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Vainikka, Linda K
Alternative names
Publications (10 of 14) Show all publications
Wäster, P., Eriksson, I., Vainikka, L., Rosdahl, I. & Öllinger, K. (2016). Extracellular vesicles are transferred from melanocytes to keratinocytes after UVA irradiation. Scientific Reports, 6(27890)
Open this publication in new window or tab >>Extracellular vesicles are transferred from melanocytes to keratinocytes after UVA irradiation
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, no 27890Article in journal (Refereed) Published
Abstract [en]

Ultraviolet (UV) irradiation induces skin pigmentation, which relies on the intercellular crosstalk of melanin between melanocytes to keratinocytes. However, studying the separate effects of UVA and UVB irradiation reveals differences in cellular response. Herein, we show an immediate shedding of extracellular vesicles (EVs) from the plasma membrane when exposing human melanocytes to UVA, but not UVB. The EV-shedding is preceded by UVA-induced plasma membrane damage, which is rapidly repaired by Ca2+-dependent lysosomal exocytosis. Using co-cultures of melanocytes and keratinocytes, we show that EVs are preferably endocytosed by keratinocytes. Importantly, EV-formation is prevented by the inhibition of exocytosis and increased lysosomal pH but is not affected by actin and microtubule inhibitors. Melanosome transfer from melanocytes to keratinocytes is equally stimulated by UVA and UVB and depends on a functional cytoskeleton. In conclusion, we show a novel cell response after UVA irradiation, resulting in transfer of lysosome-derived EVs from melanocytes to keratinocytes.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2016
National Category
Cell Biology
Identifiers
urn:nbn:se:liu:diva-130287 (URN)10.1038/srep27890 (DOI)000378036300001 ()27293048 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Cancer Society; Welander-Finsen Foundation; County Council of Ostergotland; Stiftelsen Olle Engkvist Byggmastare; Konung Gustav V och Drottning Victorias Frimurarestiftelse; Ostgotaregionens Cancerfond

Available from: 2016-08-01 Created: 2016-07-28 Last updated: 2017-11-28
Wäster, P., Eriksson, I., Vainikka, L. & Öllinger, K. (2014). Sunbathing: What’ve lysosomes got to do with it?. Communicative & Integrative Biology, 7(1), e28723-1-e28723-5
Open this publication in new window or tab >>Sunbathing: What’ve lysosomes got to do with it?
2014 (English)In: Communicative & Integrative Biology, ISSN 1942-0889, E-ISSN 1942-0889, Vol. 7, no 1, p. e28723-1-e28723-5Article in journal (Refereed) Published
Abstract [en]

Solar radiation is an important risk factor for skin cancer, the incidence of which is increasing, especially in the fair-skinned populations of the world. While the ultraviolet (UV)B component has direct DNA damaging ability, UVA-induced effects are currently mainly attributed to the production of reactive oxygen species. In our recent study, we compared the effects of UVA and UVB radiation on human keratinocytes and found that UVA-induced plasma membrane damage was rapidly repaired by lysosomal exocytosis, which was detected based on the expression of lysosomal membrane associated protein-1 (LAMP-1) on the plasma membrane of non-permeabilized cells. Later, the keratinocytes died through caspase-8 mediated apoptosis. In contrast, the plasma membranes of keratinocytes exposed to UVB showed no LAMP-1 expression, and, although the cells died by apoptosis, no initial caspase-8 activity was detected. We have also demonstrated the occurrence of UVA-induced lysosomal exocytosis in reconstructed skin and shown the relocation of lysosomes from the center of cells to the vicinity of the plasma membrane. Thus, we suggest that lysosomal exocytosis also occurs in keratinocytes covered by the stratum corneum following exposure to UVA. Our findings provide new insight into the mechanism of UVA-induced skin damage.

