19 results on '"John E. Mindur"'
Search Results
2. Brain motor and fear circuits regulate leukocytes during acute stress
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Wolfram C. Poller, Jeffrey Downey, Agnes A. Mooslechner, Nargis Khan, Long Li, Christopher T. Chan, Cameron S. McAlpine, Chunliang Xu, Florian Kahles, Shun He, Henrike Janssen, John E. Mindur, Sumnima Singh, Máté G. Kiss, Laura Alonso-Herranz, Yoshiko Iwamoto, Rainer H. Kohler, Lai Ping Wong, Kashish Chetal, Scott J. Russo, Ruslan I. Sadreyev, Ralph Weissleder, Matthias Nahrendorf, Paul S. Frenette, Maziar Divangahi, and Filip K. Swirski
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Motor Neurons ,Multidisciplinary ,Lymphoid Tissue ,Neutrophils ,SARS-CoV-2 ,Brain ,COVID-19 ,Bone Marrow Cells ,Fear ,Article ,Monocytes ,Optogenetics ,Mice ,Orthomyxoviridae Infections ,Neural Pathways ,Leukocytes ,Animals ,Humans ,Disease Susceptibility ,Lymphocytes ,Chemokines ,Glucocorticoids ,Stress, Psychological ,Paraventricular Hypothalamic Nucleus - Abstract
The nervous and immune systems are intricately linked(1). Although psychological stress is known to modulate immune function, mechanistic pathways linking stress networks in the brain to peripheral leukocytes remain poorly understood(2). Here we show that distinct brain regions shape leukocyte distribution and function throughout the body during acute stress in mice. Using optogenetics and chemogenetics, we demonstrate that motor circuits induce rapid neutrophil mobilization from the bone marrow to peripheral tissues through skeletal-muscle-derived neutrophil-attracting chemokines. Conversely, the paraventricular hypothalamus controls monocyte and lymphocyte egress from secondary lymphoid organs and blood to the bone marrow through direct, cell-intrinsic glucocorticoid signalling. These stress-induced, counter-directional, population-wide leukocyte shifts are associated with altered disease susceptibility. On the one hand, acute stress changes innate immunity by reprogramming neutrophils and directing their recruitment to sites of injury. On the other hand, corticotropin-releasing hormone neuron-mediated leukocyte shifts protect against the acquisition of autoimmunity, but impair immunity to SARS-CoV-2 and influenza infection. Collectively, these data show that distinct brain regions differentially and rapidly tailor the leukocyte landscape during psychological stress, therefore calibrating the ability of the immune system to respond to physical threats.
- Published
- 2022
3. Fecal Lcn-2 level is a sensitive biological indicator for gut dysbiosis and intestinal inflammation in multiple sclerosis
- Author
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Sudhir K, Yadav, Naoko, Ito, John E, Mindur, Hetal, Kumar, Mysra, Youssef, Shradha, Suresh, Ratuja, Kulkarni, Yaritza, Rosario, Konstantin E, Balashov, Suhayl, Dhib-Jalbut, and Kouichi, Ito
- Subjects
Inflammation ,Mice ,Multiple Sclerosis ,Encephalomyelitis, Autoimmune, Experimental ,Lipocalin-2 ,Environmental Biomarkers ,Immunology ,Humans ,Animals ,Dysbiosis ,Immunology and Allergy ,Mice, Transgenic - Abstract
Multiple Sclerosis (MS) has been reported to be associated with intestinal inflammation and gut dysbiosis. To elucidate the underlying biology of MS-linked gut inflammation, we investigated gut infiltration of immune cells during the development of spontaneous experimental autoimmune encephalomyelitis (EAE) in humanized transgenic (Tg) mice expressing HLA-DR2a and human T cell receptor (TCR) specific for myelin basic protein peptide (MBP87-99)/HLA-DR2a complexes. Strikingly, we noted the simultaneous development of EAE and colitis, suggesting a link between autoimmune diseases of the central nervous system (CNS) and intestinal inflammation. Examination of the colon in these mice revealed the infiltration of MBP-specific Th17 cells as well as recruitment of neutrophils. Furthermore, we observed that fecal Lipocalin-2 (Lcn-2), a biomarker of intestinal inflammation, was significantly elevated and predominantly produced by the gut-infiltrating neutrophils. We then extended our findings to MS patients and demonstrate that their fecal Lcn-2 levels are significantly elevated compared to healthy donors (HDs). The elevation of fecal Lcn-2 levels correlated with reduced bacterial diversity and increased levels of other intestinal inflammation markers including neutrophil elastase and calprotectin. Of interest, bacteria thought to be beneficial for inflammatory bowel disease (IBD) such as Anaerobutyricum, Blautia, and Roseburia, were reduced in fecal Lcn-2-high MS patients. We also observed a decreasing trend in serum acetate (a short-chain fatty acid) levels in MS Lcn-2-high patients compared to HDs. Furthermore, a decrease in the relative abundance of Blautia massiliensis was significantly associated with a reduction of acetate in the serum of MS patients. This study suggests that gut infiltration of Th17 cells and recruitment of neutrophils are associated with the development of gut dysbiosis and intestinal inflammation, and that fecal Lcn-2 level is a sensitive biological indicator for gut dysbiosis in multiple sclerosis.
