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Danielsson, R., Ferey, N., Mile, I. & Eriksson, H. (2023). Metabolic Reprogramming of Macrophages upon In Vitro Incubation with Aluminum-Based Adjuvant. International Journal of Molecular Sciences, 24(5), Article ID 4409.
Open this publication in new window or tab >>Metabolic Reprogramming of Macrophages upon In Vitro Incubation with Aluminum-Based Adjuvant
2023 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 24, no 5, article id 4409Article in journal (Refereed) Published
Abstract [en]

Aluminum-based adjuvants have been extensively used in vaccines. Despite their widespread use, the mechanism behind the immune stimulation properties of these adjuvants is not fully understood. Needless to say, extending the knowledge of the immune-stimulating properties of aluminum-based adjuvants is of utmost importance in the development of new, safer, and efficient vaccines. To further our knowledge of the mode of action of aluminum-based adjuvants, the prospect of metabolic reprogramming of macrophages upon phagocytosis of aluminum-based adjuvants was investigated. Macrophages were differentiated and polarized in vitro from human peripheral monocytes and incubated with the aluminum-based adjuvant Alhydrogel((R)). Polarization was verified by the expression of CD markers and cytokine production. In order to recognize adjuvant-derived reprogramming, macrophages were incubated with Alhydrogel((R)) or particles of polystyrene as control, and the cellular lactate content was analyzed using a bioluminescent assay. Quiescent M0 macrophages, as well as alternatively activated M2 macrophages, exhibited increased glycolytic metabolism upon exposure to aluminum-based adjuvants, indicating a metabolic reprogramming of the cells. Phagocytosis of aluminous adjuvants could result in an intracellular depot of aluminum ions, which may induce or support a metabolic reprogramming of the macrophages. The resulting increase in inflammatory macrophages could thus prove to be an important factor in the immune-stimulating properties of aluminum-based adjuvants.

Place, publisher, year, edition, pages
MDPI, 2023
Keywords
aluminum adjuvant, macrophages, metabolic reprogramming, lactate
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:mau:diva-59243 (URN)10.3390/ijms24054409 (DOI)000947001700001 ()36901849 (PubMedID)2-s2.0-85149854014 (Scopus ID)
Available from: 2023-04-17 Created: 2023-04-17 Last updated: 2024-02-05Bibliographically approved
Kopecky, J., Perez, J. E., Eriksson, H., Visse, E., Siesjo, P. & Darabi, A. (2022). Intratumoral administration of the antisecretory peptide AF16 cures murine gliomas and modulates macrophage functions. Scientific Reports, 12(1), Article ID 4609.
Open this publication in new window or tab >>Intratumoral administration of the antisecretory peptide AF16 cures murine gliomas and modulates macrophage functions
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2022 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, no 1, article id 4609Article in journal (Refereed) Published
Abstract [en]

Glioblastoma has remained the deadliest primary brain tumor while its current therapy offers only modest survival prolongation. Immunotherapy has failed to record notable benefits in routine glioblastoma treatment. Conventionally, immunotherapy relies on T cells as tumor-killing agents; however, T cells are outnumbered by macrophages in glioblastoma microenvironment. In this study, we explore the effect of AF16, a peptide from the endogenous antisecretory factor protein, on the survival of glioma-bearing mice, the tumor size, and characteristics of the tumor microenvironment with specific focus on macrophages. We elucidate the effect of AF16 on the inflammation-related secretome of human and murine macrophages, as well as human glioblastoma cells. In our results, AF16 alone and in combination with temozolomide leads to cure in immunocompetent mice with orthotopic GL261 gliomas, as well as prolonged survival in immunocompromised mice. We recorded decreased tumor size and changes in infiltration of macrophages and T cells in the murine glioma microenvironment. Human and murine macrophages increased expression of proinflammatory markers in response to AF16 treatment and the same effect was seen in human primary glioblastoma cells. In summary, we present AF16 as an immunomodulatory factor stimulating pro-inflammatory macrophages with a potential to be implemented in glioblastoma treatment protocols.

