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Loitto, Vesa-Matti
Alternative names
Publications (10 of 23) Show all publications
Ingelsson, B., Söderberg, D., Strid, T., Söderberg, A., Bergh, A.-C., Loitto, V.-M., . . . Rosén, A. (2018). Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C. Proceedings of the National Academy of Sciences of the United States of America, 115(3), E478-E487
Open this publication in new window or tab >>Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 3, p. E478-E487Article in journal (Refereed) Published
Abstract [en]

Circulating mitochondrial DNA (mtDNA) is receiving increasing attention as a danger-associated molecular pattern in conditions such as autoimmunity, cancer, and trauma. We report here that human lymphocytes [B cells, T cells, natural killer (NK) cells], monocytes, and neutrophils derived from healthy blood donors, as well as B cells from chronic lymphocytic leukemia patients, rapidly eject mtDNA as web filament structures upon recognition of CpG and non-CpG oligodeoxynucleotides of class C. The release was quenched by ZnCl2, independent of cell death (apoptosis, necrosis, necroptosis, autophagy), and continued in the presence of TLR9 signaling inhibitors. B-cell mtDNA webs were distinct from neutrophil extracellular traps concerning structure, reactive oxygen species (ROS) dependence, and were devoid of antibacterial proteins. mtDNA webs acted as rapid (within minutes) messengers, priming antiviral type I IFN production. In summary, our findings point at a previously unrecognized role for lymphocytes in antimicrobial defense, utilizing mtDNA webs as signals in synergy with cytokines and natural antibodies, and cast light on the interplay between mitochondria and the immune system.

Place, publisher, year, edition, pages
Washington, DC, United States: National Academy of Sciences, 2018
Keywords
CpG-C, DAMP, immune DNA sensing, lymphocyte signaling, mitochondrial DNA release
National Category
Basic Medicine Immunology in the medical area
Research subject
Economic Information Systems
Identifiers
urn:nbn:se:liu:diva-144187 (URN)10.1073/pnas.1711950115 (DOI)000423091400018 ()29295921 (PubMedID)2-s2.0-85042104216 (Scopus ID)
Funder
Swedish Cancer Society
Note

Funding agencies: Linkoping Medical Society; Linkoping University; ALF grants; Region Ostergotland, Sweden; Linkoping University Cancer; Ingrid Asp Foundation; Swedish Cancer Society

Available from: 2018-01-09 Created: 2018-01-09 Last updated: 2018-09-07Bibliographically approved
Lopes, V. R., Loitto, V., Audinot, J., Bayat, N., Gutleb, A. C. & Cristobal, S. (2016). Dose‑dependent autophagic effectof titanium dioxide nanoparticles in humanHaCaT cells at non‑cytotoxic levels. Journal of Nanobiotechnology, 14(22), 1-13
Open this publication in new window or tab >>Dose‑dependent autophagic effectof titanium dioxide nanoparticles in humanHaCaT cells at non‑cytotoxic levels
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2016 (English)In: Journal of Nanobiotechnology, ISSN 1477-3155, E-ISSN 1477-3155, Vol. 14, no 22, p. 1-13Article in journal (Refereed) Published
Abstract [en]

Background: Interactions between nanoparticles and cells are now the focus of a fast-growing area of research.Though many nanoparticles interact with cells without any acute toxic responses, metal oxide nanoparticles includingthose composed of titanium dioxide (TiO2-NPs) may disrupt the intracellular process of macroautophagy.Autophagy plays a key role in human health and disease, particularly in cancer and neurodegenerative diseases. Weherein investigated the in vitro biological effects of TiO2-NPs (18 nm) on autophagy in human keratinocytes (HaCaT)cells at non-cytotoxic levels.Results: TiO2-NPs were characterized by transmission electron microscopy (TEM) and dynamic light scatteringtechniques. Cellular uptake, as evaluated by TEM and NanoSIMS revealed that NPs internalization led to the formationof autophagosomes. TiO2-NPs treatment did not reduce cell viability of HaCaT cells nor increased oxidative stress. Cellularautophagy was additionally evaluated by confocal microscopy using eGFP-LC3 keratinocytes, western blottingof autophagy marker LC3I/II, immunodetection of p62 and NBR1 proteins, and gene expression of LC3II, p62, NBR1,beclin1 and ATG5 by RT-qPCR. We also confirmed the formation and accumulation of autophagosomes in NPs treatedcells with LC3-II upregulation. Based on the lack of degradation of p62 and NBR1 proteins, autophagosomes accumulationat a high dose (25.0 μg/ml) is due to blockage while a low dose (0.16 μg/ml) promoted autophagy. Cellularviability was not affected in either case.Conclusions: The uptake of TiO2-NPs led to a dose-dependent increase in autophagic effect under non-cytotoxicconditions. Our results suggest dose-dependent autophagic effect over time as a cellular response to TiO2-NPs. Mostimportantly, these findings suggest that simple toxicity data are not enough to understand the full impact of TiO2-NPsand their effects on cellular pathways or function.