- Published
- 2022
4. Sleep exerts lasting effects on hematopoietic stem cell function and diversity
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Cameron S. McAlpine, Máté G. Kiss, Faris M. Zuraikat, David Cheek, Giulia Schiroli, Hajera Amatullah, Pacific Huynh, Mehreen Z. Bhatti, Lai-Ping Wong, Abi G. Yates, Wolfram C. Poller, John E. Mindur, Christopher T. Chan, Henrike Janssen, Jeffrey Downey, Sumnima Singh, Ruslan I. Sadreyev, Matthias Nahrendorf, Kate L. Jeffrey, David T. Scadden, Kamila Naxerova, Marie-Pierre St-Onge, and Filip K. Swirski
- Subjects
Immunology ,Immunology and Allergy ,Humans ,Hematopoietic Stem Cells ,Sleep ,Cells, Cultured ,Hematopoiesis - Abstract
A sleepless night may feel awful in its aftermath, but sleep’s revitalizing powers are substantial, perpetuating the idea that convalescent sleep is a consequence-free physiological reset. Although recent studies have shown that catch-up sleep insufficiently neutralizes the negative effects of sleep debt, the mechanisms that control prolonged effects of sleep disruption are not understood. Here, we show that sleep interruption restructures the epigenome of hematopoietic stem and progenitor cells (HSPCs) and increases their proliferation, thus reducing hematopoietic clonal diversity through accelerated genetic drift. Sleep fragmentation exerts a lasting influence on the HSPC epigenome, skewing commitment toward a myeloid fate and priming cells for exaggerated inflammatory bursts. Combining hematopoietic clonal tracking with mathematical modeling, we infer that sleep preserves clonal diversity by limiting neutral drift. In humans, sleep restriction alters the HSPC epigenome and activates hematopoiesis. These findings show that sleep slows decay of the hematopoietic system by calibrating the hematopoietic epigenome, constraining inflammatory output, and maintaining clonal diversity.
- Published
- 2022
5. Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy
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Nicolas A. Gort-Freitas, Christina Pfirschke, Anna Kohl, Doron Merkler, Marie Siwicki, Yoshiko Iwamoto, Chiara Cianciaruso, Rapolas Zilionis, Marius Messemaker, Sara I. Pai, John E. Mindur, Montserrat Fraga, Pierre-Yves Dietrich, Angela E. Zou, Alexander Coukos, Christine Sempoux, Yi-Jang Lin, Nilesh Talele, Cecile Piot, Thibaud Koessler, Alexandre Wicky, Rakesh K. Jain, Yunkang Lin, Mikael J. Pittet, Rainer H. Kohler, Ruben Bill, Christopher Garris, Camilla Engblom, Jeremy Gungabeesoon, Allon M. Klein, Claudio deVito, Olivier Michielin, Ralph Weissleder, Evangelia Bolli, Genevieve M. Gerhard, and Mari Mino-Kenudson
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0301 basic medicine ,Liver toxicity ,Kupffer Cells ,Neutrophils ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Immunology ,MEDLINE ,Mice, Transgenic ,Inflammation ,ddc:616.07 ,Article ,03 medical and health sciences ,0302 clinical medicine ,Cancer immunotherapy ,Neoplasms ,medicine ,Animals ,Humans ,CTLA-4 Antigen ,CD40 Antigens ,Adverse effect ,Immune Checkpoint Inhibitors ,ddc:616 ,Hepatology ,Effector ,business.industry ,Macrophages ,Gastroenterology ,General Medicine ,Immunotherapy ,3. Good health ,Cancer treatment ,030104 developmental biology ,Liver ,030220 oncology & carcinogenesis ,Toxicity ,Cancer research ,Cytokines ,medicine.symptom ,610 Medizin und Gesundheit ,business - Abstract
Immunotherapy is revolutionizing cancer treatment but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions is poorly understood. Here, using anti-CD40-treatment in mice as a model of Th1-promoting immunotherapy, we showed that liver macrophages promoted local immune-related adverse events. Mechanistically, tissue-resident Kupffer cells mediated liver toxicity by sensing lymphocyte-derived IFN-𝛾 and subsequently producing IL-12. Conversely, dendritic cells were dispensable for toxicity but drove tumor control. IL-12 and IFN-𝛾 were not toxic themselves, but prompted a neutrophil response that determined the severity of tissue damage. We observed activation of similar inflammatory pathways following anti-PD-1 and anti-CTLA4 immunotherapies in mice and humans. These findings implicated macrophages and neutrophils as mediators and effectors of aberrant inflammation in Th1-promoting immunotherapy, suggesting distinct mechanisms of toxicity and antitumor immunity.