Place, publisher, year, edition, pages
Austin, Texas, USA: Landes Biosciences, 2014
Keywords
UV irradiation, keratinocytes, lysosomes, exocytosis, plasma membrane repair, lysosomal, associated membrane protein
National Category
Basic Medicine Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-107147 (URN)10.4161/cib.28723 (DOI)25346791 (PubMedID)2-s2.0-84902664460 (Scopus ID)
Note

Article Addendum to: H Appelqvist, P Waster, I Eriksson, I Rosdahl, K Ollinger. Lysosomal exocytosis and caspase-8-mediated apoptosis in UVA-irradiated keratinocytes. Journal of Cell Science 2013; 126: 5578- 5584. DOI: 10.1242/jcs.130633

Available from: 2014-06-05 Created: 2014-06-05 Last updated: 2018-01-11Bibliographically approved
Persson, H. L. & Vainikka, L. (2013). Increased lysosomal membrane permeabilization in oxidant-exposed macrophages of human fibrotic lungs. Journal of Cell Death, 6(1), 69-74
Open this publication in new window or tab >>Increased lysosomal membrane permeabilization in oxidant-exposed macrophages of human fibrotic lungs
2013 (English)In: Journal of Cell Death, ISSN 1179-0660, Vol. 6, no 1, p. 69-74Article in journal (Refereed) Published
Abstract [en]

A disrupted balance of reduced glutathione (GSH) and iron (Fe) and subsequent enhanced susceptibility of lysosomes of lung macrophages (LMs) to oxidants may play a role in lung fibrogenesis. We assessed cellular Fe/GSH, lysosomal membrane permeabilization (LMP), and cell death in cultures of oxidant exposed LMs. LMs from 7 lung fibrosis patients and healthy subjects were exposed to a physiologic concentration of H2O2 for 1 h. LMP was assessed with acridine orange green fluorescence, apoptosis/necrosis were estimated by apoptotic DNA and typical morphology, Fe was assessed with Prussian blue staining/atomic absorption spectrophotometry, and GSH was evaluated using a GSH assay kit. Oxidant-induced LMP and cell death were more pronounced in cultures of LMs from patients with lung fibrosis, and these cells contained less GSH and more cytochemically stained Fe. These observations indicate that LMP may be involved in fibrosis development, possibly through activation of the inflammasome complex. Further studies are warranted for a detailed understanding.

Place, publisher, year, edition, pages
Libertas Academica, 2013
Keywords
Apoptosis; Fibrosis; Inflammation; Iron; Macrophage
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-104950 (URN)10.4137/JCD.S13271 (DOI)
Available from: 2014-03-04 Created: 2014-03-04 Last updated: 2017-12-05
Persson, H. L., Vainikka, L., Eriksson, I. & Wennerstrom, U. (2013). TNF-alpha-stimulated macrophages protect A549 lung cells against iron and oxidation. Experimental and Toxicological Pathology, 65(1-2), 81-89
Open this publication in new window or tab >>TNF-alpha-stimulated macrophages protect A549 lung cells against iron and oxidation
2013 (English)In: Experimental and Toxicological Pathology, ISSN 0940-2993, E-ISSN 1618-1433, Vol. 65, no 1-2, p. 81-89Article in journal (Refereed) Published
Abstract [en]