Place, publisher, year, edition, pages
BioMed Central, 2016
Keywords
Autophagy, Cell-nanoparticle interactions, Dose, Keratinocytes, Titanium dioxide nanoparticles
National Category
Cell Biology
Identifiers
urn:nbn:se:liu:diva-126342 (URN)10.1186/s12951-016-0174-0 (DOI)000372577700001 ()27001369 (PubMedID)
Projects
Nanoimpact
Funder
Swedish Research Council, 621-2011-5267
Note

Funding agencies: Swedish Research Council-Natural Science; VR-NT; Carl Trygger Foundation; Oscar and Lilli Lamms Minne Foundation; Angpanneforening Research foundation; IKERBASQUE Basque Foundation for science; VINNOVA - County Councils of Ostergotland, Sweden; Linkoping 

Available from: 2016-03-22 Created: 2016-03-22 Last updated: 2017-11-30Bibliographically approved
Molinas, A., Mirazimi, A., Holm, A., Loitto, V. M., Magnusson, K.-E. & Vikström, E. (2016). Protective role of host aquaporin 6 against Hazara virus, a model for Crimean–Congo hemorrhagic fever virus infection. FEMS Microbiology Letters, 363(8), Article ID fnw058.
Open this publication in new window or tab >>Protective role of host aquaporin 6 against Hazara virus, a model for Crimean–Congo hemorrhagic fever virus infection
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2016 (English)In: FEMS Microbiology Letters, ISSN 0378-1097, E-ISSN 1574-6968, Vol. 363, no 8, article id fnw058Article in journal (Refereed) Published
Abstract [en]

Crimean–Congo hemorrhagic fever virus (CCHFV) is an arthropod-borne pathogen that causes infectious disease with severe hemorrhagic manifestations in vascular system in humans. The proper function of the cells in the vascular system is critically regulated by aquaporins (AQP), water channels that facilitate fluxes of water and small solutes across membranes. With Hazara virus as a model for CCHFV, we investigated the effects of viruses on AQP6 and the impact of AQP6 on virus infectivity in host cells, using transiently expressed GFP-AQP6 cells, immunofluorescent assay for virus detection, epifluorescent imaging of living cells and confocal microscopy. In GFP-AQP6 expressing cells, Hazara virus reduced both the cellular and perinuclear AQP6 distribution and changed the cell area. Infection of human cell with CCHFV strain IbAR 10200 downregulated AQP6 expression at mRNA level. Interestingly, the overexpression of AQP6 in host cells decreased the infectivity of Hazara virus, speaking for a protective role of AQP6. We suggest the possibility for AQP6 being a novel player in the virus–host interactions, which may lead to less severe outcomes of an infection.

Place, publisher, year, edition, pages
Oxford University Press, 2016
Keywords
Host–virus interactions; Nairovirus; Crimean–Congo hemorrhagic fever virus; aquaporin; virus infectivity; water homeostasis
National Category
Cell and Molecular Biology Microbiology in the medical area
Identifiers
urn:nbn:se:liu:diva-127499 (URN)10.1093/femsle/fnw058 (DOI)000377970600013 ()26976854 (PubMedID)
Funder
Swedish Research Council, 2010-3045European Science Foundation (ESF)Magnus Bergvall FoundationSwedish Research Council, 214–7495Linköpings universitet
Note

Funding agencies: Swedish Research Council [2010-3045]; European Science foundation; Magnus Bergvall Foundation; Faculty of Medicine and Health Sciences, Linkoping University; Infect-ERA Second Call (Swedish Research Council) [214-7495]

Available from: 2016-04-28 Created: 2016-04-28 Last updated: 2018-01-10Bibliographically approved
Vicente Carrillo, A., Edebert, I., Garside, H., Cotgreave, I., Rigler, R., Loitto, V., . . . Rodriguez-Martinez, H. (2015). Boar spermatozoa successfully predict mitochondrial modes of toxicity: Implications for drug toxicity testing and the 3R principles. Toxicology in Vitro, 29(3), 582-591
Open this publication in new window or tab >>Boar spermatozoa successfully predict mitochondrial modes of toxicity: Implications for drug toxicity testing and the 3R principles
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2015 (English)In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 29, no 3, p. 582-591Article in journal (Refereed) Published
Abstract [en]