- Published
- 2021
6. Quantity of IgG response to SARS-CoV-2 spike glycoprotein predicts pulmonary recovery from COVID-19
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Manfred Nairz, Sabina Sahanic, Alex Pizzini, Anna Böhm, Piotr Tymoszuk, Anna-Maria Mitterstiller, Laura von Raffay, Philipp Grubwieser, Rosa Bellmann-Weiler, Sabine Koppelstätter, Andrea Schroll, David Haschka, Martina Zimmermann, Silvia Blunder, Kristina Trattnig, Helene Naschberger, Werner Klotz, Igor Theurl, Verena Petzer, Clemens Gehrer, John E. Mindur, Anna Luger, Christoph Schwabl, Gerlig Widmann, Günter Weiss, Judith Löffler-Ragg, Ivan Tancevski, and Thomas Sonnweber
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Male ,Multidisciplinary ,Reverse Transcriptase Polymerase Chain Reaction ,Immunoglobulin G ,Spike Glycoprotein, Coronavirus ,Patient Acuity ,COVID-19 ,Humans ,Female ,Prospective Studies ,Middle Aged ,Lung ,Respiratory Function Tests - Abstract
The CovILD study is a prospective, multicenter, observational cohort study to systematically follow up patients after coronavirus disease-2019 (COVID-19). We extensively evaluated 145 COVID-19 patients at 3 follow-up visits scheduled for 60, 100, and 180 days after initial confirmed diagnosis based on typical symptoms and a positive reverse transcription-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We employed comprehensive pulmonary function and laboratory tests, including serum concentrations of IgG against the viral spike (S) glycoprotein, and compared the results to clinical data and chest computed tomography (CT). We found that at the 60 day follow-up, 131 of 145 (90.3%) participants displayed S-specific serum IgG levels above the cut-off threshold. Notably, the highly elevated IgG levels against S glycoprotein positively correlated with biomarkers of immune activation and negatively correlated with pulmonary function and the extent of pulmonary CT abnormalities. Based on the association between serum S glycoprotein-specific IgG and clinical outcome, we generated an S-specific IgG-based recovery score that, when applied in the early convalescent phase, accurately predicted delayed pulmonary recovery after COVID-19. Therefore, we propose that S-specific IgG levels serve as a useful immunological surrogate marker for identifying at-risk individuals with persistent pulmonary injury who may require intensive follow-up care after COVID-19.
- Published
- 2021
7. Sleep modulates hematopoiesis and protects against atherosclerosis
- Author
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Peter Libby, Vanessa Frodermann, Friedrich Felix Hoyer, Christoph J. Binder, Christopher T. Chan, Annemijn F. Gregory, Yoshiko Iwamoto, Anne Vassalli, Cameron S. McAlpine, Matthias Nahrendorf, Atsushi Anzai, Filip K. Swirski, Thomas E. Scammell, Shun He, Florian Kahles, Wolfram C. Poller, Ashley M. Fenn, Mehdi Tafti, John E. Mindur, Colin Valet, Sara Rattik, Lennard Halle, and M. Kiss
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Male ,0301 basic medicine ,medicine.medical_specialty ,Lateral hypothalamus ,Neutrophils ,Bone Marrow Cells ,Monocytes ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Monocytosis ,Orexin Receptors ,Internal medicine ,mental disorders ,medicine ,Animals ,Antigens, Ly ,Antigens, Ly/metabolism ,Atherosclerosis/metabolism ,Atherosclerosis/pathology ,Atherosclerosis/prevention & control ,Bone Marrow Cells/metabolism ,Female ,Hematopoiesis/drug effects ,Hematopoiesis/physiology ,Hypothalamic Area, Lateral/metabolism ,Monocytes/drug effects ,Monocytes/metabolism ,Myelopoiesis/drug effects ,Neutrophils/metabolism ,Orexin Receptors/deficiency ,Orexin Receptors/metabolism ,Orexins/biosynthesis ,Orexins/deficiency ,Orexins/metabolism ,Orexins/pharmacology ,Sleep/drug effects ,Sleep/physiology ,Sleep Deprivation/metabolism ,Sleep Deprivation/physiopathology ,Sleep Deprivation/prevention & control ,Fragmentation (cell biology) ,Pathological ,Myelopoiesis ,Orexins ,Multidisciplinary ,business.industry ,Macrophage Colony-Stimulating Factor ,Atherosclerosis ,medicine.disease ,Sleep in non-human animals ,Hematopoiesis ,3. Good health ,Haematopoiesis ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,nervous system ,Hypothalamic Area, Lateral ,Sleep Deprivation ,Bone marrow ,Sleep ,business ,psychological phenomena and processes ,030217 neurology & neurosurgery - Abstract
Sleep is integral to life 1 . Although insufficient or disrupted sleep increases the risk of multiple pathological conditions, including cardiovascular disease 2 , we know little about the cellular and molecular mechanisms by which sleep maintains cardiovascular health. Here we report that sleep regulates haematopoiesis and protects against atherosclerosis in mice. We show that mice subjected to sleep fragmentation produce more Ly-6C high monocytes, develop larger atherosclerotic lesions and produce less hypocretin-a stimulatory and wake-promoting neuropeptide-in the lateral hypothalamus. Hypocretin controls myelopoiesis by restricting the production of CSF1 by hypocretin-receptor-expressing pre-neutrophils in the bone marrow. Whereas hypocretin-null and haematopoietic hypocretin-receptor-null mice develop monocytosis and accelerated atherosclerosis, sleep-fragmented mice with either haematopoietic CSF1 deficiency or hypocretin supplementation have reduced numbers of circulating monocytes and smaller atherosclerotic lesions. Together, these results identify a neuro-immune axis that links sleep to haematopoiesis and atherosclerosis.