Previously, we have shown that TNF-alpha protects iron-exposed J774 macrophages against iron-catalyzed oxidative lysosomal disruption and cell death by increasing reduced glutathione and H-ferritin in cells. Because J774 cells are able to harbor large amounts of iron, which is potentially harmful in a redox-active state, we hypothesized that TNF-alpha-stimulated J774 macrophages will prevent iron-driven oxidative killing of alveolar epithelial A549 cells in co-culture. In the present study, iron trichloride (which is endocytosed by cells as hydrated iron-phosphate complexes) was mainly deposited inside the lysosomes of J774 macrophages, while A549 cells, equally iron exposed, accumulated much less iron. When challenged by oxidants, however, reactive lysosomal iron in A549 cells promoted lysosomal disruption and cell death, particularly in the presence of TNF-alpha. This effect resulted from an elevation in ROS generation by TNF-alpha, while a compensatory upregulation of protective molecules (H-ferritin and/or reduced glutathione) by TNF-alpha was absent. A549 cell death was particularly pronounced when iron and TNF-alpha were present in the conditioned medium during oxidant challenge; thus, iron-driven oxidative reactions in the culture medium were a much greater hazard to A549 cells than those taking place inside their lysosomes. Consequently, the iron chelator, deferoxamine, efficiently prevented A549 cell death when added to the culture medium during an oxidant challenge. In co-cultures of TNF-alpha-stimulated lung cells, J774 macrophages sequestered iron inside their lysosomes and protected A549 cells from oxidative reactions and cell death. Thus, the collective effect of TNF-alpha on co-cultured lung cells was mainly cytoprotective.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Apoptosis, Ferritin, Fibrosis, Lysosomes, Macrophages, Oxidative stress
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-89525 (URN)10.1016/j.etp.2011.06.004 (DOI)000314006000014 ()
Note

Funding Agencies|County Council of Ostergotland (ALF)||Medical Research Council of Southeast Sweden (FORSS)||Swedish Medical Society||Linkoping Medical Society||Olle Engkvist, Apotekare Hedberg and LiO (Ostergotland, Sweden)||

Available from: 2013-02-26 Created: 2013-02-26 Last updated: 2017-12-06
Persson, L., Vainikka, L., Sege, M., Wennerström, U., Dam-Larsen, S. & Persson, J. (2012). Leaky lysosomes in lung transplant macrophages: azithromycin prevents oxidative damage. Respiratory research (Online), 13(83)
Open this publication in new window or tab >>Leaky lysosomes in lung transplant macrophages: azithromycin prevents oxidative damage
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2012 (English)In: Respiratory research (Online), ISSN 1465-9921, E-ISSN 1465-993X, Vol. 13, no 83Article in journal (Refereed) Published
Abstract [en]

Background: Lung allografts contain large amounts of iron (Fe), which inside lung macrophages may promote oxidative lysosomal membrane permeabilization (LMP), cell death and inflammation. The macrolide antibiotic azithromycin (AZM) accumulates 1000-fold inside the acidic lysosomes and may interfere with the lysosomal pool of Fe. Objective: Oxidative lysosomal leakage was assessed in lung macrophages from lung transplant recipients without or with AZM treatment and from healthy subjects. The efficiency of AZM to protect lysosomes and cells against oxidants was further assessed employing murine J774 macrophages. Methods: Macrophages harvested from 8 transplant recipients (5 without and 3 with ongoing AZM treatment) and 7 healthy subjects, and J774 cells pre-treated with AZM, a high-molecular-weight derivative of the Fe chelator desferrioxamine or ammonium chloride were oxidatively stressed. LMP, cell death, Fe, reduced glutathione (GSH) and H-ferritin were assessed. Results: Oxidant challenged macrophages from transplants recipients without AZM exhibited significantly more LMP and cell death than macrophages from healthy subjects. Those macrophages contained significantly more Fe, while GSH and H-ferritin did not differ significantly. Although macrophages from transplant recipients treated with AZM contained both significantly more Fe and less GSH, which would sensitize cells to oxidants, these macrophages resisted oxidant challenge well. The preventive effect of AZM on oxidative LMP and J774 cell death was 60 to 300 times greater than the other drugs tested. Conclusions: AZM makes lung transplant macrophages and their lysososomes more resistant to oxidant challenge. Possibly, prevention of obliterative bronchiolitis in lung transplants by AZM is partly due to this action.