Replacement of animal testing by in vitro methods (3-R principles) requires validation of suitable cell models, preferably obtained non-invasively, defying traditional use of explants. Ejaculated spermatozoa are highly dependent on mitochondrial production and consumption of ATP for their metabolism, including motility display, thus becoming a suitable model for capturing multiple modes of action of drugs and other chemicals acting via mitochondrial disturbance. In this study, a hypothesis was tested that the boar spermatozoon is a suitable cell type for toxicity assessment, providing a protocol for 3R-replacement of animals for research and drug-testing. Boar sperm kinetics was challenged with a wide variety of known frank mito-toxic chemicals with previously shown mitochondrial effects, using a semi-automated motility analyser allied with real-time fluorescent probing of mitochondrial potential (MitoTracker and JC-1). Output of this sperm assay (obtained after 30 min) was compared to cell viability (ATP-content, data obtained after 24-48 h) of a hepatome-cell line (HepG2). Results of compound effects significantly correlated (P less than 0.01) for all sperm variables and for most variables in (HepG2). Dose-dependent decreases of relative ATP content in HepG2 cells correlated to sperm speed (r= 0.559) and proportions of motile (r = 0.55) or progressively motile (r = 0.53) spermatozoa. The significance of the study relies on the objectivity of computerized testing of sperm motility inhibition which is comparable albeit of faster output than somatic cell culture models. Sperm suspensions, easily and painlessly obtained from breeding boars, are confirmed as suitable biosensors for preclinical toxicology screening and ranking of lead compounds in the drug development processes.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Sperm; Motility; Mitochondria; Drug; Toxicity; Boar
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-117655 (URN)10.1016/j.tiv.2015.01.004 (DOI)000352050100019 ()25624015 (PubMedID)
Note

Funding Agencies|Swedish Research Council (VR); Research Council Formas, Stockholm, Sweden

Available from: 2015-05-12 Created: 2015-05-06 Last updated: 2017-12-04
Karlsson, T., Bolshakova, A., Magalhães, M. A. ., Loitto, V. & Magnusson, K.-E. (2013). Fluxes of Water through Aquaporin 9 Weaken Membrane-Cytoskeleton Anchorage and Promote Formation of Membrane Protrusions. PLoS ONE, 8(4), e59901
Open this publication in new window or tab >>Fluxes of Water through Aquaporin 9 Weaken Membrane-Cytoskeleton Anchorage and Promote Formation of Membrane Protrusions
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 4, p. e59901-Article in journal (Refereed) Published
Abstract [en]

All modes of cell migration require rapid rearrangements of cell shape, allowing the cell to navigate within narrow spaces in an extracellular matrix. Thus, a highly flexible membrane and a dynamic cytoskeleton are crucial for rapid cell migration. Cytoskeleton dynamics and tension also play instrumental roles in the formation of different specialized cell membrane protrusions, viz. lamellipodia, filopodia and membrane blebs. The flux of water through membrane-anchored water channels, known as aquaporins (AQPs) has recently been implicated in the regulation of cell motility, and here we provide novel evidence for the role of AQP9 in the development of various forms of membrane protrusion. Using multiple imaging techniques and cellular models we show that: (i) AQP9 induced and accumulated in filopodia, (ii) AQP9-associated filopodial extensions preceded actin polymerization, which was in turn crucial for their stability and dynamics, and (iii) minute, local reductions in osmolarity immediately initiated small dynamic bleb-like protrusions, the size of which correlated with the reduction in osmotic pressure. Based on this, we present a model for AQP9-induced membrane protrusion, where the interplay of water fluxes through AQP9 and actin dynamics regulate the cellular protrusive and motile activity of cells.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-90022 (URN)10.1371/journal.pone.0059901 (DOI)000318840100033 ()
Available from: 2013-03-15 Created: 2013-03-15 Last updated: 2017-12-06Bibliographically approved
Karlsson, T., Lagerholm, C. B., Vikström, E., Loitto, V. & Magnusson, K.-E. (2013). Water fluxes through aquaporin-9 prime epithelial cells for rapid wound healing. Biochemical and Biophysical Research Communications - BBRC, 430(3), 993-998
Open this publication in new window or tab >>Water fluxes through aquaporin-9 prime epithelial cells for rapid wound healing
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2013 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 430, no 3, p. 993-998Article in journal (Refereed) Published
Abstract [en]