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- 2019
8. Self-reactive CD4+ IL-3+ T cells amplify autoimmune inflammation in myocarditis by inciting monocyte chemotaxis
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Kenneth Walsh, Matthias Nahrendorf, Shun He, Filip K. Swirski, John E. Mindur, Manfred Nairz, Lennard Halle, Sara Rattik, Soichi Sano, Jennifer L. Choi, Christopher T. Chan, De Lisa Fairweather, Florian Kahles, Ashley M. Fenn, Atsushi Anzai, Colin Valet, Yoshiko Iwamoto, Peter Libby, and Cameron S. McAlpine
- Subjects
CD4-Positive T-Lymphocytes ,0301 basic medicine ,Chemokine ,Myocarditis ,Monocyte chemotaxis ,T cell ,Immunology ,Cardiomyopathy ,Inflammation ,medicine.disease_cause ,Article ,Monocytes ,Autoimmune Diseases ,Autoimmunity ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Immunology and Allergy ,Research Articles ,Cell Proliferation ,Mice, Knockout ,Mice, Inbred BALB C ,biology ,business.industry ,Effector ,Chemotaxis ,Macrophages ,medicine.disease ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,Interleukin-3 ,medicine.symptom ,business ,030215 immunology - Abstract
In autoimmune myocarditis, self-reactive T cells attack cardiac antigens and contribute to heart inflammation. In this study, Anzai et al. show that the T cell–derived cytokine and growth factor IL-3 amplifies inflammation and exacerbates autoimmune myocarditis., Acquisition of self-reactive effector CD4+ T cells is a major component of the autoimmune response that can occur during myocarditis, an inflammatory form of cardiomyopathy. Although the processes by which self-reactive T cells gain effector function have received considerable attention, how these T cells contribute to effector organ inflammation and damage is less clear. Here, we identified an IL-3–dependent amplification loop that exacerbates autoimmune inflammation. In experimental myocarditis, we show that effector organ–accumulating autoreactive IL-3+ CD4+ T cells stimulate IL-3R+ tissue macrophages to produce monocyte-attracting chemokines. The newly recruited monocytes differentiate into antigen-presenting cells that stimulate local IL-3+ CD4+ T cell proliferation, thereby amplifying organ inflammation. Consequently, Il3−/− mice resist developing robust autoimmune inflammation and myocardial dysfunction, whereas therapeutic IL-3 targeting ameliorates disease. This study defines a mechanism that orchestrates inflammation in myocarditis, describes a previously unknown function for IL-3, and identifies IL-3 as a potential therapeutic target in patients with myocarditis.
- Published
- 2019
9. Astrocytic interleukin-3 programs microglia and limits Alzheimer's disease
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Ruslan I. Sadreyev, Claudio Vinegoni, Mehdi Jorfi, Benjamin P. Kleinstiver, Shun He, Se Hoon Choi, Yoshiko Iwamoto, Lai Ping Wong, Ralph Weissleder, Rudolph E. Tanzi, Christopher T. Chan, Sumnima Singh, Joseph Park, Florian Kahles, Ana Griciuc, Kathleen A. Christie, Atsushi Anzai, John E. Mindur, Filip K. Swirski, M. Kiss, Paolo Fumene Feruglio, Wolfram C. Poller, Eunhee Kim, Matthias Nahrendorf, Jeffrey Downey, Cameron S. McAlpine, and Henrike Janssen
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Cell Communication ,Biology ,Mice ,Immune system ,Mediator ,Neural Stem Cells ,Alzheimer Disease ,medicine ,Animals ,Humans ,Cognitive decline ,Cells, Cultured ,Mice, Knockout ,Multidisciplinary ,Microglia ,Neurodegeneration ,Interleukin ,medicine.disease ,Mice, Inbred C57BL ,Neuroimmunology ,medicine.anatomical_structure ,nervous system ,Astrocytes ,Interleukin-3 ,Neuroscience ,Astrocyte - Abstract
Communication within the glial cell ecosystem is essential for neuronal and brain health1–3. The influence of glial cells on the accumulation and clearance of β-amyloid (Aβ) and neurofibrillary tau in the brains of individuals with Alzheimer’s disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of Aβ deposits, microglia increase their expression of IL-3Rα—the specific receptor for IL-3 (also known as CD123)—making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of Aβ and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte–microglia cross-talk and a node for therapeutic intervention in AD. Interleukin-3 signalling from astrocytes to microglia readies microglia to defend against Alzheimer’s disease.
- Published
- 2020
10. Surface Layer Protein A Expressed in Clostridioides difficile DJNS06-36 Possesses an Encephalitogenic Mimotope of Myelin Basic Protein
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Mitsutoshi Senoh, Kouichi Ito, John E. Mindur, Naoko Ito, Haru Kato, Sudhir K. Yadav, and Suhayl Dhib-Jalbut
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0301 basic medicine ,Microbiology (medical) ,surface layer protein A ,multiple sclerosis ,Microbiology ,Clostridioides difficile ,Article ,03 medical and health sciences ,0302 clinical medicine ,Virology ,medicine ,Surface layer ,lcsh:QH301-705.5 ,biology ,Mimotope ,Multiple sclerosis ,mimotope ,medicine.disease ,myelin basic protein ,Cell biology ,Myelin basic protein ,030104 developmental biology ,lcsh:Biology (General) ,biology.protein ,Protein A ,030217 neurology & neurosurgery ,Clostridioides - Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Recent studies suggest that migration of Th1 and Th17 cells specific for enteric bacteria from the gut to the CNS may lead to the initiation and/or exacerbation of autoimmune diseases including MS. Human leukocyte antigen (HLA)-DR15 is an MHC class II (MHCII) haplotype highly associated with the development of MS that contains the two HLA-DRB* genes, DRB1*1501 (DR2b) and DRB5*0101 (DR2a). To identify enteric bacteria which harbor antigenic epitopes that activate myelin-specific T cells and drive CNS inflammation, we screened for enteric bacteria which express cross-reactive epitopes (&lsquo, mimotopes&rsquo, ) of an immunodominant myelin basic protein 89&ndash, 98 (MBP89-98) epitope. Based on known MHCII HLA-DR2a amino acid binding motifs and cultivation with splenic T cells isolated from MBP-T cell receptor (TCR)/DR2a transgenic (Tg) mice, we discovered that a certain variant of surface layer protein A (SLPA), which is expressed by a subtype of Clostridioides difficile, contains an amino acid sequence that activates MBP89-98-reactive T cells. Furthermore, activation of MBP-specific T cells by SLPA upon active immunization induced experimental autoimmune encephalomyelitis (EAE) in MBP-TCR/DR2a Tg mice. This study suggests that a unique strain of C. difficile possesses an encephalitogenic mimotope of MBP that activates autoreactive, myelin-specific T cells.
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- 2020
11. Liver X receptors are required for thymic resilience and T cell output
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Nina K. Harder, Jyoti Patel, Florian Kahles, Yoshiko Iwamoto, John E. Mindur, Cameron S. McAlpine, Jan-Åke Gustafsson, Ruslan I. Sadreyev, Laurent Yvan-Charvet, Filip K. Swirski, Shun He, Henrike Janssen, David R. Koolbergen, Wolfram C. Poller, Lai Ping Wong, Ashley M. Fenn, Christopher T. Chan, Sara Rattik, Alan R. Tall, Carlos Fernández-Hernando, Anja M. van der Laan, Marit Westerterp, Colin Valet, Atsushi Anzai, Matthias Nahrendorf, Center for Liver, Digestive and Metabolic Diseases (CLDM), Translational Immunology Groningen (TRIGR), Cardiothoracic Surgery, Cardiology, Amsterdam Cardiovascular Sciences, and ACS - Heart failure & arrhythmias
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T cell ,Immunology ,Experimental autoimmune encephalomyelitis ,T lymphocyte ,Biology ,medicine.disease ,Acquired immune system ,Article ,Cell biology ,Negative selection ,Metabolism ,medicine.anatomical_structure ,medicine ,Immunodeficiency ,Immunology and Allergy ,Involution (medicine) ,Liver X receptor ,Transcription factor - Abstract
Liver X receptors (LXRs) orchestrate cholesterol metabolism with diverse metabolic and immune functions. Chan et al. show that in the thymus, thymic epithelial cells protect against involution and promote regeneration, whereas T cells require LXRs to escape negative selection., The thymus is a primary lymphoid organ necessary for optimal T cell development. Here, we show that liver X receptors (LXRs)—a class of nuclear receptors and transcription factors with diverse functions in metabolism and immunity—critically contribute to thymic integrity and function. LXRαβ-deficient mice develop a fatty, rapidly involuting thymus and acquire a shrunken and prematurely immunoinhibitory peripheral T cell repertoire. LXRαβ’s functions are cell specific, and the resulting phenotypes are mutually independent. Although thymic macrophages require LXRαβ for cholesterol efflux, thymic epithelial cells (TECs) use LXRαβ for self-renewal and thymocytes for negative selection. Consequently, TEC-derived LXRαβ protects against homeostatic premature involution and orchestrates thymic regeneration following stress, while thymocyte-derived LXRαβ limits cell disposal during negative selection and confers heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXRαβ governs T lymphocyte education and illuminate LXRαβ’s indispensable roles in adaptive immunity.
- Published
- 2020
12. The infarcted myocardium solicits GM-CSF for the detrimental oversupply of inflammatory leukocytes
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Benoit Tricot, Atsushi Anzai, Manfred Nairz, Filip K. Swirski, Ashley M. Fenn, Sara Rattik, Ralph Weissleder, Yoshiko Iwamoto, John E. Mindur, Jennifer L. Choi, Cameron S. McAlpine, Burkhard Becher, Matthias Nahrendorf, Peter Libby, Gregory R. Wojtkiewicz, James R. Stone, Shun He, Christopher T. Chan, University of Zurich, and Swirski, Filip K
- Subjects
0301 basic medicine ,Male ,Neutrophils ,medicine.medical_treatment ,Myocardial Infarction ,030204 cardiovascular system & hematology ,10263 Institute of Experimental Immunology ,Monocytes ,Cytokine Receptor Common beta Subunit ,0302 clinical medicine ,Bone Marrow ,Leukocytes ,Immunology and Allergy ,Macrophage ,Myeloid Cells ,Myocardial infarction ,Research Articles ,Mice, Knockout ,Flow Cytometry ,medicine.anatomical_structure ,2723 Immunology and Allergy ,cardiovascular system ,medicine.symptom ,Chemokines ,Immunology ,Ischemia ,610 Medicine & health ,Inflammation ,Mice, Transgenic ,Granulocyte ,Article ,03 medical and health sciences ,medicine ,Animals ,Humans ,cardiovascular diseases ,2403 Immunology ,business.industry ,Growth factor ,Granulocyte-Macrophage Colony-Stimulating Factor ,medicine.disease ,Survival Analysis ,Mice, Inbred C57BL ,030104 developmental biology ,Heart failure ,570 Life sciences ,biology ,Bone marrow ,business - Abstract
Myocardial infarction elicits massive recruitment of monocytes and neutrophils to the myocardium, but the mechanisms that control these processes are not fully understood. Here, Anzai et al. show that GM-CSF is a powerful orchestrator contributing to monocyte and neutrophil production, recruitment, and function., Myocardial infarction (MI) elicits massive inflammatory leukocyte recruitment to the heart. Here, we hypothesized that excessive leukocyte invasion leads to heart failure and death during acute myocardial ischemia. We found that shortly and transiently after onset of ischemia, human and mouse cardiac fibroblasts produce granulocyte/macrophage colony-stimulating factor (GM-CSF) that acts locally and distally to generate and recruit inflammatory and proteolytic cells. In the heart, fibroblast-derived GM-CSF alerts its neighboring myeloid cells to attract neutrophils and monocytes. The growth factor also reaches the bone marrow, where it stimulates a distinct myeloid-biased progenitor subset. Consequently, hearts of mice deficient in either GM-CSF or its receptor recruit fewer leukocytes and function relatively well, whereas mice producing GM-CSF can succumb from left ventricular rupture, a complication mitigated by anti–GM-CSF therapy. These results identify GM-CSF as both a key contributor to the pathogenesis of MI and a potential therapeutic target, bolstering the idea that GM-CSF is a major orchestrator of the leukocyte supply chain during inflammation.
- Published
- 2017
13. Cibinetide dampens innate immune cell functions thus ameliorating the course of experimental colitis
- Author
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Thomas Sonnweber, Manfred Nairz, Igor Theurl, Dominik Wolf, Günter Weiss, Stefanie Dichtl, Patrizia Moser, John E. Mindur, David Haschka, Andrea Schroll, Filip K. Swirski, Anthony Cerami, Malte Aßhoff, and Michael Brines
- Subjects
Male ,0301 basic medicine ,Chemokine ,Myeloid ,Inflammatory bowel disease ,Cytokine Receptor Common beta Subunit ,Phosphatidylinositol 3-Kinases ,Receptors, Erythropoietin ,Myeloid Cells ,Intestinal Mucosa ,Phosphorylation ,Multidisciplinary ,biology ,Dextran Sulfate ,T-Lymphocytes, Helper-Inducer ,Colitis ,medicine.anatomical_structure ,Disease Progression ,Medicine ,Female ,Chemokines ,Oligopeptides ,medicine.drug ,Science ,Article ,03 medical and health sciences ,Immune system ,medicine ,Animals ,Humans ,Erythropoietin ,Innate immune system ,business.industry ,Macrophages ,Transcription Factor RelA ,Janus Kinase 2 ,medicine.disease ,Immunity, Innate ,Erythropoietin receptor ,Mice, Inbred C57BL ,030104 developmental biology ,Solubility ,Immunology ,Cancer research ,biology.protein ,business - Abstract
Two distinct forms of the erythropoietin receptor (EPOR) mediate the cellular responses to erythropoietin (EPO) in different tissues. EPOR homodimers signal to promote the maturation of erythroid progenitor cells. In other cell types, including immune cells, EPOR and the ß-common receptor (CD131) form heteromers (the innate repair receptor; IRR), and exert tissue protective effects. We used dextran sulphate sodium (DSS) to induce colitis in C57BL/6 N mice. Once colitis was established, mice were treated with solvent, EPO or the selective IRR agonist cibinetide. We found that both cibinetide and EPO ameliorated the clinical course of experimental colitis in mice, resulting in improved weight gain and survival. Correspondingly, DSS-exposed mice treated with cibinetide or EPO displayed preserved tissue integrity due to reduced infiltration of myeloid cells and diminished production of pro-inflammatory disease mediators including cytokines, chemokines and nitric oxide synthase-2. Experiments using LPS-activated primary macrophages revealed that the anti-inflammatory effects of cibinetide were dependent on CD131 and JAK2 functionality and were mediated via inhibition of NF-κB subunit p65 activity. Cibinetide activation of the IRR exerts potent anti-inflammatory effects, especially within the myeloid population, reduces disease activity and mortality in mice. Cibinetide thus holds promise as novel disease-modifying therapeutic of inflammatory bowel disease.
- Published
- 2017
14. IL-27: a potential biomarker for responders to glatiramer acetate therapy
- Author
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Kouichi Ito, John E. Mindur, Sudhir K. Yadav, Reuben M. Valenzuela, Sridhar Boppana, and Suhayl Dhib-Jalbut
- Subjects
0301 basic medicine ,Adult ,Male ,Immunology ,Pharmacology ,Peripheral blood mononuclear cell ,03 medical and health sciences ,Young Adult ,Multiple Sclerosis, Relapsing-Remitting ,medicine ,Immunology and Allergy ,Humans ,Glatiramer acetate ,Receptor ,Cells, Cultured ,business.industry ,Multiple sclerosis ,Interleukins ,Interleukin ,EBI3 ,Glatiramer Acetate ,Middle Aged ,medicine.disease ,Interleukin 10 ,030104 developmental biology ,HEK293 Cells ,Treatment Outcome ,Neurology ,Leukocytes, Mononuclear ,Biomarker (medicine) ,Female ,Neurology (clinical) ,business ,Biomarkers ,Immunosuppressive Agents ,medicine.drug ,Protein Binding - Abstract
Glatiramer acetate (GA) is an FDA-approved efficacious drug for the treatment of relapsing-remitting multiple sclerosis (RRMS). However, this treatment is not effective for all RRMS patients. Therefore, it is important to identify reliable biomarkers that can predict a beneficial clinical response to GA therapy. Since an increase in IL-27 has been demonstrated to suppress autoimmune and allergic diseases of inflammatory origin, we examined the effect of GA on the production of IL-27. We observed that IL-27 production in PBMCs cultured with GA was heterogeneous amongst MS patients and healthy donors (HD), and thus, defined these MS patients as either efficient, weak, or non-IL-27 producers. Interestingly, GA could induce the expression of the IL-27p28 subunit more efficiently than the IL-27 EBI3 subunit, and the production of IL-27 depended on MHC class II binding by GA. In addition, we found that GA could augment Toll-like receptor (TLR)-mediated IL-27 production. Importantly, serum production of IL-27 and IL-10 was significantly increased at 6months during GA therapy in clinical responders to GA, but not in GA non-responders. Altogether, our data suggest that GA-induced IL-27 may represent a therapeutic mechanism of GA-mediated immunomodulation and that GA-mediated IL-27 production in PBMCs is worth exploring as a biomarker to screen for GA responders prior to the initiation of GA treatment.
- Published
- 2016
15. Sleep Modulates Hematopoiesis and Protects Against Atherosclerosis
- Author
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Yoshiko Iwamoto, Lennard Halle, M. Kiss, Friedrich Felix Hoyer, John E. Mindur, Matthias Nahrendorf, Colin Valet, Shun He, Christopher T. Chan, Cameron S. McAlpine, Atsushi Anzai, Peter Libby, Filip K. Swirski, Florian Kahles, Sara Rattik, and Ralph Weissleder
- Subjects
Haematopoiesis ,business.industry ,Internal Medicine ,Medicine ,General Medicine ,Cardiology and Cardiovascular Medicine ,business ,Sleep in non-human animals ,Neuroscience - Published
- 2018
16. Advances in the immunopathogenesis of multiple sclerosis
- Author
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Suhayl Dhib-Jalbut, Sudhir K. Yadav, Kouichi Ito, and John E. Mindur
- Subjects
Central Nervous System ,Multiple Sclerosis ,animal diseases ,Multiple sclerosis ,Neurodegeneration ,Central nervous system ,chemical and pharmacologic phenomena ,biochemical phenomena, metabolism, and nutrition ,Biology ,Immune dysregulation ,medicine.disease ,medicine.disease_cause ,Pathogenesis ,Degenerative disease ,medicine.anatomical_structure ,Neurology ,Immune System ,Immunology ,medicine ,bacteria ,Animals ,Cytokines ,Humans ,Neurology (clinical) - Abstract
Recent studies indicate a role for immune dysregulation in the pathogenesis of multiple sclerosis, an inflammatory demyelinating and degenerative disease of the central nervous system. This review addresses the current mechanisms of immune dysregulation in the development of multiple sclerosis, including the impact of environmental risk factors on immunity in both multiple sclerosis and its animal models.CD4 T-helper (Th) cells have long been implicated as the main drivers of pathogenesis of multiple sclerosis. However, current studies indicate that multiple sclerosis is largely a heterogeneous disease process, which involves both innate and adaptive immune-mediated inflammatory mechanisms that ultimately contribute to demyelination and neurodegeneration. Therefore, B cells, CD8 T cells, and microglia/macrophages can also play an important role in the immunopathogenesis of multiple sclerosis apart from proinflammatory CD4 Th1/Th17 cell subsets. Furthermore, increasing evidence indicates that environmental risk factors, such as Vitamin D deficiency, Epstein-Barr virus, smoking, Western diet, and the commensal microbiota, influence the development of multiple sclerosis through interactions with genetic variants of multiple sclerosis, thus leading to the dysregulation of immune responses.A better understanding of immune-mediated mechanisms in the pathogenesis of multiple sclerosis and the contribution of environmental risk factors toward the development of multiple sclerosis will help further improve therapeutic approaches to prevent disease progression.
- Published
- 2015
17. Early treatment with anti-VLA-4 mAb can prevent the infiltration and/or development of pathogenic CD11b+CD4+ T cells in the CNS during progressive EAE
- Author
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Suhayl Dhib-Jalbut, John E. Mindur, Naoko Ito, and Kouichi Ito
- Subjects
CD4-Positive T-Lymphocytes ,Central Nervous System ,lcsh:Medicine ,Autoimmunity ,Integrin alpha4beta1 ,Immunoenzyme Techniques ,Mice ,White Blood Cells ,Natalizumab ,Animal Cells ,Medicine and Health Sciences ,lcsh:Science ,Multidisciplinary ,CD11b Antigen ,Microglia ,T Cells ,Experimental autoimmune encephalomyelitis ,Antibodies, Monoclonal ,Animal Models ,Flow Cytometry ,medicine.anatomical_structure ,Neurology ,Cellular Types ,medicine.drug ,Research Article ,Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,Leukocyte adhesion molecule ,Immune Cells ,Immunology ,Mouse Models ,Biology ,Research and Analysis Methods ,Neuroprotection ,Autoimmune Diseases ,Model Organisms ,Antigen ,medicine ,Animals ,Pharmacology ,Blood Cells ,Multiple sclerosis ,Macrophages ,lcsh:R ,VLA-4 ,Biology and Life Sciences ,Cell Biology ,medicine.disease ,Demyelinating Disorders ,Mice, Inbred C57BL ,Pharmacodynamics ,lcsh:Q ,Clinical Immunology ,Clinical Medicine - Abstract
Natalizumab is a humanized monoclonal antibody against the leukocyte adhesion molecule very late antigen (VLA)-4, and is currently an approved therapy for patients with relapsing-remitting multiple sclerosis (RRMS). However, it is unknown whether natalizumab is beneficial for progressive forms of MS. Therefore, we assessed the effects of anti-VLA-4 monoclonal antibody (mAb) therapy in a progressive experimental autoimmune encephalomyelitis (EAE) mouse model. Notably, we found that early therapy could significantly reduce the severity of progressive EAE, while treatment initiated at an advanced stage was less efficient. Furthermore, we observed the accumulation of a novel subset of GM-CSF-producing CD11b+CD4+ T cells in the CNS throughout disease progression. Importantly, early therapeutic anti-VLA-4 mAb treatment suppressed the accumulation of these GM-CSF-producing CD11b+CD4+ T cells in the CNS along with activated microglia/macrophages populations, and also conferred a protective effect against inflammation-mediated neurodegeneration, including demyelination and axonal loss. Collectively, our data suggest that early treatment with anti-VLA-4 mAb can provide neuroprotection against progressive CNS autoimmune disease by preventing the accumulation of pathogenic GM-CSF-producing CD11b+CD4+ T cells in the CNS.
- Published
- 2013
18. Comparison of IFN-β inducible gene expression in primary-progressive and relapsing-remitting multiple sclerosis
- Author
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Kouichi Ito, Konstantin E. Balashov, Suhayl Dhib-Jalbut, John E. Mindur, and Sridhar Boppana
- Subjects
HLA-G Antigens ,Candidate gene ,Multiple sclerosis ,Immunology ,Interleukin-1beta ,Interferon-beta ,Biology ,Multiple Sclerosis, Chronic Progressive ,medicine.disease ,Peripheral blood mononuclear cell ,In vitro ,Up-Regulation ,Primary progressive ,Immune system ,Multiple Sclerosis, Relapsing-Remitting ,Neurology ,Interferon ,medicine ,Leukocytes, Mononuclear ,Immunology and Allergy ,Humans ,Neurology (clinical) ,Gene ,medicine.drug - Abstract
Interferon (IFN)-β is a type I IFN commonly produced by the innate immune system in response to viral infection. IFN-β is also used for the treatment of patients with the relapsing-remitting form of multiple sclerosis (RRMS); however, IFN-β therapy is unable to confer a significant benefit for primary-progressive MS (PPMS) patients. In this study, we assessed the gene profiles of peripheral blood mononuclear cells (PBMCs) isolated from PPMS, RRMS, and healthy donors (HD) in response to IFN-β treatment in vitro to examine genetic mechanisms underlying the inadequate response of IFN-β therapy in PPMS patients. Here, we show that HLA-G was significantly less up-regulated in response to IFN-β in PBMCs from PPMS compared to those from RRMS. This data suggests HLA-G to be a possible candidate gene found impaired in IFN-β-mediated immune regulation in PPMS patients.
- Published
- 2013
19. Dysregulation of immune response to enteric bacteria triggers the development of spontaneous experimental autoimmune encephalomyelitis
- Author
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Sudhir Kumar Yadav, Naoko Ito, John E Mindur, Martin Mathay, Suhayl Dhib-Jalbut, and Kouichi Ito
- Subjects
Immunology ,Immunology and Allergy - Abstract
Multiple sclerosis (MS) is an autoimmune disease against the central nervous system (CNS). Although the etiology of MS is still unknown, breakage of peripheral immune tolerance to CNS antigens is believed to be an initial event of CNS autoimmune diseases. It has been indicated that gut microbiota is an important environmental risk factor in MS/EAE pathogenesis; however, the exact mechanism for pathogenesis has not been elucidated. To examine how the immune tolerance to myelin basic protein (MBP) is broken, we created a humanized transgenic (Tg) mice that express MS-associated HLA-DR2a and MBP-specific TCR (3A6 TCR) genes isolated from an MS patient. The 3A6/DR2a Tg mice develop EAE spontaneously, and antibiotic treatment, which can reduce the population of commensal bacteria, was found to abolish the development of spontaneous EAE. Since fecal IgM is a marker of expansion of enteric bacteria, we examined the association of fecal IgM with spontaneous EAE development. Interestingly, raised levels of fecal IgM and expansion of enteric bacteria were associated with the development of spontaneous EAE, and a massive infiltration of MBP-specific Tg T cells and neutrophils, along with complement deposits, were detected in the colon of spontaneous EAE mice. Furthermore, MBP-specific GM-CSF+ Th1 and Th17 cells were expanding in the colon but not in the small intestine, and CNS-homing integrin, α4β1, was highly up-regulated in the MBP-specific T cells in the mesenteric lymph nodes in the spontaneous EAE mice. These data suggest that enteric bacteria-mediated dysregulation of gut immunity may be involved in the initiation and progression of CNS-autoimmune diseases.
- Published
- 2016
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