Place, publisher, year, edition, pages
BioMed Central, 2012
Keywords
Apoptosis; Bronchiolitis; Ferritin; Fibrosis; Inflammation; Iron; Macrophage
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-87232 (URN)10.1186/1465-9921-13-83 (DOI)000311745500001 ()
Available from: 2013-01-14 Created: 2013-01-14 Last updated: 2017-12-06Bibliographically approved
Farnebo, L., Jerhammar, F., Ceder, R., Grafström, R. C., Vainikka, L., Thunell, L., . . . Roberg, K. (2011). Combining factors on protein and gene level to predict radioresponse in head and neck cancer cell lines. Journal of Oral Pathology & Medicine, 40(10), 739-746
Open this publication in new window or tab >>Combining factors on protein and gene level to predict radioresponse in head and neck cancer cell lines
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2011 (English)In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 40, no 10, p. 739-746Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Radiotherapy is the main therapy for head and neck squamous cell carcinoma (HNSCC); however, treatment resistance and local recurrence are significant problems, highlighting the need for predictive markers. In this study, we evaluated selected proteins, mutations, and single nucleotide polymorphisms (SNPs) involved in apoptosis, cell proliferation, and DNA repair alone or combined as predictive markers for radioresponse in 42 HNSCC cell lines.

METHODS: The expression of epidermal growth factor receptor, survivin, Bax, Bcl-2, Bcl-XL, cyclooxygenase-2, and heat shock protein 70 was analyzed by ELISA. Furthermore, mutations and SNPs in the p53 gene as well as SNPs in the MDM2, XRCC1, and XRCC3 genes were analyzed for their relation to radioresponse. To enable the evaluation of the predictive value of several factors combined, each cell line was allocated points based on the number of negative points (NNP) system, and the NNP sum was correlated with radioresponse.

RESULTS: Survivin was the only factor that alone was significantly correlated with the intrinsic radiosensitivity (r=0.36, p=0.02). The combination of survivin, Bax, Bcl-2, Bcl-XL, cyclooxygenase-2, and the p53 Arg72Pro polymorphism was found to most strongly correlate with radioresponse (r=0.553, p<0.001).

CONCLUSION: These data indicate that the intrinsic radiosensitivity of 42 HNSCC cell lines can be predicted by a panel of factors on both the protein and gene levels. Moreover, among the investigated factors, survivin was the most promising biomarker of radioresponse.

Place, publisher, year, edition, pages
John Wiley and sons, 2011
Keywords
head and neck tumors, radiotherapy, survivin, Bcl-2 family, p53 Arg72Pro
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-61585 (URN)10.1111/j.1600-0714.2011.01036.x (DOI)000296607200002 ()
Note
Funding agencies|Swedish Laryng Foundation||County Council of Ostergotland (OLL)||Swedish Cancer Foundation||Foundation of Olle Engkvist||Linkoping University Hospital||Available from: 2010-11-16 Created: 2010-11-16 Last updated: 2017-12-12Bibliographically approved
Samuelsson, M., Vainikka, L. & Öllinger, K. (2011). Glutathione in the blood and cerebrospinal fluid: A study in healthy male volunteers. Neuropeptides, 45(4), 287-292
Open this publication in new window or tab >>Glutathione in the blood and cerebrospinal fluid: A study in healthy male volunteers
2011 (English)In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 45, no 4, p. 287-292Article in journal (Refereed) Published
Abstract [en]

Glutathione (GSH) is an important regulator of intracellular redox homeostasis. In the brain, glutathione is considered a major antioxidant, which is also found at high concentrations in the extracellular environment. Altered GSH balance in plasma, blood and cerebrospinal fluid (CSF) has been observed in several disorders suggesting that an impaired antioxidant function is part of the pathophysiology. The aim of the present study was to investigate a possible relationship between glutathione in plasma and CSF. Blood samples were collected from 26 healthy male volunteers at 8 a.m., noon, 4 p.m. and 8 p.m. At 8 a.m. the following morning, blood was drawn and three 6-ml fractions of CSF were collected by lumbar puncture. In CSF, a disrupted gradient was found showing the highest glutathione concentration in the second compared to the first and third fraction (P andlt; 0.002). Moreover, correlation and regression analyses between glutathione in plasma and CSF revealed an association between the third fraction CSF and plasma glutathione 8 p.m. the day before lumbar puncture. Thus, if carefully standardised due to the disrupted gradient in CSF, it might be possible to estimate glutathione levels in CSF by analysing plasma in healthy males.