Cells move along surfaces both as single cells and multi-cellular units. Recent research points toward pivotal roles for water flux through aquaporins (AQPs) in single cell migration. Their expression is known to facilitate this process by promoting rapid shape changes. However, little is known about the impact on migrating epithelial sheets during wound healing and epithelial renewal. Here, we investigate and compare the effects of AQP9 on single cell and epithelial sheet migration. To achieve this, MDCK-1 cells stably expressing AQP9 were subjected to migration assessment. We found that AQP9 facilitated cell locomotion at both the single and multi-cellular level. Furthermore, we identified major differences in the monolayer integrity and cell size upon expression of AQP9 during epithelial sheet migration, indicating a rapid volume-regulatory mechanism. We suggest a novel mechanism for epithelial wound healing based on AQP-induced swelling and expansion of the monolayer.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Cell migration, Aquaporins, AQP9, Wound healing, Cell motility
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-89749 (URN)10.1016/j.bbrc.2012.11.125 (DOI)000314376100021 ()
Note

Funding Agencies|Swedish Research Council for Medicine and Health|2007-34832009-66492010-3045|

Available from: 2013-03-05 Created: 2013-03-05 Last updated: 2017-12-06
Karlsson, T., Glogauer, M., Ellen, R. P., Loitto, V., Magnusson, K.-E. & Magalhaes, M. A. (2011). Aquaporin 9 phosphorylation mediates membrane localization and neutrophil polarization. Journal of Leukocyte Biology, 90(5), 963-973
Open this publication in new window or tab >>Aquaporin 9 phosphorylation mediates membrane localization and neutrophil polarization
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2011 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 90, no 5, p. 963-973Article in journal (Refereed) Published
Abstract [en]

Neutrophils are of prime importance in the host innate defense against invading microorganisms by using two primary mechanisms-locomotion toward and phagocytosis of the prey. Recent research points to pivotal roles for water channels known as AQPs in cell motility. Here, we focused on the role of AQP9 in chemoattractant-induced polarization and migration of primary mouse neutrophils and neutrophil-like HL60 cells. We found that AQP9 is phosphorylated downstream of fMLFR or PMA stimulation in primary human neutrophils. The dynamics of AQP9 were assessed using GFP-tagged AQP9 constructs and other fluorescent markers through various live-cell imaging techniques. Expression of WT or the phosphomimic S11D AQP9 changed cell volume regulation as a response to hyperosmotic changes and enhanced neutrophil polarization and chemotaxis. WT AQP9 and S11D AQP9 displayed a very dynamic distribution at the cell membrane, whereas the phosphorylation-deficient S11A AQP9 failed to localize to the plasma membrane. Furthermore, we found that Rac1 regulated the translocation of AQP9 to the plasma membrane. Our results show that AQP9 plays an active role in neutrophil volume regulation and migration. The display of AQP9 at the plasma membrane depends on AQP9 phosphorylation, which appeared to be regulated through a Rac1-dependent pathway.

Place, publisher, year, edition, pages
Society for Leukocyte Biology, 2011
Keywords
AQP9, cell migration, Rac, water fluxes, osmosis, hydrostatic pressure
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-72257 (URN)10.1189/jlb.0910540 (DOI)000296716000014 ()
Note
Funding Agencies|Swedish Research Council-Medicine|2006-74991007-34832010-3045|Swedish Research Council Natural Sciences|2009-6649|European Sciences Foundation (TraPPs-Euromembrane)||CIHR|MOP-86550|CIHR Group||Available from: 2011-11-24 Created: 2011-11-24 Last updated: 2017-12-08
Hagbom, M., Istrate, C., Engblom, D., Karlsson, T., Rodriguez-Diaz, J., Buesa, J., . . . Svensson, L. (2011). Rotavirus Stimulates Release of Serotonin (5-HT) from Human Enterochromaffin Cells and Activates Brain Structures Involved in Nausea and Vomiting. PLOS PATHOGENS, 7(7)
Open this publication in new window or tab >>Rotavirus Stimulates Release of Serotonin (5-HT) from Human Enterochromaffin Cells and Activates Brain Structures Involved in Nausea and Vomiting
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2011 (English)In: PLOS PATHOGENS, ISSN 1553-7366, Vol. 7, no 7Article in journal (Refereed) Published
Abstract [en]

