015.1018557] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Macrophages importantly contribute to sepsis-induced lung injury. As their impact on pulmonary endothelial injury and dysregulation of hypoxic pulmonary vasoconstriction (HPV) remains unclear, we assessed pulmonary endothelial dysfunction and HPV by macrophage inhibition via gadolinium chloride (GC) pre-treatment in rats with peritonitis (cecal ligation and puncture [CLP]). METHODS The following four study groups were made: Group I: SHAM and group II: SHAM + GC (pre-treatment with NaCl 0.9% or GC 14 mg/kg body weight (b.w.) intravenously 24 hours prior to sham laparotomy); group III: CLP and group IV: CLP + GC (pre-treatment with NaCl 0.9% or GC 14 mg/kg b.w. 24 hours prior to induction of peritonitis). Exhaled nitric oxide (exNO), bradykinin-induced pulmonary vasoconstriction (=surrogate marker of endothelial dysfunction) and HPV were investigated in isolated and perfused lungs (n = 40). Using the same protocol wet to dry lung weight ratio and myeloperoxidase (MPO) activity were investigated in separate rats (n = 28). In additional rats (n = 12) of groups III and IV nitrite levels in alveolar macrophages (AM) were measured. RESULTS In sepsis, GC pre-treatment significantly attenuated exNO levels, AM-derived nitrite levels, lung MPO activity, and restored blunted HPV, but severely enhanced endothelial dysfunction in healthy and septic animals. CONCLUSION Macrophages exhibit a controversial role in sepsis-induced lung injury. The GC-induced restoration of inflammation parameters to sham levels is clearly limited by the negative impact on CLP-induced endothelial injury in this setting. The exact link between the GC-associated modulation of the NO pathway demonstrated and septic lung injury needs to be determined in future studies.
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Affiliation(s)
- Stefan Lauer
- 1Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital of Muenster , Muenster , Germany
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14
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Liao YR, Lin JY. Quercetin intraperitoneal administration ameliorates lipopolysaccharide-induced systemic inflammation in mice. Life Sci 2015. [DOI: 10.1016/j.lfs.2015.07.015] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Abstract
Sepsis can be defined as a systemic inflammatory response syndrome occurring in the presence of an infectious source. Over the past 25 years, numerous guidelines have been established to clarify definitions and improve the overall management of clinical sepsis. In light of these multiple paradigm shifts, this review attempts to summarize the innate immunologic alterations that manifest during sepsis, establish and compare mouse models of sepsis with the clinical course, and discuss the authors' views on additional elements that should be considered in modeling and predicting clinical sepsis from the standpoint of a basic research setting.
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Affiliation(s)
- Peter Chen
- Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada
| | - Mile Stanojcic
- Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada
| | - Marc G Jeschke
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada; Division of Plastic Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Ross Tilley Burn Centre, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
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A Petri net model of granulomatous inflammation: implications for IL-10 mediated control of Leishmania donovani infection. PLoS Comput Biol 2013; 9:e1003334. [PMID: 24363630 PMCID: PMC3867212 DOI: 10.1371/journal.pcbi.1003334] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2013] [Accepted: 09/27/2013] [Indexed: 11/30/2022] Open
Abstract
Experimental visceral leishmaniasis, caused by infection of mice with the protozoan parasite Leishmania donovani, is characterized by focal accumulation of inflammatory cells in the liver, forming discrete “granulomas” within which the parasite is eventually eliminated. To shed new light on fundamental aspects of granuloma formation and function, we have developed an in silico Petri net model that simulates hepatic granuloma development throughout the course of infection. The model was extensively validated by comparison with data derived from experimental studies in mice, and the model robustness was assessed by a sensitivity analysis. The model recapitulated the progression of disease as seen during experimental infection and also faithfully predicted many of the changes in cellular composition seen within granulomas over time. By conducting in silico experiments, we have identified a previously unappreciated level of inter-granuloma diversity in terms of the development of anti-leishmanial activity. Furthermore, by simulating the impact of IL-10 gene deficiency in a variety of lymphocyte and myeloid cell populations, our data suggest a dominant local regulatory role for IL-10 produced by infected Kupffer cells at the core of the granuloma. Granulomatous inflammation is a common feature of chronic infectious and non-infectious disease. In the parasitic disease visceral leishmaniasis, the formation of granulomas in the liver is a hallmark of effective cellular immunity and host resistance to infection. Conventional experimental models, however, have inherent limitations in their capacity to assess the dynamics of this complex inflammatory response and in their ability to discriminate the local contribution of different immune cells and mediators to the outcome of infection. To overcome these limitations and to provide a future platform for evaluating how novel drugs might be used to improve host resistance, we have developed a computational model of the Leishmania granuloma. Using this model, we show that conventional measures of parasite load potentially mask an underlying heterogeneity in the ability of individual granulomas to control parasite number. In addition, we have used our model to provide novel insights into the relative importance of IL-10 production by different immune cells found within the granuloma microenvironment. Our model thus provides a complementary tool to increase understanding of granulomatous inflammation in this and other important human diseases.
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Zimmermann HW, Reuken PA, Koch A, Bartneck M, Adams DH, Trautwein C, Stallmach A, Tacke F, Bruns T. Soluble urokinase plasminogen activator receptor is compartmentally regulated in decompensated cirrhosis and indicates immune activation and short-term mortality. J Intern Med 2013; 274:86-100. [PMID: 23432143 DOI: 10.1111/joim.12054] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Patients with decompensated cirrhosis are susceptible to bacterial infections, which are associated with organ failure and a high mortality rate. Reliable biomarkers are needed to identify patients who require intensified treatment. Our objective was to study the regulation and prognostic relevance of elevated concentrations of soluble urokinase plasminogen activator receptor (suPAR) in patients with advanced cirrhosis. DESIGN, SETTING AND PARTICIPANTS We examined the associations between serum and ascitic fluid (AF) suPAR and liver function, bacterial infection, and short-term mortality in 162 consecutive patients with decompensated cirrhosis undergoing diagnostic paracentesis in a tertiary health care centre in Germany. MAIN OUTCOME MEASURE Twenty-eight-day mortality. RESULTS Circulating suPAR levels were increased in patients with decompensated cirrhosis and correlated with the severity of liver dysfunction and systemic inflammation but were not indicative of bacterial infection. Circulating suPAR levels >14.4 ng mL(-1) predicted 28-day mortality, even after adjustment for liver function and confounders [HR = 3.05 (1.35-6.90); P = 0.0076] equal to the MELD score (AUC = 0.71; 95% CI = 0.61-0.81; P < 0.001). Cut-off levels derived from cohorts without liver disease were not applicable due to the low specificity. AF suPAR levels were elevated during spontaneous bacterial peritonitis (SBP), but not during episodes in which bacteria or bacterial DNA was translocated into the ascites. AF suPAR levels correlated poorly with systemic suPAR but were associated with a more severe course of SBP and a worse outcome. In vitro experiments revealed that monocytes, and to a lesser extent neutrophils, secrete suPAR after Toll-like-receptor ligation, which led to rapid urokinase plasminogen activator receptor cleavage followed by increased synthesis. CONCLUSION Blood and ascitic suPAR levels provide distinct, but relevant prognostic information on the severity of complications in patients with end-stage liver disease.
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Affiliation(s)
- H W Zimmermann
- Department of Medicine III, University Hospital Aachen, Aachen, Germany
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18
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Attenuated antigen-specific T cell responses in cirrhosis are accompanied by elevated serum interleukin-10 levels and down-regulation of HLA-DR on monocytes. BMC Gastroenterol 2013; 13:37. [PMID: 23446058 PMCID: PMC3598528 DOI: 10.1186/1471-230x-13-37] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Accepted: 02/21/2013] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Advanced liver disease predisposes to bacterial translocation and endotoxaemia which can contribute to elevated circulating levels of IL-10 and down-regulation of MHC class II on antigen-presenting cells. We sought to evaluate antigen-specific T-cell responses toward common viral antigens in order to investigate defects in cellular immunity in cirrhosis. METHODS Peripheral blood was obtained from 22 cirrhotic patients with systemic inflammation, 13 cirrhotic patients without systemic inflammation and 14 healthy controls. C-reactive protein was used as an indicator for systemic inflammation using a cut-off of 10 mg/l. Intracellular Th1 cytokines were quantified after T cell-stimulation with the viral peptides EBNA1 and BZLF1 or the bacterial superantigen SEB by flow cytometry. Serum levels of lipopolysaccharide-binding protein (LBP) and IL-10 were quantified by ELISA. RESULTS Compared to healthy controls, patients with cirrhosis had higher circulating levels of LBP and IL-10, an expansion of peripheral blood CD14+ monocytes with low HLA-DR expression and an increased fraction of CD25-positive CD4+ and CD8+ T cells. These findings were most pronounced in cirrhotic patients with systemic inflammation but fell short of reaching statistical significance when comparing against cirrhotic patients without systemic inflammation. In the former group TNF-α production in CD4+ and CD8+ T cells was reduced after stimulation with SEB, whereas there was no significant difference between the total cohort of cirrhotic patients and controls. After stimulation with the overlapping peptide pools for viral antigens EBNA1 and BZLF1, the number of responding T cells and the amount of TNF-α or IFN-γ production did not differ between the three pre-defined groups. However, cirrhotic patients with null-responses to EBV peptides had significantly higher serum IL-10 levels than responders to EBV peptides. Furthermore, TNF-α production in responding T cells was attenuated in patients with a high frequency of CD14+ HLA-DR- monocytes. CONCLUSION Our data suggest that bacterial translocation, endotoxaemia, inflammation and T cell activation in cirrhosis are accompanied by an increase in circulating anti-inflammatory cytokines, reduced monocytic MHC class II expression and attenuated cytokine production in T cells. These changes are likely to contribute to altered adaptive immune responses during infection or after vaccination.
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Hutchins NA, Chung CS, Borgerding JN, Ayala CA, Ayala A. Kupffer cells protect liver sinusoidal endothelial cells from Fas-dependent apoptosis in sepsis by down-regulating gp130. THE AMERICAN JOURNAL OF PATHOLOGY 2013; 182:742-54. [PMID: 23306157 DOI: 10.1016/j.ajpath.2012.11.023] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Revised: 10/05/2012] [Accepted: 11/08/2012] [Indexed: 02/07/2023]
Abstract
Endothelial cell (EC) dysfunction is a key feature of multiple organ injury, the primary cause of fatality seen in critically ill patients. Although the development of EC dysfunction in the heart and lung is well studied in sepsis, it remains unclear in the liver. Herein, we report that liver sinusoidal ECs (LSECs; defined as CD146(+)CD45(-)) exhibit increased intercellular adhesion molecule-1 (CD54) and Fas in response to sepsis induced by cecal ligation and puncture (CLP). By using magnetically enriched LSEC (CD146(+)) populations, we show evidence of marked apoptosis, with a twofold decline in viable LSECs in CLP animals compared with sham controls. These changes and increased serum alanine aminotransferase levels were all mitigated in septic Fas(-/-) and Fas ligand(-/-) animals. Although we previously reported increased numbers of Fas ligand expressing CD8(+) T lymphocytes in the septic liver, CD8(+) T-cell deficiency did not reverse the onset of LSEC apoptosis/damage. However, Kupffer cell depletion with clodronate liposomes resulted in greater apoptosis and Fas expression after CLP and a decrease in glycoprotein 130 expression on LSECs, suggesting that STAT3 activation may protect these cells from injury. Our results document a critical role for death receptor-mediated LSEC injury and show the first evidence that Kupffer cells are essential to the viability of LSECs, which appears to be mediated through glycoprotein 130 expression in sepsis.
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Affiliation(s)
- Noelle A Hutchins
- Brown University Pathobiology Graduate Program, Warren Alpert School of Medicine, Providence, Rhode Island, USA
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20
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The role of Src kinase in macrophage-mediated inflammatory responses. Mediators Inflamm 2012; 2012:512926. [PMID: 23209344 PMCID: PMC3504478 DOI: 10.1155/2012/512926] [Citation(s) in RCA: 219] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2012] [Accepted: 09/28/2012] [Indexed: 12/28/2022] Open
Abstract
Src kinase (Src) is a tyrosine protein kinase that regulates cellular metabolism, survival, and proliferation. Many studies have shown that Src plays multiple roles in macrophage-mediated innate immunity, such as phagocytosis, the production of inflammatory cytokines/mediators, and the induction of cellular migration, which strongly implies that Src plays a pivotal role in the functional activation of macrophages. Macrophages are involved in a variety of immune responses and in inflammatory diseases including rheumatoid arthritis, atherosclerosis, diabetes, obesity, cancer, and osteoporosis. Previous studies have suggested roles for Src in macrophage-mediated inflammatory responses; however, recently, new functions for Src have been reported, implying that Src functions in macrophage-mediated inflammatory responses that have not been described. In this paper, we discuss recent studies regarding a number of these newly defined functions of Src in macrophage-mediated inflammatory responses. Moreover, we discuss the feasibility of Src as a target for the development of new pharmaceutical drugs to treat macrophage-mediated inflammatory diseases. We provide insights into recent reports regarding new functions for Src that are related to macrophage-related inflammatory responses and the development of novel Src inhibitors with strong immunosuppressive and anti-inflammatory properties, which could be applied to various macrophage-mediated inflammatory diseases.
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Miao P, Kong Y, Ma Y, Zeng H, Yu Z. Hypothermia predicts the prognosis in colon ascendens stent peritonitis mice. J Surg Res 2012; 181:129-35. [PMID: 22739046 DOI: 10.1016/j.jss.2012.05.078] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2011] [Revised: 05/17/2012] [Accepted: 05/30/2012] [Indexed: 11/27/2022]
Abstract
BACKGROUND The mortality rate of severe sepsis remains unacceptably high. It is difficult to make advances in the treatment of this problematic and increasingly frequent medical condition. In severe sepsis, hypothermia can be recognized as an important feature. The present study investigated the role of hypothermia in the prognosis of the colon ascendens stent peritonitis (CASP) model. METHODS We employed the CASP model for wild-type C57BL/6 mice. We compared physiologic indices in survivor and non-survivor groups after CASP to test whether low temperature might be a helpful predictor in sepsis. To certify this hypothesis, we examined the survival rate, peritoneal leukocytes, and organ damage. We also measured the bacterial burden and inflammatory cytokine levels at different times. RESULTS The temperature varied dramatically in the survivors' group compared with the non-survivors' group at 18 h. We divided the CASP models into a mild group and a severe group, based on temperatures above or below 32°C at 18 h. Mice in the severe group had a lower survival rate (0% versus 87.5%), more peritoneal leukocytes, more bacterial culture results, higher expressions of cytokines, and more classical features in pathology compared with the mild group. CONCLUSIONS Hypothermia (below 32°C at 18 h) might be a predictor of prognosis in CASP-induced sepsis.
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Affiliation(s)
- Peng Miao
- Department of General Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
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22
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Ismail N, Walker DH, Ghose P, Tang YW. Immune mediators of protective and pathogenic immune responses in patients with mild and fatal human monocytotropic ehrlichiosis. BMC Immunol 2012; 13:26. [PMID: 22607204 PMCID: PMC3517396 DOI: 10.1186/1471-2172-13-26] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Accepted: 05/03/2012] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Ehrlichia chaffeensis is a bacterial pathogen that causes fatal human monocytic ehrlichiosis (HME) that mimic toxic shock-like syndrome. Murine studies indicate that over activation of cellular immunity followed by immune suppression plays a central role in mediating tissue injury and organ failure during fatal HME. However, there are no human studies that examine the correlates of resistance or susceptibility to severe and fatal HME. RESULTS In this study, we compared the immune responses in two patients with mild/non fatal and severe/fatal HME who had marked lymphopenia, thrombocytopenia and elevated liver enzymes. The levels of different immunological factors in the blood of those patients were examined and compared to healthy controls. Our data showed that fatal HME is associated with defective production of Th1 cytokines such as ( IFNγ and IL-2), increased anti-inflammatory (IL-10 and IL-13) and pro-inflammatory (TNF-α, IL-1α, IL-1β, and IL-6) cytokines, increased levels of macrophages, T cells, and NK cells chemokines such as MCP-1, MIP-1α, MIP-1β, but not RANTES and IP-10, increased levels of neutrophils chemokine and growth factor (IL-8 and G-CSF), and elevated expression of tumor necrosis factor receptor (TNFR), and toll like receptors 2 and 4 compared to patients with non fatal HME and healthy controls. CONCLUSIONS Fatal Ehrlichia-induced toxic shock is associated with defective Th1 responses, possible immune suppression mediated by IL-10. In addition, marked leukopenia observed in patients with fatal disease could be attributed to enhanced apoptosis of leukocytes and/or elevated chemokine production that could promote migration of immune cells to sites of infection causing tissue injury.
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Affiliation(s)
- Nahed Ismail
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
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Gais P, Reim D, Jusek G, Rossmann-Bloeck T, Weighardt H, Pfeffer K, Altmayr F, Janssen KP, Holzmann B. Cutting edge: Divergent cell-specific functions of MyD88 for inflammatory responses and organ injury in septic peritonitis. THE JOURNAL OF IMMUNOLOGY 2012; 188:5833-7. [PMID: 22586041 DOI: 10.4049/jimmunol.1200038] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Although global MyD88 deficiency attenuates lethal inflammation in sepsis, cell-specific functions of MyD88 remain largely unknown. Using mice with selective expression of MyD88 in myeloid cells (Myd88(MYEL)), we show that, during polymicrobial septic peritonitis, both myeloid and nonmyeloid cells contribute to systemic inflammation, whereas myeloid cell MyD88 was sufficient to fully establish the peritoneal cytokine response. Importantly, Myd88(MYEL) mice developed markedly aggravated liver injury that was linked to impaired upregulation of cellular inhibitor of apoptosis protein 2 and an excessive production of TNF-α. Upregulation of inducible cAMP early repressor (ICER), a known transcriptional repressor of the Tnfa gene, was impaired in Myd88(MYEL) mice. Moreover, Myd88(MYEL) mice showed enhanced transcription of the Tnfa gene and an excessive production of CCL3, which is also negatively regulated by ICER, but they had normal levels of CXCL1, which is expressed in an ICER-independent manner. Together, these findings suggest a novel protective role for nonmyeloid cell MyD88 in attenuating liver injury during septic peritonitis.
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Affiliation(s)
- Petra Gais
- Chirurgische Klinik und Poliklinik, Technische Universität München, 81675 Munich, Germany
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Jusek G, Reim D, Tsujikawa K, Holzmann B. Deficiency of the CGRP receptor component RAMP1 attenuates immunosuppression during the early phase of septic peritonitis. Immunobiology 2012; 217:761-7. [PMID: 22656887 DOI: 10.1016/j.imbio.2012.04.009] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2012] [Accepted: 04/27/2012] [Indexed: 01/15/2023]
Abstract
The neuropeptide CGRP contributes to the control of excessive cytokine production in endotoxemia models. However, the function of CGRP in sepsis caused by infection with viable pathogens is unknown. Here, we show that mice deficient for the CGRP receptor component RAMP1 have an improved anti-bacterial defense during the early, but not late, phase of polymicrobial septic peritonitis. The protective effect of Ramp1-deficiency was associated with reduced levels of IL-10 in plasma and peritoneal lavage fluid. Consistent with these findings, CGRP markedly increased IL-10 production of peritoneal and bone marrow-derived macrophages in response to short term stimulation with LPS in vitro. In addition, the lack of an intact CGRP receptor resulted in an increased recruitment and activation of neutrophils and caused an enhanced release of defensin-α1 in the peritoneal cavity. Considered together, our results identify the neuropeptide CGRP as a crucial immunosuppressive mediator impairing host defense during the early, but not late, phase of septic peritonitis.
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Affiliation(s)
- Gabriela Jusek
- Department of Surgery, Technical University Munich, Ismaninger Strasse 22, 81675 Munich, Germany
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Kushiyama T, Oda T, Yamada M, Higashi K, Yamamoto K, Oshima N, Sakurai Y, Miura S, Kumagai H. Effects of liposome-encapsulated clodronate on chlorhexidine gluconate-induced peritoneal fibrosis in rats. Nephrol Dial Transplant 2011; 26:3143-54. [DOI: 10.1093/ndt/gfr068] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Hammer M, Echtenachter B, Weighardt H, Jozefowski K, Rose-John S, Männel DN, Holzmann B, Lang R. Increased inflammation and lethality of Dusp1-/- mice in polymicrobial peritonitis models. Immunology 2011; 131:395-404. [PMID: 20561086 DOI: 10.1111/j.1365-2567.2010.03313.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The mitogen-activated protein kinase phosphatase Dusp1 (also known as MKP-1) is essential for control of the inflammatory response to systemic challenge with the lipopolysaccharide of Gram-negative bacteria. Here, we have investigated the consequences of Dusp1-deficiency in colon ascendens stent peritonitis (CASP) and caecal ligation and puncture (CLP), two mouse models of septic peritonitis. Following CASP, Dusp1(-/-) mice had increased serum levels of CCL4, interleukin-10 (IL-10) and IL-6, with differences from wild-type mice being dependent on severity of sepsis. These cytokines, along with inducible nitric oxide synthase messenger RNA, were also expressed at higher levels in spleen and liver. Similar over-production of these cytokines was detected in the CLP model, with even larger differences from wild-type mice. Despite the increased inflammatory response, bacterial clearance was impaired in Dusp1(-/-) mice subjected to CASP and CLP. Dusp1(-/-) mice suffered increased lethality in both peritonitis models. Together our data indicate that exaggerated inflammatory responses to gut bacteria introduced into the peritoneum in the absence of Dusp1 do not help to control bacterial replication but are detrimental for the host.
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Affiliation(s)
- Michael Hammer
- Institute of Medical Microbiology, Immunology and Hygiene, Technical University Munich, Munich, Germany
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Lenz AM, Fairweather M, Peyton JC, Gardner SA, Cheadle WG. Liver injury and abscess formation in secondary murine peritonitis. Inflamm Res 2010; 60:337-45. [DOI: 10.1007/s00011-010-0273-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2009] [Revised: 10/08/2010] [Accepted: 10/12/2010] [Indexed: 01/08/2023] Open
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Kupffer cell depletion reduces hepatic inflammation and apoptosis but decreases survival in abdominal sepsis. Eur J Gastroenterol Hepatol 2010; 22:1039-49. [PMID: 20300005 DOI: 10.1097/meg.0b013e32833847db] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVE During abdominal sepsis, the activation of hepatic Kupffer cells (KC) and its consequences are of central interest. This study evaluates the impact of selective KC depletion on hepatic microcirculation, cytokine release, and systemic alterations in the colon ascendens stent peritonitis (CASP), a model of polymicrobial abdominal sepsis. METHODS For KC depletion clodronate liposomes were injected 24 h before CASP surgery in female C57BL/6N mice. Three and 12 h after CASP, in-vivo fluorescence microscopy of the liver was performed. Analysis of hepatocellular apoptosis was conducted by immunohistochemistry. In addition, levels of tumor necrosis factor (TNF), IL-6, and IL-10 in the liver, lungs, spleen, and plasma were determined, and bacteriology and survival analysis were performed. RESULTS CASP led to significant sinusoidal perfusion failure, increased leukocyte recruitment, hepatocellular apoptosis and increased levels of TNF, IL-6, and IL-10 in the liver and plasma. KC depletion before CASP significantly reduced leukocyte recruitment to the liver and hepatocellular apoptosis. IL-10 secretion decreased dramatically in the liver and plasma of KC-depleted septic mice. In contrast, TNF levels were clearly elevated after clodronate treatment. In the lung and spleen, a compensatory upregulation of IL-10 could be detected after KC depletion. Clodronate treatment resulted in a significant reduction in survival. CONCLUSION The results indicate that KC depletion is locally protective in polymicrobial abdominal sepsis, as it reduces hepatic inflammation and apoptosis. These effects could be observed in the presence of clearly elevated TNF levels. However, the lack of IL-10 in KC-depleted mice resulted in a detrimental systemic proinflammation.
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Bugelski PJ, Achuthanandam R, Capocasale RJ, Treacy G, Bouman-Thio E. Monoclonal antibody-induced cytokine-release syndrome. Expert Rev Clin Immunol 2010; 5:499-521. [PMID: 20477639 DOI: 10.1586/eci.09.31] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Monoclonal antibodies (mAbs) are widely used in anti-inflammatory and tumor therapy. Although effective, mAbs can cause a variety of adverse effects. An important toxicity seen with a few mAbs is cytokine-release syndrome (CRS). These mAbs include: alemtuzumab, muromonab-CD3, rituximab, tosituzumab, CP-870,893, LO-CD2a/BTI-322 and TGN1412. By contrast, over 30 mAbs used clinically are not associated with CRS. In this review, the clinical aspects of CRS, the mAbs associated with CRS, the cytokines involved and putative mechanisms mediating cytokine release will be discussed. This will be followed by a discussion of the poor predictive value of studies in animals and the prospects for creating in vitro screens. Finally, approaches to decreasing the probability of CRS, decreasing the severity or treating CRS, should it occur, will be described.
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Affiliation(s)
- Peter J Bugelski
- Toxicology and Investigational Pharmacology, Centocor R&D, R-4-2, 145 King of Prussia Road, Radnor, PA 19087, USA.
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Wang HJ, Zakhari S, Jung MK. Alcohol, inflammation, and gut-liver-brain interactions in tissue damage and disease development. World J Gastroenterol 2010; 16:1304-13. [PMID: 20238396 PMCID: PMC2842521 DOI: 10.3748/wjg.v16.i11.1304] [Citation(s) in RCA: 193] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Chronic inflammation is often associated with alcohol-related medical conditions. The key inducer of such inflammation, and also the best understood, is gut microflora-derived lipopolysaccharide (LPS). Alcohol can significantly increase the translocation of LPS from the gut. In healthy individuals, the adverse effects of LPS are kept in check by the actions and interactions of multiple organs. The liver plays a central role in detoxifying LPS and producing a balanced cytokine milieu. The central nervous system contributes to anti-inflammatory regulation through neuroimmunoendocrine actions. Chronic alcohol use impairs not only gut and liver functions, but also multi-organ interactions, leading to persistent systemic inflammation and ultimately, to organ damage. The study of these interactions may provide potential new targets for therapeutic intervention.
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Abstract
In this review, we start with a general discussion of relevant factors that can determine the validity of a sepsis animal model. We briefly review some of the currently used animal models of sepsis (small animal models and large animal models). We discuss the clinical relevance of animal models in sepsis research today and address potential reasons for the apparent underperformance of animal models in predicting therapeutic success of novel drugs in clinical trials.
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Affiliation(s)
- Sergio L Zanotti-Cavazzoni
- Division of Critical Care Medicine, Cooper University Hospital, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Camden, NJ 08103, USA.
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Assfalg V, Hüser N, Reim D, Kaiser-Moore S, Rossmann-Bloeck T, Weighardt H, Novotny AR, Stangl MJ, Holzmann B, Emmanuel KL. Combined immunosuppressive and antibiotic therapy improves bacterial clearance and survival of polymicrobial septic peritonitis. Shock 2010; 33:155-61. [PMID: 19487979 DOI: 10.1097/shk.0b013e3181ab9014] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Effective immunosuppressive therapy is essential to prevent transplant rejection but renders patients vulnerable to opportunistic infections. The present study investigates the effects of common immunosuppressive drugs on the course of septic peritonitis in an experimental mouse model. We show that treatment with a combination of tacrolimus, mycophenolate mofetil, and methylprednisolone resulted in highly elevated lethality of septic peritonitis. When immunosuppressive drugs were combined with antibiotic therapy, however, mice were almost completely protected. The combination of mycophenolate mofetil and methylprednisolone was shown to be required and sufficient to improve outcome of septic peritonitis in the presence of antibiotic therapy. Combined immunosuppressive and antibiotic therapy, but not antibiotic therapy alone, resulted in enhanced bacterial clearance. These beneficial effects were linked to an elevated expression of activation markers and an increased production of reactive oxygen metabolites by peritoneal neutrophils and correlated with a reduced messenger RNA expression of the inhibitory cytokine IL-22. In contrast, systemic or peritoneal levels of IL-10, IL-12, TNF-alpha, keratinocyte chemoattractant, and monocyte chemoattractant protein 1, and splenic messenger RNA levels of IFN-gamma were not influenced by the immunosuppressive therapy. These results therefore suggest that combined immunosuppressive and antibiotic therapy may improve bacterial clearance and survival of septic peritonitis by a mechanism that involves enhanced activation and antimicrobial activity of neutrophils and reduced production of IL-22.
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Affiliation(s)
- Volker Assfalg
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
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Rettew JA, Huet YM, Marriott I. Estrogens augment cell surface TLR4 expression on murine macrophages and regulate sepsis susceptibility in vivo. Endocrinology 2009; 150:3877-84. [PMID: 19406943 DOI: 10.1210/en.2009-0098] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Gender-based differences exist in infectious disease susceptibility. In general, females generate more robust and potentially protective humoral and cell-mediated immune responses after antigenic challenge than their male counterparts. Furthermore, evidence is accumulating that sex may also influence the early perception of microbial challenges and the generation of inflammatory immune responses such as sepsis. These differences have previously been attributed to the actions of reproductive hormones. Whereas androgens have been shown to suppress acute host immune responses to bacterial endotoxin challenge, estrogens have been found to promote increased resistance to bacterial infections. However, the mechanisms by which estrogens exert immunoprotective effects have not been established. In this study, we investigated the in vivo effects of 17beta-estradiol on endotoxin susceptibility in mice. Importantly, we have examined the actions of this female reproductive hormone on the expression of pattern recognition receptors that recognize bacterial endotoxin by key innate immune sentinel cells. We show that removal of endogenous estrogens decreases both pro- and antiinflammatory cytokine production, with a concomitant reduction in circulating levels of lipopolysaccharide-binding protein and cell surface expression of Toll-like receptor 4 on murine macrophages. Exogenous in vivo replacement of 17beta-estradiol, but not progesterone, significantly elevates sera lipopolysaccharide-binding protein levels and cell surface expression of Toll-like receptor 4 and CD14 on macrophages. Furthermore, this effect corresponds with significantly higher inflammatory cytokine levels after in vivo lipopolysaccharide challenge and a marked increase in endotoxin-associated morbidity. Taken together, these data provide a potential mechanism underlying the immunoenhancing effects of estrogens.
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Affiliation(s)
- Jennifer A Rettew
- Department of Biology, University of North Carolina at Charlotte, Charlotte, North Carolina 28223, USA
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35
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Corazza N, Badmann A, Lauer C. Immune cell-mediated liver injury. Semin Immunopathol 2009; 31:267-77. [DOI: 10.1007/s00281-009-0168-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2009] [Accepted: 05/27/2009] [Indexed: 02/07/2023]
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Abstract
Although it is generally accepted that early defense mechanisms are controlled by cells of the innate immune system, T cells were found to be crucial for host resistance against acute septic peritonitis. However, the mechanisms by which T cells mediate protection are not fully understood. Here, we demonstrate mice deficient for recombinase-activating gene (RAG) 1, which lack mature B and T cells, showed enhanced susceptibility and impaired bacterial clearance in a model of acute septic peritonitis. Whereas B-cell-deficient muMT mice showed no significant difference in the survival rate after peritonitis induction, T-cell-deficient Balb/c nude mice exhibited reduced survival. Importantly, analysis of cytokine production in both RAG-1-deficient and T-cell-deficient nude mice indicated strongly attenuated production of IL-12, interferon (IFN) gamma, and IL-10 during sepsis. Reduced cytokine levels were detected both in serum and in organ extracts of septic mice. Direct analysis of T cells isolated from septic mice demonstrated that T cells respond to an acute septic challenge by increased production of IFN-gamma and IL-10. Moreover, bacterial numbers in spleens of septic RAG-1-deficient mice were significantly increased as compared with controls, suggesting that T cells are engaged in the early antibacterial immune defense during sepsis, possibly via the production of IFN-gamma. In summary, these results imply that T cells contribute to protective immune responses against acute systemic infections via their ability to produce crucial immune mediators.
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Kurahashi K, Sawa T, Ota M, Kajikawa O, Hong K, Martin TR, Wiener-Kronish JP. Depletion of phagocytes in the reticuloendothelial system causes increased inflammation and mortality in rabbits with Pseudomonas aeruginosa pneumonia. Am J Physiol Lung Cell Mol Physiol 2009; 296:L198-209. [PMID: 19028978 PMCID: PMC2643994 DOI: 10.1152/ajplung.90472.2008] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2008] [Accepted: 11/14/2008] [Indexed: 11/22/2022] Open
Abstract
Phagocytes of the reticuloendothelial system are important in clearing systemic infection; however, the role of the reticuloendothelial system in the response to localized infection is not well-documented. The major goals of this study were to investigate the roles of phagocytes in the reticuloendothelial system in terms of bacterial clearance and inflammatory modulation in sepsis caused by Pseudomonas pneumonia. Macrophages in liver and spleen were depleted by administering liposome encapsulated dichloromethylene diphosphonate (clodronate) intravenously 36 h before the instillation of Pseudomonas aeruginosa into the lungs of anesthetized rabbits. Blood samples were analyzed for bacteria and cytokine concentrations. Lung injury was assessed by the bidirectional flux of albumin and by wet-to-dry weight ratios. Blood pressure and cardiac outputs decreased more rapidly and bacteremia occurred earlier in the clodronate-treated rabbits compared with the nondepleted rabbits. Plasma TNF-alpha (1.08 +/- 0.54 vs. 0.08 +/- 0.02 ng/ml) and IL-8 (6.8 +/- 1.5 vs. 0.0 +/- 0.0 ng/ml) were higher in the depleted rabbits. The concentration of IL-10 in liver of the macrophage-depleted rabbits was significantly lower than in normal rabbits at 5 h. Treatment of macrophage-depleted rabbits with intravenous IL-10 reduced plasma proinflammatory cytokine concentrations and reduced the decline in blood pressure and cardiac output. These results show that macrophages in the reticuloendothelial system have critical roles in controlling systemic bacteremia and reducing systemic inflammation, thereby limiting the systemic effects of a severe pulmonary bacterial infection.
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Affiliation(s)
- Kiyoyasu Kurahashi
- Dept. of Anesthesiology and Critical Care Medicine, Yokohama City Univ. Graduate School of Medicine, Kanazawa-ku, Yokohama, 236-0004, Japan.
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38
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Kono H, Fujii H, Tsuchiya M, Hirai Y, Ishii K, Hosomura N, Tanaka N. Inhibition of the Kupffer Cell and Neutralization of IL-10 Increase the Expression of Chemokines in the Lung in a Rat Peritonitis Model. J Surg Res 2008; 150:169-82. [DOI: 10.1016/j.jss.2008.04.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2007] [Revised: 02/26/2008] [Accepted: 04/10/2008] [Indexed: 12/26/2022]
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Abstract
CC chemokine receptor 4 (CCR4) and its two ligands, CCL17 and CCL22, are critically involved in different immune processes. In models of lipopolysaccharide-induced shock, CCR4-deficient (CCR4(-/-)) mice showed improved survival rates associated with attenuated proinflammatory cytokine release. Using CCR4(-/-) mice with a C57BL/6 background, this study describes for the first time the role of CCR4 in a murine model of polymicrobial abdominal sepsis, the colon ascendens stent peritonitis (CASP). CASP-induced sepsis led to a massive downregulation of CCR4 in lymphoid and nonlymphoid tissues, whereas the expression of CCL17 and CCL22 was independent of the presence of CCR4. After CASP, CCR4(-/-) animals showed a strongly enhanced bacterial clearance in several organs but not in the peritoneal lavage fluid and the blood. In addition, significantly reduced levels of proinflammatory cytokines/chemokines were measured in organ supernatants as well as in the sera of CCR4(-/-) mice. CCR4 deficiency consequently resulted in an attenuated severity of systemic sepsis and a strongly improved survival rate after CASP or CASP with intervention. Thus, our data provide clear evidence that CCR4 plays a strictly detrimental role in the course of polymicrobial sepsis.
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Flohé SB, Agrawal H, Flohé S, Rani M, Bangen JM, Schade FU. Diversity of interferon gamma and granulocyte-macrophage colony-stimulating factor in restoring immune dysfunction of dendritic cells and macrophages during polymicrobial sepsis. Mol Med 2008; 14:247-56. [PMID: 18297128 PMCID: PMC2249752 DOI: 10.2119/2007-00120.flohe] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2007] [Accepted: 02/15/2008] [Indexed: 01/12/2023] Open
Abstract
The development of immunosuppression during polymicrobial sepsis is associated with the failure of dendritic cells (DC) to promote the polarization of T helper (Th) cells toward a protective Th1 type. The aim of the study was to test potential immunomodulatory approaches to restore the capacity of splenic DC to secrete interleukin (IL) 12 that represents the key cytokine in Th1 cell polarization. Murine polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Splenic DC were isolated at different time points after CLP or sham operation, and stimulated with bacterial components in the presence or absence of neutralizing anti-IL-10 antibodies, murine interferon (IFN) gamma, and/or granulocyte macrophage colony-stimulating factor (GM-CSF). DC from septic mice showed an impaired capacity to release the pro-inflammatory and Th1-promoting cytokines tumor necrosis factor alpha, IFN-gamma, and IL-12 in response to bacterial stimuli, but secreted IL-10. Endogenous IL-10 was not responsible for the impaired IL-12 secretion. Up to 6 h after CLP, the combined treatment of DC from septic mice with IFN-gamma and GM-CSF increased the secretion of IL-12. Later, DC from septic mice responded to IFN-gamma and GM-CSF with increased expression of the co-stimulatory molecule CD86, while IL-12 secretion was no more enhanced. In contrast, splenic macrophages from septic mice during late sepsis responded to GM-CSF with increased cytokine release. Thus, therapy of sepsis with IFN-gamma/GM-CSF might be sufficient to restore the activity of macrophages, but fails to restore DC function adequate for the development of a protective Th1-like immune response.
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Affiliation(s)
- Stefanie B Flohé
- Surgical Research, Department of Trauma Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Hemant Agrawal
- Surgical Research, Department of Trauma Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany
- Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Sascha Flohé
- Surgical Research, Department of Trauma Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Meenakshi Rani
- Surgical Research, Department of Trauma Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Jörg M Bangen
- Surgical Research, Department of Trauma Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - F Ulrich Schade
- Surgical Research, Department of Trauma Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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Eipel C, Kidess E, Abshagen K, LeMinh K, Menger MD, Burkhardt H, Vollmar B. Antileukoproteinase protects against hepatic inflammation, but not apoptosis in the response of D-galactosamine-sensitized mice to lipopolysaccharide. Br J Pharmacol 2007; 151:406-13. [PMID: 17420780 PMCID: PMC2013978 DOI: 10.1038/sj.bjp.0707230] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2006] [Revised: 01/23/2007] [Accepted: 02/13/2007] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND AND PURPOSE There is major evidence for the strong bi-directional interrelation of parenchymal cell apoptosis and leukocyte accumulation and inflammation in acute liver injury. Therefore, the aim of this in vivo study was to investigate the anti-apoptotic and anti-inflammatory potential of antileukoproteinase (ALP) in a murine model of acute liver failure. EXPERIMENTAL APPROACH C57BL/6J mice were given galactosamine (D-GalN) and E. coli lipopolysaccharide (LPS) followed by administration of saline or ALP. Besides survival rate, hepatic tissue damage and inflammatory response were analyzed by intravital fluorescence microscopy 6 hours after treatment. In addition, immunohistochemical analysis of NFkappaB-p65 and hepatocellular apoptosis, plasma levels of AST/ALT, TNF-alpha and IL-10 were determined. KEY RESULTS Administration of D-GalN/LPS provoked hepatic damage, including marked leukocyte recruitment and microvascular perfusion failure, as well as hepatocellular apoptosis and enzyme release. NFkappaB-p65 became increasingly detectable in hepatocellular nuclei, accompanied by a rise of TNF-alpha and IL-10 plasma levels. ALP markedly reduced intrahepatic leukocyte accumulation, nuclear translocation of NFkappaB and plasma levels of TNF-alpha and IL-10. Moreover, liver enzyme levels indicated the absence of necrotic parenchymal cell death. In contrast, ALP failed to block both apoptosis and caspase-3 levels and the mortality rate of ALP-treated animals was comparable to that of saline-treated mice. CONCLUSIONS AND IMPLICATIONS ALP could effectively prevent D-GalN/LPS-associated intrahepatic inflammatory responses by inhibition of NFkappaB activity, but not apoptosis-driven mortality. Thus, a protease-inactivating approach such as application of ALP seems to be inadequate in damaged liver where apoptosis represents the predominant mode of cell death.
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Affiliation(s)
- C Eipel
- Institute for Experimental Surgery, University of Rostock Rostock, Germany
| | - E Kidess
- Institute for Experimental Surgery, University of Rostock Rostock, Germany
| | - K Abshagen
- Institute for Experimental Surgery, University of Rostock Rostock, Germany
| | - K LeMinh
- Institute for Experimental Surgery, University of Rostock Rostock, Germany
| | - M D Menger
- Institute of Clinical and Experimental Surgery, University of Saarland Homburg-Saar, Germany
| | - H Burkhardt
- Division of Rheumatology, Johann Wolfgang Goethe University Frankfurt am Main Frankfurt am Main, Germany
| | - B Vollmar
- Institute for Experimental Surgery, University of Rostock Rostock, Germany
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Lin JY, Lai YS, Liu CJ, Wu AR. Effects of lotus plumule supplementation before and following systemic administration of lipopolysaccharide on the splenocyte responses of BALB/c mice. Food Chem Toxicol 2007; 45:486-93. [PMID: 17092622 DOI: 10.1016/j.fct.2006.09.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2005] [Revised: 07/31/2006] [Accepted: 09/20/2006] [Indexed: 11/22/2022]
Abstract
To determine whether lotus plumule supplementation alleviates acute systemic inflammation in vivo, the BALB/c mice were continuously supplemented with lotus plumule for 3 weeks, following administration with an intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) at a concentration of 10mg/kg body weight (BW) to induce acute systemic inflammation. At 24h after injection of LPS, the mice were sacrificed and the visceral organ weight and splenocyte responses were measured. The results showed that lotus plumule supplementation did not significantly affect body weights and IL-6 secretion of splenocyte cultures from BALB/c mice. LPS challenge significantly increased the relative organ weights of the lungs, liver, and spleen, however low dose supplementation (40 mg/kg BW/day) with lotus plumule significantly decreased the relative organ weights of the inflammatory liver, spleen and kidney. Low dose supplementation with lotus plumule significantly increased IL-10 production of splenocyte cultures, however high dose supplementation (800 mg/kg BW/day) significantly decreased IL-10 production. These results suggest that low dose and 3-week supplementation of lotus plumule might alleviate acute systemic inflammation in vivo via decreasing the visceral organ inflammation and increasing the production of anti-inflammatory cytokine IL-10 from splenocytes. These results are valuable for developing future nutraceuticals and anti-inflammatory agents from traditional medicinal foods.
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Affiliation(s)
- Jin-Yuarn Lin
- Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan, ROC.
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Westerholt A, Maier S, Traeger T, Gründling M, Heidecke CD. Management bei abdomineller Sepsis. Visc Med 2007. [DOI: 10.1159/000100519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Cytokine production during the inhibition of acute vascular rejection in a concordant hamster-to-rat cardiac xenotransplantation model. Chin Med J (Engl) 2007. [DOI: 10.1097/00029330-200701020-00015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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45
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Weighardt H, Kaiser-Moore S, Schlautkötter S, Rossmann-Bloeck T, Schleicher U, Bogdan C, Holzmann B. Type I IFN Modulates Host Defense and Late Hyperinflammation in Septic Peritonitis. THE JOURNAL OF IMMUNOLOGY 2006; 177:5623-30. [PMID: 17015750 DOI: 10.4049/jimmunol.177.8.5623] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
TLRs are considered important for the control of immune responses during endotoxic shock or polymicrobial sepsis. Signaling by TLRs may proceed through the adapter proteins MyD88 or TIR domain-containing adaptor inducinng IFN-beta. Both pathways can lead to the production of type I IFNs (IFN-alphabeta). In the present study, the role of the type I IFN pathway for host defense and immune pathology in sepsis was investigated using a model of mixed bacterial peritonitis. Systemic levels of IFN-alphabeta protein were markedly elevated during septic peritonitis. More detailed analyses revealed production of IFN-beta, but not IFN-alpha subtypes, and identified CD11b+ CD11c- macrophage-like cells as major producers of IFN-beta. The results further demonstrate that in IFN-alphabeta receptor I chain (IFNARI)-deficient mice, the early recruitment of neutrophils to the infected peritoneal cavity was augmented, most likely due to an increased local production of MCP-1 and leukotriene B4. In the absence of IFNARI, peritoneal neutrophils also exhibited enhanced production of reactive oxygen intermediates and elevated expression of Mac-1. Conversely, administration of recombinant IFN-beta resulted in reduced leukotriene B4 levels and decreased peritoneal neutrophil recruitment and activation. Analysis of the cytokine response to septic peritonitis revealed that IFNARI deficiency strongly attenuated late, but not early, hyperinflammation. In accordance with these findings, bacterial clearance and overall survival of IFNARI(-/-) mice were improved. Therefore, the present study reveals critical functions of the type I IFN pathway during severe mixed bacterial infections leading to sepsis. The results suggest that type I IFN exerts predominantly adverse effects under these conditions.
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Affiliation(s)
- Heike Weighardt
- Department of Surgery, Technische Universität München, Munich, Germany.
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Risøe PK, Wang Y, Stuestøl JF, Aasen AO, Wang JE, Dahle MK. Lipopolysaccharide attenuates mRNA levels of several adenylyl cyclase isoforms in vivo. Biochim Biophys Acta Mol Basis Dis 2006; 1772:32-9. [PMID: 17008068 DOI: 10.1016/j.bbadis.2006.08.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2006] [Revised: 08/02/2006] [Accepted: 08/21/2006] [Indexed: 11/30/2022]
Abstract
Signals that elevate intracellular levels of cyclic adenosine monophosphate (cAMP) are among the factors that control lipopolysaccharide (LPS)-mediated inflammatory mediator production by macrophages. cAMP signaling is also involved in maintaining body functions that are commonly impaired in sepsis, including the endothelial cell barrier function and heart function. Several agents successfully used for sepsis intervention target cAMP signaling, and it was recently shown that liver and lung may be protected from inflammation injury by cAMP-elevating phosphodiesterase inhibitors. Here, we show that LPS attenuates adenylyl cyclase (AC) mRNA levels in liver, lung, heart, spleen and kidney in an animal model of endotoxemia, and in macrophages from liver and lung. In particular, AC5, AC6, AC7 and AC9 mRNA were reduced in most tissues examined and in tissue macrophages. In Kupffer cells, prostaglandin E2-mediated cAMP production was inhibited by LPS treatment. The reduction in AC mRNA by LPS would be expected to lead to a lowered potential for cAMP production in most organs, and in particular, changes in AC6 mRNA may affect endothelial cell barrier function and heart function. In contrast, AC4 mRNA was elevated in heart and lung. The present work indicates a possible mechanism for LPS-mediated alteration of cAMP signaling in vivo.
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Affiliation(s)
- Petter Kirkeby Risøe
- University of Oslo, Faculty Division Rikshospitalet, Institute for Surgical Research, Rikshospitalet University Hospital, Oslo, Norway
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Weighardt H, Mages J, Jusek G, Kaiser-Moore S, Lang R, Holzmann B. Organ-specific role of MyD88 for gene regulation during polymicrobial peritonitis. Infect Immun 2006; 74:3618-32. [PMID: 16714594 PMCID: PMC1479251 DOI: 10.1128/iai.01681-05] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Sepsis leads to the rapid induction of proinflammatory signaling cascades by activation of the innate immune system through Toll-like receptors (TLR). To characterize the role of TLR signaling through MyD88 for sepsis-induced transcriptional activation, we investigated gene expression during polymicrobial septic peritonitis by microarray analysis. Comparison of gene expression profiles for spleens and livers from septic wild-type and MyD88-deficient mice revealed striking organ-specific differences. Whereas MyD88 deficiency strongly reduced sepsis-induced gene expression in the liver, gene expression in the spleen was largely independent of MyD88, indicating organ-specific transcriptional regulation during polymicrobial sepsis. In addition to genes regulated by MyD88 in an organ-dependent manner, we also identified genes that exhibited an organ-independent influence of MyD88 and mostly encoded cytokines and chemokines. Notably, the expression of interferon (IFN)-regulated genes was markedly increased in septic MyD88-deficient mice compared to that in septic wild-type controls. Expression of IFN-regulated genes was dependent on the adapter protein TRIF. These results suggest that the influence of MyD88 on gene expression during sepsis strongly depends on the organ compartment affected by inflammation and that the lack of MyD88 may lead to disbalance of the expression of IFN-regulated genes.
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Affiliation(s)
- Heike Weighardt
- Department of Surgery, Technische Universität München, Ismaningerstrasse 22, 81675 Munich, Germany.
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van Till JWO, Lamme B, van Esch TJH, van der Poll T, van Gulik TM, Boermeester MA. Surgical Therapy Attenuates Abdominal and Extra-Abdominal Inflammation in Experimental Peritonitis. Eur Surg Res 2006; 38:76-82. [PMID: 16557024 DOI: 10.1159/000092303] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2005] [Accepted: 01/26/2006] [Indexed: 12/22/2022]
Abstract
BACKGROUND This study examines the influence of surgical management (elimination of the infectious focus and abdominal lavage) on survival and the inflammatory response in the various compartments of the body: local (abdomen), systemic (blood) and distant organ (lungs). MATERIALS AND METHODS Peritonitis was established in mice by cecal ligation and puncture (CLP). After 24 h, a group was made in which the infected cecum was resected and the abdominal cavity was lavaged (RES), and another group that received no surgical resection (NoRES). Survival was examined over a period of 96 h. Mice were sacrificed at 24 (sham and CLP), 48 and 72 h after CLP to measure inflammatory parameters. RESULTS Survival was significantly lower is NoRES compared to sham and RES (p = 0.006, p = 0.014, respectively). Intraperitoneal parameters were improved in the RES group compared to sham but results were not significantly different between groups. In plasma, levels of interleukin-6 (IL-6) were decreased in RES (p = 0.048). Accordingly, anti-inflammatory IL-10 in plasma was increased in this group (p = 0.031). In the lung, keratinocyte-derived chemokine (KC) and myeloperoxidase (MPO) was reduced indicating decreased granulocytes accumulation in the lung in the RES group (p = 0.012 and p = 0.004, respectively). CONCLUSIONS In experimental secondary peritonitis surgical management improves survival and attenuates the inflammatory response predominantly in the extra-abdominal compartments. This illustrates the importance of surgery in prevention of multiple organ failure and denotes the compartmentalized character of the inflammatory response. This polymicrobial model with implicated surgical intervention reflects the clinical situation and may be more appropriate to test therapeutic interventions than a model involving only CLP.
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Affiliation(s)
- J W O van Till
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
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VanDeusen JB, Shah MH, Becknell B, Blaser BW, Ferketich AK, Nuovo GJ, Ahmer BMM, Durbin J, Caligiuri MA. STAT-1-mediated repression of monocyte interleukin-10 gene expression in vivo. Eur J Immunol 2006; 36:623-30. [PMID: 16482512 DOI: 10.1002/eji.200535241] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
There have been substantial advances in understanding the events that regulate gene expression at the cellular and molecular level; however, there has been limited progress integrating this information to understand how biological systems function in vivo. For example, the anti-inflammatory cytokine IL-10 is thought to down-regulate the effects of the pro-inflammatory cytokine IFN-gamma on monocyte activation following LPS stimulation. However, the often-postulated reciprocal regulation of IL-10 gene expression by IFN-gamma has not been studied in vivo. Here we demonstrate that the regulation of IL-10 gene expression has at least two phases following challenge with LPS or a gram-negative organism. In C57BL/6 mice, early IL-10 induction occurs independently of STAT-1, while a delayed active repression of IL-10 gene expression is critically dependent on STAT-1, but only partially dependent upon IFN-alpha/beta and IFN-gamma. This in vivo IL-10 production comes from blood monocytes, but not tissue macrophages, and cannot be reproduced in vitro. This study provides new insights into the regulation of IL-10 following challenge with a gram-negative organism, and highlights the importance of studying these cytokine regulatory pathways in vivo.
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Affiliation(s)
- Jeffrey B VanDeusen
- Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA
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Kessler W, Traeger T, Westerholt A, Neher F, Mikulcak M, Müller A, Maier S, Heidecke CD. The vagal nerve as a link between the nervous and immune system in the instance of polymicrobial sepsis. Langenbecks Arch Surg 2006; 391:83-7. [PMID: 16568325 DOI: 10.1007/s00423-006-0031-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2005] [Accepted: 01/29/2006] [Indexed: 10/24/2022]
Abstract
BACKGROUND The role of the vagal nerve in the autonomic nervous system is widely well known. Recently, an additional function was revealed serving as a connector between the nervous and immune system. This connection is called the "cholinergic inflammatory pathway." Through stimulation of the acetylcholine receptors located upon the macrophages, the "unspecific" immune system can be directly influenced. METHODS The vagal nerve was completely transected directly posterior to its passage through the diaphragm. The effect of complete vagotomy was analyzed using a murine model of polymicrobial peritonitis (colon ascendens stent peritonitis, CASP). Survival and clinical course of vagotomized or sham-operated mice were analyzed in the CASP model. RESULTS After CASP surgery, vagotomy led to a significantly increased mortality (64.7%) in comparison to sham-vagotomized animals (34%). No difference in the bacterial load of various tissues (lung, liver, spleen, blood, lavage fluid, and kidney) from septic animals with or without vagotomy was observed. Vagotomized animals reveal elevated serum cytokine levels (TNF, IL-6, IL-10, and MCP-1) 20 h after the induction of polymicrobial peritonitis. CONCLUSION The vagal nerve is therefore an important modulator of the immune system.
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Affiliation(s)
- Wolfram Kessler
- Department of Surgery, Abteilung für Allgemeine Chirurgie, Visceral-Thorax- und Gefässchirurgie, Universitätsklinikum Greifswald der Ernst-Moritz-Arndt-Universität, Friedrich-Loeffler-Strasse 23b, 17475, Greifswald, Germany.
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