Place, publisher, year, edition, pages
Elsevier, 2011
Keywords
Glutathione, Plasma, Blood, Cerebrospinal fluid, Lumbar puncture
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-71560 (URN)10.1016/j.npep.2011.05.004 (DOI)000295349600005 ()
Note
Funding Agencies|Ostergotland County Council||Available from: 2011-10-21 Created: 2011-10-21 Last updated: 2017-12-08
Persson, L., Vainikka, L., Eriksson, H. & Wennerstrom, U. (2011). Lane-Hamilton Syndrome Ferritin Protects Lung Macrophages Against Iron and Oxidation. CHEST, 139(2), 361-367
Open this publication in new window or tab >>Lane-Hamilton Syndrome Ferritin Protects Lung Macrophages Against Iron and Oxidation
2011 (English)In: CHEST, ISSN 0012-3692, Vol. 139, no 2, p. 361-367Article in journal (Refereed) Published
Abstract [en]

Background: Lysosomal disruption and consequent apoptosis have been implicated in lung diseases characterized by iron overload. Free reactive iron in lysosomes sensitizes cells to oxidative stress. Apoptosis is prevented by heavy-chain (H)-ferritin, which can incorporate lysosomal iron into ferritin molecules. Tumor necrosis factor (TNF)-alpha stimulates the synthesis of H-ferritin. Idiopathic pulmonary hemosiderosis presents with the accumulation of iron and the upregulation of ferritin synthesis. We therefore analyzed the lysosomal response to oxidants and the role of H-ferritin synthesis in lung macrophages (LMs) harvested from the first Swedish case, to our knowledge, of Lane-Hamilton syndrome. Methods: Iron-exposed murine macrophages were used as a reference. Both cell types were stimulated with TNF-alpha (or not), then iron was assessed cytochemically and by atomic absorption spectrophotometry. H-ferritin expression was analyzed by Western blot and reduced glutathione (GSH) by spectrofluorometry. Following exposure to hydrogen peroxide, lysosomal membrane integrity and DNA degradation were analyzed by flow cytometry, whereas morphologic signs of apoptosis and necrosis were assessed by light microscopy. Results: GSH levels were approximately equal in LMs and murine macrophages. Although LMs contained much more iron than murine macrophages, lysosomal iron was bound in a harmless unreactive state by ample amounts of ferritin and hemosiderin, its lysosomal degradation product. Therefore, lysosomes of LMs were more oxidant resistant, and these cells were more adept at surviving oxidative stress. In both cell types, TNF-alpha prevented oxidant-induced lysosomal damage and cell death by upregulating synthesis of H-ferritin and GSH. Conclusions: Iron-overloaded LMs are equipped with an efficient armor of antioxidative mechanisms of which H-ferritin and hemosiderin seem to be particularly important.

Place, publisher, year, edition, pages
American College of Chest Physicians, 2011
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-66311 (URN)10.1378/chest.10-0818 (DOI)000287773100019 ()
Available from: 2011-03-11 Created: 2011-03-11 Last updated: 2012-03-25Bibliographically approved
Persson, L. & Vainikka, L. (2010). TNF-alpha preserves lysosomal stability in macrophages: A potential defense against oxidative lung injury. TOXICOLOGY LETTERS, 192(2), 261-267
Open this publication in new window or tab >>TNF-alpha preserves lysosomal stability in macrophages: A potential defense against oxidative lung injury
2010 (English)In: TOXICOLOGY LETTERS, ISSN 0378-4274, Vol. 192, no 2, p. 261-267Article in journal (Refereed) Published
Abstract [en]

Iron-catalyzed oxidative damage on the respiratory epithelium is prevented by alveolar macrophages depositing iron inside their lysosomes. Bound in an un-reactive state to various metalloproteins, e.g. ferritin, most lysosomal iron is kept separated from reactive oxygen species (ROS) by intracellular anti-oxidative enzyme systems. Some ROS may, however, escape this protective shield of antioxidants, react with small amounts of free redox-active iron within lysosomes, thereby causing peroxidative damage on lysosomes and possibly also ensuing cell death. Since macrophages, containing large amounts of lysosomal iron, are very resistant to TNF-alpha, we hypothesized that this cell type has developed specific defense mechanisms against TNF-alpha-induced ROS generation. Murine macrophages were exposed (or not) to non-toxic concentrations of TNF-alpha and/or iron and were then challenged with H2O2. Iron-exposed oxidatively stressed cells exhibited extensive lysosomal disruption resulting in pronounced cell death. In contrast, TNF-alpha stabilized lysosomes and protected cells, particularly those iron-exposed, by reducing cellular iron and increasing H-ferritin. Intracellular generation of H2O2 under oxidative stress was kept unchanged by TNF-alpha and/or iron. However, TNF-alpha increased basal levels of glutathione by up-regulating the synthesis of gamma-glutamylcystein synthetase, thereby strengthening the anti-oxidative capacity. TNF-alpha inhibitors would block this novel anti-oxidative defense system, possibly explaining their adverse effects on the lung.

Keywords
Apoptosis, Ferritin, Inflammation, Lysosomes, Oxidative stress
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-54247 (URN)10.1016/j.toxlet.2009.10.031 (DOI)000274743300025 ()
Available from: 2010-03-05 Created: 2010-03-05 Last updated: 2010-12-21
Persson, H. L. & Vainikka, L. K. (2009). Lysosomal iron in pulmonary alveolar proteinosis: a case report.. The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology, 33(3), 673-679
Open this publication in new window or tab >>Lysosomal iron in pulmonary alveolar proteinosis: a case report.
2009 (English)In: The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology, ISSN 1399-3003, Vol. 33, no 3, p. 673-679Article in journal (Refereed) Published
Abstract [en]

Pulmonary alveolar proteinosis is characterised by accumulation of surfactant-like material in the distal air spaces. Since lysosomes play a crucial role for degradation of large biomolecules taken up from the cell's environment, it was hypothesised that oxidant-induced lysosomal disruption and ensuing cell death might play a role in disease development. In the present study, alveolar macrophages, harvested by whole-lung lavage from a patient diagnosed with pulmonary alveolar proteinosis, are shown to contain large amounts of undigested material within lysosomes, and the same organelle exhibits increased amounts of haemosiderin-bound iron. Compared with murine macrophage-like J774 cells (iron exposed or not), the status of human macrophages was pro-oxidative, i.e. macrophages exhibited a low level of the antioxidant glutathione and large amounts of iron available for Fenton-type chemistry. As a consequence, macrophageal lysosomes were particularly fragile when exposed to physiological concentrations of hydrogen peroxide (generated by glucose oxidase in culture medium). Such lysosomal disruption resulted in extensive cell death by both necrosis and apoptosis independent of caspase-3 activation. Considering the potential role of iron-catalysed oxidant-induced lysosomal rupture and ensuing cell killing for pulmonary alveolar proteinosis pathology and disease progression, whole-lung lavage might be considered early in those cases in which cytochemical staining reveals great numbers of haemosiderin-laden alveolar macrophages.

Keywords
Alveolar macrophages, ferritin, lung lavage, lysosomes, oxidative stress
Identifiers
urn:nbn:se:liu:diva-17075 (URN)10.1183/09031936.00044108 (DOI)19251804 (PubMedID)
Available from: 2009-03-05 Created: 2009-03-05 Last updated: 2009-10-07
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