otavirus (RV) is the major cause of severe gastroenteritis in young children. A virus-encoded enterotoxin, NSP4 is proposed to play a major role in causing RV diarrhoea but how RV can induce emesis, a hallmark of the illness, remains unresolved. In this study we have addressed the hypothesis that RV-induced secretion of serotonin (5-hydroxytryptamine, 5-HT) by enterochromaffin (EC) cells plays a key role in the emetic reflex during RV infection resulting in activation of vagal afferent nerves connected to nucleus of the solitary tract (NTS) and area postrema in the brain stem, structures associated with nausea and vomiting. Our experiments revealed that RV can infect and replicate in human EC tumor cells ex vivo and in vitro and are localized to both EC cells and infected enterocytes in the close vicinity of EC cells in the jejunum of infected mice. Purified NSP4, but not purified virus particles, evoked release of 5-HT within 60 minutes and increased the intracellular Ca(2+) concentration in a human midgut carcinoid EC cell line (GOT1) and ex vivo in human primary carcinoid EC cells concomitant with the release of 5-HT. Furthermore, NSP4 stimulated a modest production of inositol 1,4,5-triphosphate (IP(3)), but not of cAMP. RV infection in mice induced Fos expression in the NTS, as seen in animals which vomit after administration of chemotherapeutic drugs. The demonstration that RV can stimulate EC cells leads us to propose that RV disease includes participation of 5-HT, EC cells, the enteric nervous system and activation of vagal afferent nerves to brain structures associated with nausea and vomiting. This hypothesis is supported by treating vomiting in children with acute gastroenteritis with 5-HT(3) receptor antagonists.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69989 (URN)10.1371/journal.ppat.1002115 (DOI)000293339300012 ()
Note
Original Publication: Marie Hagbom, Claudia Istrate, David Engblom, Thommie Karlsson, Jesus Rodriguez-Diaz, Javier Buesa, John A Taylor, Vesa Loitto, Karl-Eric Magnusson, Hakan Ahlman, Ove Lundgren and Lennart Svensson, Rotavirus Stimulates Release of Serotonin (5-HT) from Human Enterochromaffin Cells and Activates Brain Structures Involved in Nausea and Vomiting, 2011, PLOS PATHOGENS, (7), 7, . http://dx.doi.org/10.1371/journal.ppat.1002115 Licensee: Public Library of Science (PLoS) http://www.plos.org/Available from: 2011-08-12 Created: 2011-08-12 Last updated: 2015-05-13
Loitto, V., Karlsson, T. & Magnusson, K.-E. (2009). Water Flux in Cell Motility: Expanding the Mechanisms of Membrane Protrusion. CELL MOTILITY AND THE CYTOSKELETON, 66(5), 237-247
Open this publication in new window or tab >>Water Flux in Cell Motility: Expanding the Mechanisms of Membrane Protrusion
2009 (English)In: CELL MOTILITY AND THE CYTOSKELETON, ISSN 0886-1544, Vol. 66, no 5, p. 237-247Article, review/survey (Refereed) Published
Abstract [en]

Transmembrane water fluxes through aquaporins (AQPs) are suggested to play, pivotal roles in cell polarization and directional cell motility. Local dilution by W water influences the dynamics of the subcortical actin polymerization and directs the formation of nascent membrane protrusions. In this paper. recent evidence is discussed in support of such a central role of AQP in membrane protrusion formation, and cell migration as a basis for our Understanding AQP9 Underlying molecular mechanisms of directional motility. Specifically. AQP9 in a physiological context controls transmembrane water fluxes driving, membrane protrusion formation, as an initial cellular response to a chemoattractant or other migratory signals. The importance of AQP-facilitated water fluxes in directional cell motility is underscored the observation that blocking or modifying specific sites in AQP9 also interferes with the molecular machinery that govern actin-mediated cellular shape changes. Cell Motil.

Keywords
aquaporins, cell motility, polarity, morphology, filopodia
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18290 (URN)10.1002/cm.20357 (DOI)
Available from: 2009-05-17 Created: 2009-05-15 Last updated: 2010-05-24
Turina, D., Loitto, V., Björnström, K., Sundqvist, T. & Eintrei, C. (2008). Propofol causes neurite retraction in neurons. Paper presented at SFAI möte Uppsala.
Open this publication in new window or tab >>Propofol causes neurite retraction in neurons
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2008 (English)Conference paper, Published paper (Refereed)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69414 (URN)
Conference
SFAI möte Uppsala
Available from: 2011-06-27 Created: 2011-06-27 Last updated: 2011-07-01
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