Place, publisher, year, edition, pages
Nature Publishing Group, 2022
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:mau:diva-50907 (URN)10.1038/s41598-022-08618-x (DOI)000770396200055 ()35301393 (PubMedID)2-s2.0-85126536923 (Scopus ID)
Available from: 2022-04-04 Created: 2022-04-04 Last updated: 2024-02-05Bibliographically approved
Sternbæk, L., Kimani, M., Gawlitza, K., Rurack, K., Janicke, B., Alm, K., . . . Eriksson, H. (2022). Molecularly Imprinted Polymers Exhibit Low Cytotoxic and Inflammatory Properties in Macrophages In Vitro. Applied Sciences, 12, 1-16, Article ID 6091.
Open this publication in new window or tab >>Molecularly Imprinted Polymers Exhibit Low Cytotoxic and Inflammatory Properties in Macrophages In Vitro
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2022 (English)In: Applied Sciences, E-ISSN 2076-3417, Vol. 12, p. 1-16, article id 6091Article in journal (Refereed) Published
Abstract [en]

Molecularly imprinted polymers (MIPs) against sialic acid (SA) have been developed as a detection tool to target cancer cells. Before proceeding to in vivo studies, a better knowledge of the overall effects of MIPs on the innate immune system is needed. The aim of this study thus was to exemplarily assess whether SA-MIPs lead to inflammatory and/or cytotoxic responses when administered to phagocytosing cells in the innate immune system. The response of monocytic/macrophage cell lines to two different reference particles, Alhydrogel and PLGA, was compared to their response to SA-MIPs. In vitro culture showed a cellular association of SA-MIPs and Alhydrogel, as analyzed by flow cytometry. The reference particle Alhydrogel induced secretion of IL-1β from the monocytic cell line THP-1, whereas almost no secretion was provoked for SA-MIPs. A reduced number of both THP-1 and RAW 264.7 cells were observed after incubation with SA-MIPs and this was not caused by cytotoxicity. Digital holographic cytometry showed that SA-MIP treatment affected cell division, with much fewer cells dividing. Thus, the reduced number of cells after SA-MIP treatment was not linked to SA-MIPs cytotoxicity. In conclusion, SA-MIPs have a low degree of inflammatory properties, are not cytotoxic, and can be applicable for future in vivo studies.

Place, publisher, year, edition, pages
MDPI, 2022
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:mau:diva-53523 (URN)10.3390/app12126091 (DOI)000818495900001 ()2-s2.0-85132751550 (Scopus ID)
Available from: 2022-06-24 Created: 2022-06-24 Last updated: 2023-10-02Bibliographically approved
Danielsson, R. & Eriksson, H. (2021). Aluminium adjuvants in vaccines: A way to modulate the immune response. Seminars in Cell and Developmental Biology, 115, 3-9, Article ID S1084-9521(20)30202-0.
Open this publication in new window or tab >>Aluminium adjuvants in vaccines: A way to modulate the immune response
2021 (English)In: Seminars in Cell and Developmental Biology, ISSN 1084-9521, E-ISSN 1096-3634, Vol. 115, p. 3-9, article id S1084-9521(20)30202-0Article in journal (Refereed) Published
Abstract [en]

Aluminium salts have been used as adjuvants in vaccines for almost a century, but still no clear understanding of the mechanisms behind the immune stimulating properties of aluminium based adjuvants is recognized. Aluminium adjuvants consist of aggregates and upon administration of a vaccine, the aggregates will be recognized and phagocytosed by sentinel cells such as macrophages or dendritic cells. The adjuvant aggregates will persist intracellularly, maintaining a saturated intracellular concentration of aluminium ions over an extended time. Macrophages and dendritic cells are pivotal cells of the innate immune system, linking the innate and adaptive immune systems, and become inflammatory and antigen-presenting upon activation, thus mediating the initiation of the adaptive immune system. Both types of cell are highly adaptable, and this review will discuss and highlight how the occurrence of intracellular aluminium ions over an extended time may induce the polarization of macrophages into inflammatory and antigen presenting M1 macrophages by affecting the: endosomal pH; formation of reactive oxygen species (ROS); stability of the phagosomal membrane; release of damage associated molecular patterns (DAMPs); and metabolism (metabolic re-programming). This review emphasizes that a persistent intracellular presence of aluminium ions over an extended time has the potential to affect the functionality of sentinel cells of the innate immune system, inducing polarization and activation. The immune stimulating properties of aluminium adjuvants is presumably mediated by several discrete events, however, a persistent intracellular presence of aluminium ions appears to be a key factor regarding the immune stimulating properties of aluminium based adjuvants.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
Aluminium based adjuvant, Immune stimulation, Inflammation, Macrophages, Vaccine
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:mau:diva-39076 (URN)10.1016/j.semcdb.2020.12.008 (DOI)000665718100002 ()33423930 (PubMedID)2-s2.0-85099179205 (Scopus ID)
Available from: 2021-01-12 Created: 2021-01-12 Last updated: 2024-02-05Bibliographically approved
Aleksejeva, O., Sokolov, A. V., Marquez, I., Gustafsson, A., Bushnev, S., Eriksson, H., . . . Shleev, S. (2021). Autotolerant ceruloplasmin based biocathodes for implanted biological power sources. Bioelectrochemistry, 140
Open this publication in new window or tab >>Autotolerant ceruloplasmin based biocathodes for implanted biological power sources
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2021 (English)In: Bioelectrochemistry, ISSN 1567-5394, E-ISSN 1878-562X, Vol. 140Article in journal (Refereed) Published
Abstract [en]

High-performance autotolerant bioelectrodes should be ideally suited to design implantable bioelectronic devices. Because of its high redox potential and ability to reduce oxygen directly to water, human ceruloplasmin, HCp, the only blue multicopper oxidase present in human plasma, appears to be the ultimate biocatalyst for oxygen biosensors and also biocathodes in biological power sources. In comparison to fungal and plant blue multicopper oxidases, e.g. Myrothecium verrucaria bilirubin oxidase and Rhus vernicifera laccase, respectively, the inflammatory response to HCp in human blood is significantly reduced. Partial purification of HCp allowed to preserve the native conformation of the enzyme and its biocatalytic activity. Therefore, electrochemical studies were carried out with the partially purified enzyme immobilised on nanostructured graphite electrodes at physiological pH and temperature. Amperometric investigations revealed low reductive current densities, i.e. about 1.65 µA cm−2 in oxygenated electrolyte and in the absence of any mediator, demonstrating nevertheless direct electron transfer based O2 bioelectroreduction by HCp for the first time. The reductive current density obtained in the mediated system was about 12 µA cm−2. Even though the inflammatory response of HCp is diminished in human blood, inadequate bioelectrocatalytic performance hinders its use as a cathodic bioelement in a biofuel cell.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
Biological fuel cells; Blood; Electrolytes; Electron transport properties; Enzyme activity; Enzyme electrodes; Oxygen; pH; Purification; Redox reactions, Biocatalytic activity; Bioelectronic device; Direct electron transfer; Electrochemical studies; Inflammatory response; Nanostructured graphite; Native conformation; Partial purification, Graphite electrodes
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:mau:diva-42684 (URN)10.1016/j.bioelechem.2021.107794 (DOI)000663599600011 ()33744681 (PubMedID)2-s2.0-85102974379 (Scopus ID)
Available from: 2021-06-03 Created: 2021-06-03 Last updated: 2023-11-29Bibliographically approved
Danielsson, R., Sandberg, T. & Eriksson, H. (2018). Aluminium Adjuvants: a Nanomaterial used as Adjuvants in Human Vaccines for Decades (ed.). Open Biotechnology Journal, 12, 140-153
Open this publication in new window or tab >>Aluminium Adjuvants: a Nanomaterial used as Adjuvants in Human Vaccines for Decades
2018 (English)In: Open Biotechnology Journal, ISSN 1874-0707, Vol. 12, p. 140-153Article, review/survey (Refereed)
Abstract [en]

Background: Aluminium salts have been used for decades in vaccines as adjuvants to facilitate the adaptive immune response against co-administered antigens. Two types of aluminium adjuvant are mostly used, aluminium oxyhydroxide and aluminium hydroxyphosphate. Both types of aluminium adjuvant consist of nanoparticles that form loose, micrometre sized aggregates at circumneutral pH. Aluminium adjuvants constitute a well-documented example of administration of nanomaterials to humanswith infrequent side effects and a safety record generally regarded as excellent. However, despite its prolonged use in human and veterinary medicine, the mechanisms behind the enhanced response and the immune stimulatory effect are still by and large unknown. Methods: The present paper reviews existing ideas regarding the immunostimulatory effects of aluminium adjuvants, with a focus on the induction of an inflammatory response by cellular stress. Reviewed information was obtained from peer-reviewed scientific papers published in 1988 to date with one exception, a paper published 1931. Results: Cellular stress causes extra cellular signalling of danger associated molecular patterns (DAMPs) and upon phagocytosis of aluminium adjuvants the cells need to manage the ingested particles. Conclusion: A persistent intracellular accumulation of aluminium adjuvants will be a solid depository of sparingly soluble aluminium salts maintaining a constant concentration of Al3+ ions in the cytoplasm and this will affect multiple biochemical processes. The cell will be under constant stress and DAMP signalling will occur and we would like to suggest the maintenance of a constant concentration Al3+ ions in the cytoplasm as a general underlying feature of the immune stimulation properties of aluminium adjuvants.

Place, publisher, year, edition, pages
Bentham eBooks, 2018
Keywords
Aluminium adjuvants, cellular stress, DAMP, vaccine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:mau:diva-823 (URN)10.2174/1874070701812010140 (DOI)2-s2.0-85053711845 (Scopus ID)24182 (Local ID)24182 (Archive number)24182 (OAI)
Available from: 2020-02-27 Created: 2020-02-27 Last updated: 2024-02-06Bibliographically approved
Danielsson, R., Svensson, A., Falkman, P. & Eriksson, H. (2018). Tracing Aluminium-based Adjuvants: Their Interactions with Immune Competent Cells and their Effect on Mitochondrial Activity (ed.). Open Immunology Journal, 8, 1-15
Open this publication in new window or tab >>Tracing Aluminium-based Adjuvants: Their Interactions with Immune Competent Cells and their Effect on Mitochondrial Activity
2018 (English)In: Open Immunology Journal, ISSN 1874-2262, Vol. 8, p. 1-15Article in journal (Refereed)
Abstract [en]

Background: Studies revealing the immune stimulatory properties of aluminium-based adjuvants (ABAs) have been impaired by the absence of simple and reliable methods of tracing the adjuvants and their effect on biochemical processes upon endocytosis. Objective: To verify that labelling of ABAs with lumogallion doesn’t affect the physicochemical properties of the adjuvant; tracing cellular interaction with aluminium adjuvants; explore their effect on metabolic activity upon endocytosis. Methods: Physicochemical characterization by Z-potential and size distribution of ABAs labelled with lumogallion. Cellular interactions with ABAs by flow cytometry and confocal microscopy. Metabolic activity explored by measuring transformation of tetrazolium into formazan. Results: No or minor change of zeta potential and average particle size of lumogallion labelled aluminium oxyhydroxide, AlO(OH) and aluminium hydroxyphosphate, Al(OH)x(PO4 )y. Both phagocytosing and non-phagocytosing leukocytes became associated with ABAs at concentrations expected after in vivo administration of a vaccine. The ABAs were relatively toxic, affecting both lymphocytes and monocytes, and Al(OH)x(PO4 )y was more toxic than AlO(OH). Endocytosed aluminium adjuvant particles were not secreted from the cells and remained intracellular throughout several cell divisions. The presence of ABAs increased the mitochondrial activity of the monocytic cell line THP-1 and peripheral monocytes, as based on the transformation of tetrazolium into formazan. Conclusion: Lumogallion labelled ABAs is a valuable tool tracing interactions between ABAs and cells. Labelled ABAs can be traced intracellularly and ABAs are likely to remain intracellular for a long period of time. