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1. Single-cell multi-ome and immune profiles of the Inspiration4 crew reveal conserved, cell-type, and sex-specific responses to spaceflight

Author

JangKeun Kim, Braden T. Tierney, Eliah G. Overbey, Ezequiel Dantas, Matias Fuentealba, Jiwoon Park, S. Anand Narayanan, Fei Wu, Deena Najjar, Christopher R. Chin, Cem Meydan, Conor Loy, Begum Mathyk, Remi Klotz, Veronica Ortiz, Khiem Nguyen, Krista A. Ryon, Namita Damle, Nadia Houerbi, Laura I. Patras, Nathan Schanzer, Gwyneth A. Hutchinson, Jonathan Foox, Chandrima Bhattacharya, Matthew Mackay, Evan E. Afshin, Jeremy Wain Hirschberg, Ashley S. Kleinman, Julian C. Schmidt, Caleb M. Schmidt, Michael A. Schmidt, Afshin Beheshti, Irina Matei, David Lyden, Sean Mullane, Amran Asadi, Joan S. Lenz, Omary Mzava, Min Yu, Saravanan Ganesan, Iwijn De Vlaminck, Ari M. Melnick, Darko Barisic, Daniel A. Winer, Sara R. Zwart, Brian E. Crucian, Scott M. Smith, Jaime Mateus, David Furman, and Christopher E. Mason

Subjects
Science
Abstract

Abstract Spaceflight induces an immune response in astronauts. To better characterize this effect, we generated single-cell, multi-ome, cell-free RNA (cfRNA), biochemical, and hematology data for the SpaceX Inspiration4 (I4) mission crew. We found that 18 cytokines/chemokines related to inflammation, aging, and muscle homeostasis changed after spaceflight. In I4 single-cell multi-omics data, we identified a “spaceflight signature” of gene expression characterized by enrichment in oxidative phosphorylation, UV response, immune function, and TCF21 pathways. We confirmed the presence of this signature in independent datasets, including the NASA Twins Study, the I4 skin spatial transcriptomics, and 817 NASA GeneLab mouse transcriptomes. Finally, we observed that (1) T cells showed an up-regulation of FOXP3, (2) MHC class I genes exhibited long-term suppression, and (3) infection-related immune pathways were associated with microbiome shifts. In summary, this study reveals conserved and distinct immune disruptions occurring and details a roadmap for potential countermeasures to preserve astronaut health.

Published
2024
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2. TIMP1 is an early biomarker for detection and prognosis of lung cancer

Author

Ezequiel Dantas, Anirudh Murthy, Tanvir Ahmed, Mujmmail Ahmed, Shakti Ramsamooj, Maurice A. Hurd, Tiffany Lam, Murtaza Malbari, Christopher Agrusa, Olivier Elemento, Chen Zhang, Darryl J. Pappin, Timothy E. McGraw, Brendon M. Stiles, Nasser K. Altorki, and Marcus D. Goncalves

Subjects
biomarkers, lung cancer, prognosis, TIMP1, Medicine (General), R5-920
Abstract

Abstract Background Lung cancer remains the major cause of cancer‐related deaths worldwide. Early stages of lung cancer are characterized by long asymptomatic periods that are ineffectively identified with the current screening programs. This deficiency represents a lost opportunity to improve the overall survival of patients. Serum biomarkers are among the most effective strategies for cancer screening and follow up. Methods Using bead‐based multiplexing assays we screened plasma and tumours of the KrasG12D/+; Lkb1f/f (KL) mouse model of lung cancer for cytokines that could be used as biomarkers. We identified tissue inhibitor of metalloproteinase 1 (TIMP1) as an early biomarker and validated this finding in the plasma of lung cancer patients. We used immunohistochemistry (IHC), previously published single‐cell RNA‐seq and bulk RNA‐seq data to assess the source and expression of TIMP1in the tumour. The prognostic value of TIMP1 was assessed using publicly available human proteomic and transcriptomic databases. Results We found that TIMP1 is a tumour‐secreted protein with high sensitivity and specificity for aggressive cancer, even at early stages in mice. We showed that TIMP1 levels in the tumour and serum correlate with tumour burden and worse survival in mice. We validated this finding using clinical samples from our institution and publicly available human proteomic and transcriptomic databases. These data support the finding that high tumour expression of TIMP1 correlates with an unfavorable prognosis in lung cancer patients. Conclusion TIMP1 is a suitable biomarker for lung cancer detection.

Published
2023
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3. Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer

Author

Andre Lima Queiroz, Ezequiel Dantas, Shakti Ramsamooj, Anirudh Murthy, Mujmmail Ahmed, Elizabeth R. M. Zunica, Roger J. Liang, Jessica Murphy, Corey D. Holman, Curtis J. Bare, Gregory Ghahramani, Zhidan Wu, David E. Cohen, John P. Kirwan, Lewis C. Cantley, Christopher L. Axelrod, and Marcus D. Goncalves

Subjects
Science
Abstract

Cancer-associated cachexia is characterized by loss of body weight, skeletal muscle and adipose tissue which relates to higher mortality in cancer patients. Here, the authors show in a lung cancer murine model that both ActRIIB signalling inhibition and restoring appetite are necessary to revert cachexia and improve survival in female mice.

Published
2022
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4. GLUT5 (SLC2A5) enables fructose-mediated proliferation independent of ketohexokinase

Author

Roger J. Liang, Samuel Taylor, Navid Nahiyaan, Junho Song, Charles J. Murphy, Ezequiel Dantas, Shuyuan Cheng, Ting-Wei Hsu, Shakti Ramsamooj, Rahul Grover, Seo-Kyoung Hwang, Bryan Ngo, Lewis C. Cantley, Kyu Y. Rhee, and Marcus D. Goncalves

Subjects
Fructose, Ketohexokinase, Hexokinase, GLUT5 (SLC2A5), Metabolism, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Fructose is an abundant source of carbon and energy for cells to use for metabolism, but only certain cell types use fructose to proliferate. Tumor cells that acquire the ability to metabolize fructose have a fitness advantage over their neighboring cells, but the proteins that mediate fructose metabolism in this context are unknown. Here, we investigated the determinants of fructose-mediated cell proliferation. Methods Live cell imaging and crystal violet assays were used to characterize the ability of several cell lines (RKO, H508, HepG2, Huh7, HEK293T (293T), A172, U118-MG, U87, MCF-7, MDA-MB-468, PC3, DLD1 HCT116, and 22RV1) to proliferate in fructose (i.e., the fructolytic ability). Fructose metabolism gene expression was determined by RT-qPCR and western blot for each cell line. A positive selection approach was used to “train” non-fructolytic PC3 cells to utilize fructose for proliferation. RNA-seq was performed on parental and trained PC3 cells to find key transcripts associated with fructolytic ability. A CRISPR-cas9 plasmid containing KHK-specific sgRNA was transfected in 293T cells to generate KHK -/- cells. Lentiviral transduction was used to overexpress empty vector, KHK, or GLUT5 in cells. Metabolic profiling was done with seahorse metabolic flux analysis as well as LC/MS metabolomics. Cell Titer Glo was used to determine cell sensitivity to 2-deoxyglucose in media containing either fructose or glucose. Results We found that neither the tissue of origin nor expression level of any single gene related to fructose catabolism determine the fructolytic ability. However, cells cultured chronically in fructose can develop fructolytic ability. SLC2A5, encoding the fructose transporter, GLUT5, was specifically upregulated in these cells. Overexpression of GLUT5 in non-fructolytic cells enabled growth in fructose-containing media across cells of different origins. GLUT5 permitted fructose to flux through glycolysis using hexokinase (HK) and not ketohexokinase (KHK). Conclusions We show that GLUT5 is a robust and generalizable driver of fructose-dependent cell proliferation. This indicates that fructose uptake is the limiting factor for fructose-mediated cell proliferation. We further demonstrate that cellular proliferation with fructose is independent of KHK.

Published
2021
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5. Extracellular Acidosis and mTOR Inhibition Drive the Differentiation of Human Monocyte-Derived Dendritic Cells

Author

Fernando Erra Díaz, Valeria Ochoa, Antonela Merlotti, Ezequiel Dantas, Ignacio Mazzitelli, Virginia Gonzalez Polo, Juan Sabatté, Sebastián Amigorena, Elodie Segura, and Jorge Geffner

Subjects
Monocytes, dendritic cells, differentiation, acidosis, low pH, metabolism, Biology (General), QH301-705.5
Abstract

Summary: During inflammation, recruited monocytes can differentiate either into macrophages or dendritic cells (DCs); however, little is known about the environmental factors that determine this cell fate decision. Low extracellular pH is a hallmark of a variety of inflammatory processes and solid tumors. Here, we report that low pH dramatically promotes the differentiation of monocytes into DCs (monocyte-derived DCs [mo-DCs]). This process is associated with a reduction in glucose consumption and lactate production, the upregulation of mitochondrial respiratory chain genes, and the inhibition of mTORC1 activity. Interestingly, we also find that both serum starvation and pharmacological inhibition of mTORC1 markedly promote the differentiation of mo-DCs. Our study contributes to better understanding the mechanisms that govern the differentiation of monocytes into DCs and reveals the role of both extracellular pH and mTORC1 as master regulators of monocyte cell fate.

Published
2020
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11. Tumor Cytokine-Induced Hepatic Gluconeogenesis Contributes to Cancer Cachexia: Insights from Full Body Single Nuclei Sequencing

Author

Ying Liu, Ezequiel Dantas, Miriam Ferrer, Yifang Liu, Aram Comjean, Emma E. Davidson, Yanhui Hu, Marcus D. Goncalves, Tobias Janowitz, and Norbert Perrimon

Subjects
Article
Abstract

SummaryA primary cause of death in cancer patients is cachexia, a wasting syndrome attributed to tumor-induced metabolic dysregulation. Despite the major impact of cachexia on the treatment, quality of life, and survival of cancer patients, relatively little is known about the underlying pathogenic mechanisms. Hyperglycemia detected in glucose tolerance test is one of the earliest metabolic abnormalities observed in cancer patients; however, the pathogenesis by which tumors influence blood sugar levels remains poorly understood. Here, utilizing aDrosophilamodel, we demonstrate that the tumor secreted interleukin-like cytokine Upd3 induces fat body expression ofPepck1andPdk, two key regulatory enzymes of gluconeogenesis, contributing to hyperglycemia. Our data further indicate a conserved regulation of these genes by IL-6/JAK STAT signaling in mouse models. Importantly, in both fly and mouse cancer cachexia models, elevated gluconeogenesis gene levels are associated with poor prognosis. Altogether, our study uncovers a conserved role of Upd3/IL-6/JAK-STAT signaling in inducing tumor-associated hyperglycemia, which provides insights into the pathogenesis of IL-6 signaling in cancer cachexia.Graphical Abstract

Published
2023
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12. GLUT5 (SLC2A5) enables fructose-mediated proliferation independent of ketohexokinase

Author

Ezequiel Dantas, Marcus D. Goncalves, Lewis C. Cantley, Rahul Grover, Samuel Taylor, Ting-Wei Hsu, Roger Liang, Charles J. Murphy, Kyu Y. Rhee, Bryan Ngo, Shakti Ramsamooj, Junho Song, Seo-Kyoung Hwang, Shuyuan Cheng, and Navid Nahiyaan

Subjects
Cell type, biology, Cell growth, Research, HEK 293 cells, Fructose, Transfection, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, GLUT5 (SLC2A5), lcsh:RC254-282, Cell biology, Psychiatry and Mental health, chemistry.chemical_compound, Metabolism, chemistry, Cell culture, Hexokinase, biology.protein, Glycolysis, Ketohexokinase, GLUT5
Abstract

BackgroundFructose is an abundant source of carbon and energy for cells to use for metabolism, but only certain cell types use fructose to proliferate. Tumor cells that acquire the ability to metabolize fructose have a fitness advantage over their neighboring cells, but the proteins that mediate fructose metabolism in this context are unknown. Here, we investigated the determinants of fructose-mediated cell proliferation.MethodsLive cell imaging and crystal violet assays were used to characterize the ability of several cell lines (RKO, H508, HepG2, Huh7, HEK293T (293T), A172, U118-MG, U87, MCF-7, MDA-MB-468, PC3, DLD1 HCT116, and 22RV1) to proliferate in fructose (i.e., the fructolytic ability). Fructose metabolism gene expression was determined by RT-qPCR and western blot for each cell line. A positive selection approach was used to “train” non-fructolytic PC3 cells to utilize fructose for proliferation. RNA-seq was performed on parental and trained PC3 cells to find key transcripts associated with fructolytic ability. A CRISPR-cas9 plasmid containingKHK-specific sgRNA was transfected in 293T cells to generateKHK-/-cells. Lentiviral transduction was used to overexpress empty vector, KHK, or GLUT5 in cells. Metabolic profiling was done with seahorse metabolic flux analysis as well as LC/MS metabolomics. Cell Titer Glo was used to determine cell sensitivity to 2-deoxyglucose in media containing either fructose or glucose.ResultsWe found that neither the tissue of origin nor expression level of any single gene related to fructose catabolism determine the fructolytic ability. However, cells cultured chronically in fructose can develop fructolytic ability.SLC2A5, encoding the fructose transporter, GLUT5, was specifically upregulated in these cells. Overexpression of GLUT5 in non-fructolytic cells enabled growth in fructose-containing media across cells of different origins. GLUT5 permitted fructose to flux through glycolysis using hexokinase (HK) and not ketohexokinase (KHK).ConclusionsWe show that GLUT5 is a robust and generalizable driver of fructose-dependent cell proliferation. This indicates that fructose uptake is the limiting factor for fructose-mediated cell proliferation. We further demonstrate that cellular proliferation with fructose is independent of KHK.

Published
2021

13. Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer

Author

Andre Lima Queiroz, Ezequiel Dantas, Shakti Ramsamooj, Anirudh Murthy, Mujmmail Ahmed, Elizabeth R. M. Zunica, Roger J. Liang, Jessica Murphy, Corey D. Holman, Curtis J. Bare, Gregory Ghahramani, Zhidan Wu, David E. Cohen, John P. Kirwan, Lewis C. Cantley, Christopher L. Axelrod, and Marcus D. Goncalves

Subjects
Male, Multidisciplinary, Cachexia, Lung Neoplasms, General Physics and Astronomy, Appetite, General Chemistry, General Biochemistry, Genetics and Molecular Biology, Anorexia, Mice, Carcinoma, Non-Small-Cell Lung, Animals, Humans, Female
Abstract

Cancer cachexia is a common, debilitating condition with limited therapeutic options. Using an established mouse model of lung cancer, we find that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. We identify Activin A as a purported driver of cachexia and treat with ActRIIB-Fc, a decoy ligand for TGF-β/activin family members, together with anamorelin (Ana), a ghrelin receptor agonist, to reverse muscle dysfunction and anorexia, respectively. Ana effectively increases food intake but only the combination of drugs increases lean mass, restores spontaneous activity, and improves overall survival. These beneficial effects are limited to female mice and are dependent on ovarian function. In agreement, high expression of Activin A in human lung adenocarcinoma correlates with unfavorable prognosis only in female patients, despite similar expression levels in both sexes. This study suggests that multimodal, sex-specific, therapies are needed to reverse cachexia.

Published
2021

14. Blocking ActRIIB signaling and restoring appetite reverses cachexia and improves survival in mice with lung cancer

Author

Marcus D. Goncalves, Gregory Ghahramani, Charles J. Murphy, Ezequiel Dantas, Anirudh Murthy, Andre Lima Queiroz, Curtis J. Bare, Roger Liang, Elizabeth R M Zunica, John P. Kirwan, Shakti Ramsamooj, Lewis C. Cantley, Christopher L. Axelrod, Zhidan Wu, David E. Cohen, and Corey D. Holman

Subjects
Blocking (radio), business.industry, media_common.quotation_subject, digestive, oral, and skin physiology, medicine, Cancer research, Appetite, Lung cancer, medicine.disease, business, media_common, Cachexia
Abstract

The cancer anorexia-cachexia syndrome (CACS) is a common, debilitating condition with limited therapeutic options. The defining feature of CACS is weight loss, which suggests a state of negative energy balance. It is unclear whether this net reduction in energy is due solely to anorexia or if a combination of anorexia and increased energy expenditure (EE) occurs. To address this question, we induced lung cancer in mice and measured changes in food intake, EE, and body composition. Mice with CACS developed reductions in food intake, spontaneous activity, and EE. There was severe atrophy and markers of metabolic dysfunction in the adipose and skeletal muscle tissues as compared to mice without CACS and pair-fed wild-type mice. We used anamorelin fumarate (Ana), a ghrelin receptor agonist, alone or in combination ActRIIB-Fc, a ligand trap for TGF-β/activin family members, to reverse anorexia and skeletal muscle atrophy, respectively. Ana effectively increased food intake and the combination of drugs increased lean mass, restored spontaneous activity, and improved overall survival. These beneficial effects were limited to female mice. Our findings suggest that multimodal, gender-specific, therapies are needed to reverse CACS.

Published
2021
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15. Extracellular acidosis enhances Zika virus infection both in human cells and ex-vivo tissue cultures from female reproductive tract

Author

F Di Diego García, Augusto Varese, M Dodes Traian, F Remes Lenicov, W Fitzgerald, L Margolis, Jorge Geffner, Gonzalo Cabrerizo, Horacio M. Pallarés, Ezequiel Dantas, Lucas A. Defelipe, Andrea V. Gamarnik, Ana Luz Paletta, Ana Ceballos, and F Erra Diaz

Subjects
0301 basic medicine, Epidemiology, EX-VIVO TISSUES, Cervix Uteri, Zika virus, purl.org/becyt/ford/1 [https], chemistry.chemical_compound, Tissue culture, heparan sulphate, Drug Discovery, Chlorocebus aethiops, Acidosis, Zika Virus Infection, General Medicine, Heparan sulfate, Hydrogen-Ion Concentration, HEPARAN SULPHATE, Infectious Diseases, Vagina, Female, medicine.symptom, Female Reproductive Tract, Research Article, Sexual transmission, 030106 microbiology, Immunology, Biology, Microbiology, ex-vivo tissues, Cell Line, 03 medical and health sciences, Virology, Extracellular, medicine, Animals, Humans, extracellular acidosis, purl.org/becyt/ford/1.6 [https], Vero Cells, ZIKV, SEXUAL TRANSMISSION, Zika Virus, biology.organism_classification, sexual transmission, EXTRACELLULAR ACIDOSIS, 030104 developmental biology, chemistry, Microscopy, Fluorescence, Parasitology, Heparitin Sulfate, Ex vivo
Abstract

Zika virus (ZIKV) is a flavivirus transmitted by mosquitoes of the genus Aedes, but unlike other flaviviruses, ZIKV can be sexually transmitted by vaginal intercourse. The healthy vaginal pH ranges from 4.0 to 6.0, reaching values of 6.0–7.0 after semen deposition. Here, we report that low extracellular pH values (range 6.2–6.6) dramatically increase ZIKV infection on cell lines of different origin including some derived from the female genital tract and monocyte-derived macrophages. Furthermore, low pH significantly increased ZIKV infection of human ectocervix and endocervix cultured ex-vivo. Enhancement of infection by low pH was also observed using different ZIKV strains and distinct methods to evaluate viral infection, i.e. plaque assays, RT–PCR, flow cytometry, and fluorescence microscopy. Analysis of the mechanisms involved revealed that the enhancement of ZIKV infection induced by low pH was associated with increased binding of the viral particles to the heparan sulphate expressed on the target cell surface. Acidosis represents a critical but generally overlooked feature of the female genital tract, with major implications for sexual transmission diseases. Our results suggest that low vaginal pH might promote male-to-female transmission of ZIKV infection. Fil: Varese, Augusto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Dantas, Ezequiel Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Paletta, Ana Luz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Fitzgerald, W.. National Institutes of Health; Estados Unidos Fil: Di Diego García, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Cabrerizo, Gonzalo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Erra Diaz, Fernando Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Defelipe, Lucas Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Pallarés, Horacio Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Dodes Traian, Martín Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Gamarnik, Andrea Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Geffner, Jorge Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Remes Lenicov, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Margolis, L.. National Institutes of Health; Estados Unidos Fil: Ceballos, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina

Published
2021

16. Histidine-Rich Glycoprotein Inhibits HIV-1 Infection in a pH-Dependent Manner

Author

Augusto Varese, Fernando Erra Díaz, Matias Ostrowski, Alberto L. Epstein, Ana Ceballos, Julieta Pandolfi, Juan Sabatté, Ezequiel Dantas, Diana Jerusalinsky, Jorge Geffner, Pehuén Pereyra Gerber, Hernán García Rivello, and Ana del Valle Jaén

Subjects
ACIDOSIS, PH, Herpesvirus 2, Human, HIV Infections, medicine.disease_cause, Ligands, Jurkat cells, chemistry.chemical_compound, Chlorocebus aethiops, chemistry.chemical_classification, 0303 health sciences, biology, 030302 biochemistry & molecular biology, RSV, Heparan sulfate, purl.org/becyt/ford/3.1 [https], Blood Proteins, Hydrogen-Ion Concentration, HSV-2, HSV-1, Respiratory Syncytial Viruses, Medicina Básica, Virus Diseases, Cervix Mucus, purl.org/becyt/ford/3 [https], Female, Antibody, CIENCIAS MÉDICAS Y DE LA SALUD, Histidine-rich glycoprotein, Immunology, Inmunología, Microbiology, Antiviral Agents, Virus, Cell Line, 03 medical and health sciences, Virology, medicine, Animals, Humans, Histidine, Vero Cells, 030304 developmental biology, Glycoproteins, Proteins, HRG, Herpes simplex virus, chemistry, Insect Science, HISTIDINE-RICH GLYCOPROTEIN, biology.protein, Vero cell, HIV-1, Pathogenesis and Immunity, Heparitin Sulfate, Glycoprotein
Abstract

Histidine-rich glycoprotein (HRG) is an abundant plasma protein with a multidomain structure, allowing its interaction with many ligands, including phospholipids, plasminogen, fibrinogen, IgG antibodies, and heparan sulfate. HRG has been shown to regulate different biological responses, such as angiogenesis, coagulation, and fibrinolysis. Here, we found that HRG almost completely abrogated the infection of Ghost cells, Jurkat cells, CD4+ T cells, and macrophages by HIV-1 at a low pH (range, 6.5 to 5.5) but not at a neutral pH. HRG was shown to interact with the heparan sulfate expressed by target cells, inhibiting an early postbinding step associated with HIV-1 infection. More importantly, by acting on the viral particle itself, HRG induced a deleterious effect, which reduces viral infectivity. Because cervicovaginal secretions in healthy women show low pH values, even after semen deposition, our observations suggest that HRG might represent a constitutive defense mechanism in the vaginal mucosa. Of note, low pH also enabled HRG to inhibit the infection of HEp-2 cells and Vero cells by respiratory syncytial virus (RSV) and herpes simplex virus 2 (HSV-2), respectively, suggesting that HRG might display broad antiviral activity under acidic conditions. Fil: Dantas, Ezequiel Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Díaz, Fernando Erra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Pereyra Gerber, Federico Pehuén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Varese, Augusto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Jerusalinsky, Diana Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina Fil: Epstein, Alberto Luis. Université de Versailles Saint-quentin-en-yvelines.; Francia. Inserm; Francia Fil: García Rivello, Hernán J.. Hospital Italiano. Instituto Universitario. Escuela de Medicina; Argentina Fil: del Valle Jaén, Ana. Hospital Italiano. Instituto Universitario. Escuela de Medicina; Argentina Fil: Pandolfi, Julieta Belen. Hospital Italiano. Instituto Universitario. Escuela de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Ceballos, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Ostrowski, Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Sabatté, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Geffner, Jorge Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina

Published
2019

17. Unravelling the Interplay between Extracellular Acidosis and Immune Cells

Author

Ezequiel Dantas, Fernando Erra Díaz, and Jorge Geffner

Subjects
0301 basic medicine, ACIDOSIS, CIENCIAS MÉDICAS Y DE LA SALUD, Inflammasomes, Immunology, Inmunología, Inflammation, Review Article, IMMUNITY, CD8-Positive T-Lymphocytes, Monocytes, 03 medical and health sciences, Immune system, INFLAMMATION, medicine, Extracellular, Cytotoxic T cell, Animals, Humans, Tumor microenvironment, Innate immune system, Chemistry, Inflammasome, Cell Differentiation, Cell Biology, purl.org/becyt/ford/3.1 [https], Hydrogen-Ion Concentration, CANCER, Medicina Básica, 030104 developmental biology, Cancer research, purl.org/becyt/ford/3 [https], medicine.symptom, Acidosis, CD8, medicine.drug
Abstract

The development of an acidic tissue environment is a hallmark of a variety of inflammatory processes and solid tumors. However, little attention has been paid so far to analyze the influence exerted by extracellular pH on the immune response. Tissue acidosis (pH 6.0 to 7.0) is usually associated with the course of infectious processes in peripheral tissues. Moreover, it represents a prominent feature of solid tumors. In fact, values of pH ranging from 5.7 to 7.0 are usually found in a number of solid tumors such as breast cancer, brain tumors, sarcomas, malignant melanoma, squamous cell carcinomas, and adenocarcinomas. Both the innate and adaptive arms of the immune response appear to be finely regulated by extracellular acidosis in the range of pH values found at inflammatory sites and tumors. Low pH has been shown to delay neutrophil apoptosis, promoting their differentiation into a proangiogenic profile. Acting on monocytes and macrophages, it induces the activation of the inflammasome and the production of IL-1β, while the exposure of conventional dendritic cells to low pH promotes the acquisition of a mature phenotype. Overall, these observations suggest that high concentrations of protons could be recognized by innate immune cells as a danger-associated molecular pattern (DAMP). On the other hand, by acting on T lymphocytes, low pH has been shown to suppress the cytotoxic response mediated by CD8+ T cells as well as the production of IFN-γ by TH1 cells. Interestingly, modulation of tumor microenvironment acidity has been shown to be able not only to reverse anergy in human and mouse tumor-infiltrating T lymphocytes but also to improve the antitumor immune response induced by checkpoint inhibitors. Here, we provide an integrated view of the influence exerted by low pH on immune cells and discuss its implications in the immune response against infectious agents and tumor cells. Fil: Erra Diaz, Fernando Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Dantas, Ezequiel Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Geffner, Jorge Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina

Published
2018

18. Histidine-rich glycoprotein and idiopathic pulmonary fibrosis

Author

Fabian Caro, Glenda Ernst, Pedro Grynblat, Ezequiel Dantas, J. Sabatté, Alejandro Salvado, and Jorge Geffner

Subjects
Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Histidine-rich glycoprotein, medicine.medical_treatment, Vital Capacity, Enzyme-Linked Immunosorbent Assay, Fibrinogen, chemistry.chemical_compound, Idiopathic pulmonary fibrosis, Internal medicine, Fibrinolysis, Humans, Medicine, Thrombospondin, business.industry, Smoking, Acute-phase protein, Proteins, Heparan sulfate, Middle Aged, respiratory system, medicine.disease, Idiopathic Pulmonary Fibrosis, humanities, respiratory tract diseases, Complement system, Endocrinology, chemistry, Immunology, Female, business, Bronchoalveolar Lavage Fluid, Biomarkers, medicine.drug
Abstract

Histidine-rich glycoprotein (HRG) is an enigmatic glycoprotein able to interact with a variety of ligands such as IgG, complement components, heparan sulfate, thrombospondin, fibrinogen and plasminogen. HRG is present at high concentrations in plasma and there is evidence indicating that it is able to modulate the course of biological processes such as angiogenesis, fibroblast proliferation, complement activation, coagulation and fibrinolysis. Because these processes are involved in the pathogeneses of lung fibrosis we here analyzed a possible link between HRG and idiopathic pulmonary fibrosis (IPF). We found that plasma concentrations of HRG are significantly diminished in IPF patients compared to healthy subjects. Moreover, we found a positive correlation between HRG plasma levels and forced vital capacity (FVC) values, suggesting that plasma concentration of HRG would be a useful indicator of disease activity in IPF. HRG has been described as a negative acute phase reactant able to accumulate at sites of tissue injury. Hence, we also measured the concentrations of HRG in BAL samples from IPF patients. We found that the concentrations of HRG in samples from IPF patients were significantly higher compared to controls, suggesting that the reduced concentration of HRG in plasma from IPF patients could be due, at least in part, to an enhanced uptake of this protein in the lung.

Published
2015
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19. Low pH impairs complement-dependent cytotoxicity against IgG-coated target cells

Author

Antonela Merlotti, Pehuén Pereyra Gerber, Ezequiel Dantas, Matias Ostrowski, Jorge Geffner, Augusto Varese, Juan Sabatté, and Fernando Erra Díaz

Subjects
0301 basic medicine, ACIDOSIS, CIENCIAS MÉDICAS Y DE LA SALUD, medicine.drug_class, PH, Inmunología, Monoclonal antibody, Peripheral blood mononuclear cell, COMPLEMENT, 03 medical and health sciences, Immune system, rituximab, medicine, cancer, Humans, complement, RITUXIMAB, Cytotoxicity, business.industry, pH, Antibody-Dependent Cell Cytotoxicity, purl.org/becyt/ford/3.1 [https], Complement System Proteins, Hydrogen-Ion Concentration, Virology, Molecular biology, Burkitt Lymphoma, CANCER, Complement-dependent cytotoxicity, Complement system, Medicina Básica, 030104 developmental biology, Oncology, Cell culture, Immunoglobulin G, Rituximab, purl.org/becyt/ford/3 [https], acidosis, business, medicine.drug, Research Paper
Abstract

Local acidosis is a common feature of allergic, vascular, autoimmune, and cancer diseases. However, few studies have addressed the effect of extracellular pH on the immune response. Here, we analyzed whether low pH could modulate complementdependent cytotoxicity (CDC) against IgG-coated cells. Using human serum as a complement source, we found that extracellular pH values of 5.5 and 6.0 strongly inhibit CDC against either B lymphoblast cell lines coated with the chimeric anti-CD20 mAb rituximab or PBMCs coated with the humanized anti-CD52 mAb alemtuzumab. Suppression of CDC by low pH was observed either in cells suspended in culture medium or in whole blood assays. Interestingly, not only CDC against IgG-coated cells, but also the activation of the complement system induced by the alternative and lectin pathways was prevented by low pH. Tumor-targeting mAbs represent one of the most successful tools for cancer therapy, however, the use of mAb monotherapy has only modest effects on solid tumors. Our present results suggest that severe acidosis, a hallmark of solid tumors, might impair complement-mediated tumor destruction directed by mAb. Fil: Dantas, Ezequiel Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Erra Diaz, Fernando Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Pereyra Gerber, Federico Pehuén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Merlotti Ippólito, Antonela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Varese, Augusto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Ostrowski, Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Sabatte, Juan Atilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Geffner, Jorge Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina

Published
2016

20. Fucosylated clusterin in semen promotes the uptake of stress-damaged proteins by dendritic cells via DC-SIGN

Author

Ana Ceballos, Antonela Merlotti, Ezequiel Dantas, Juan Sabatté, Julia Rubione, S. Stover, F Remes Lenicov, Augusto Varese, Jorge Geffner, and Carolina Jancic

Subjects
Adult, Male, CIENCIAS MÉDICAS Y DE LA SALUD, Inmunología, Semen, Receptors, Cell Surface, DC-SIGN, Humans, Lectins, C-Type, TOLERANCE, SEMEN, CLUSTERIN, Heat-Shock Proteins, biology, Clusterin, Rehabilitation, Obstetrics and Gynecology, purl.org/becyt/ford/3.1 [https], Dendritic Cells, Middle Aged, Molecular biology, DENDRITIC, Medicina Básica, Reproductive Medicine, biology.protein, purl.org/becyt/ford/3 [https], Cell Adhesion Molecules
Abstract

STUDY QUESTION: Could seminal plasma clusterin play a role in the uptake of stress-damaged proteins by dendritic cells? SUMMARY ANSWER: Seminal plasma clusterin, but not serum clusterin, promotes the uptake of stress-damaged proteins by dendritic cells via DC-SIGN. WHAT IS KNOWN ALREADY: Clusterin is one of the major extracellular chaperones. It interacts with a variety of stressed proteins to prevent their aggregation, guiding them for receptor-mediated endocytosis and intracellular degradation. The concentration of clusterin in semen is almost 20-fold higher than that found in serum, raising the question about the role of seminal plasma clusterin in reproduction. No previous studies have analyzed whether seminal plasma clusterin has chaperone activity. We have previously shown that seminal plasma clusterin, but not serum clusterin, expresses an extreme abundance of fucosylated glycans. These motifs enable seminal plasma clusterin to bind DC-SIGN with very high affinity. STUDY DESIGN, SIZE, DURATION: In vitro experiments were performed to evaluate the ability of seminal plasma clusterin to inhibit the precipitation of stressed proteins, promoting their uptake by dendritic cells via DC-SIGN (a C-type lectin receptor selectively expressed on dendritic cells (DC)). Moreover, the ability of seminal plasma clusterin to modulate the phenotype and function of DCs was also assessed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Clusterin was purified from human semen and human serum. Catalase, bovine serum albumin, glutathione S-transferase, and normal human serum were stressed and the ability of seminal plasma clusterin to prevent the precipitation of these proteins, guiding them to DC-SIGN expressed by DCs, was evaluated using a fluorescence-activated cell sorter (FACS). Endocytosis of stressed proteins was analyzed by confocal microscopy and the ability of seminal plasma clusterin-treated DCs to stimulate the proliferation of CD25+FOXP3+CD4+ T cells was also evaluated by FACS. MAIN RESULTS AND THE ROLE OF CHANCE: Seminal plasma clusterin interacts with stressed proteins, inhibits their aggregation (P < 0.01) and efficiently targets them to dendritic cells via DC-SIGN (P < 0.01). DCs efficiently endocytosed clusterin-client complexes and sorted them to degradative compartments involved in antigen processing and presentation. Moreover, we also found that the interaction of seminal plasma clusterin with DC-SIGN did not change the phenotype of DCs, but stimulates their ability to induce the expansion of CD25+FOXP3+CD4+ T lymphocytes (P < 0.05 versus control). LIMITATIONS, REASONS FOR CAUTION: All the experiments were performed in vitro; hence the relevance of our observations should be validated in vivo. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that by inducing the endocytosis of stress-damaged proteins by DCs via DC-SIGN, seminal plasma clusterin might promote a tolerogenic response to male antigens, thereby contributing to female tolerance to seminal antigens. STUDY FUNDING/COMPETING INTEREST(S): The present research was supported by the Consejo Nacional de Investigaciones Científicas y Técnicas, the Buenos Aires University School of Medicine, and the Agencia Nacional de Promoción Científica y Tecnológica (Argentina). The authors have no conflicts of interest to declare. Fil: Merlotti Ippólito, Antonela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina Fil: Dantas, Ezequiel Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Remes Lenicov, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Ceballos, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Jancic, Carolina Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Varese, Augusto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Rubione, Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Stover, Juliana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Geffner, Jorge Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: Sabatte, Juan Atilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina

Published
2014

21. Fever-range hyperthermia improves the anti-apoptotic effect induced by low pH on human neutrophils promoting a proangiogenic profile

Author

Norberto Sanjuan, Gabriel Duette, Maia Diana Eliana Cabrera, Jorge Geffner, María Victoria Delpino, Julia Rubione, Analía Silvina Trevani, Constanza A Benítez, Ezequiel Dantas, and Fernando Erra Díaz

Subjects
0301 basic medicine, Hyperthermia, Cancer Research, Fever, Neutrophils, Phagocytosis, T-Lymphocytes, Immunology, Neovascularization, Physiologic, Inflammation, Apoptosis, Biology, Proinflammatory cytokine, 03 medical and health sciences, Cellular and Molecular Neuroscience, medicine, Extracellular, Humans, Cell Proliferation, chemistry.chemical_classification, Reactive oxygen species, Cell Biology, Hyperthermia, Induced, Hydrogen-Ion Concentration, medicine.disease, Amiloride, Cell biology, 030104 developmental biology, Phenotype, chemistry, Original Article, medicine.symptom, medicine.drug
Abstract

Neutrophils have the shortest lifespan among leukocytes and usually die via apoptosis, limiting their deleterious potential. However, this tightly regulated cell death program can be modulated by pathogen-associated molecular patterns (PAMPs), danger-associated molecular pattern (DAMPs), and inflammatory cytokines. We have previously reported that low pH, a hallmark of inflammatory processes and solid tumors, moderately delays neutrophil apoptosis. Here we show that fever-range hyperthermia accelerates the rate of neutrophil apoptosis at neutral pH but markedly increases neutrophil survival induced by low pH. Interestingly, an opposite effect was observed in lymphocytes; hyperthermia plus low pH prevents lymphocyte activation and promotes the death of lymphocytes and lymphoid cell lines. Analysis of the mechanisms through which hyperthermia plus low pH increased neutrophil survival revealed that hyperthermia further decreases cytosolic pH induced by extracellular acidosis. The fact that two Na+/H+ exchanger inhibitors, 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and amiloride, reproduced the effects induced by hyperthermia suggested that it prolongs neutrophil survival by inhibiting the Na+/H+ antiporter. The neutrophil anti-apoptotic effect induced by PAMPs, DAMPs, and inflammatory cytokines usually leads to the preservation of the major neutrophil effector functions such as phagocytosis and reactive oxygen species (ROS) production. In contrast, our data revealed that the anti-apoptotic effect induced by low pH and hyperthermia induced a functional profile characterized by a low phagocytic activity, an impairment in ROS production and a high ability to suppress T-cell activation and to produce the angiogenic factors VEGF, IL-8, and the matrix metallopeptidase 9 (MMP-9). These results suggest that acting together fever and local acidosis might drive the differentiation of neutrophils into a profile able to promote both cancer progression and tissue repair during the late phase of inflammation, two processes that are strongly dependent on the local production of angiogenic factors by infiltrating immune cells.

Published
2016

22. Decreased Plasmatic Levels of Histidine-Rich Glycoprotein in Patients With Idiopathic Pulmonary Fibrosis: Relationship With Lung Diffusion Capacity and Walking Test

Author

Antonella Merlotti, Jorge Geffner, Fabian Caro, Glenda Ernst, Pedro Grynblat, Santiago E. Rossi, Ezequiel Dantas, Augusto Varesse, and Gabriel Duette

Subjects
Pulmonary and Respiratory Medicine, chemistry.chemical_classification, medicine.medical_specialty, Pathology, Lung, Histidine-rich glycoprotein, Walking test, business.industry, Critical Care and Intensive Care Medicine, medicine.disease, Gastroenterology, Lung diffusion capacity, Idiopathic pulmonary fibrosis, medicine.anatomical_structure, chemistry, Internal medicine, medicine, In patient, Cardiology and Cardiovascular Medicine, Glycoprotein, business, Histidine
Published
2014
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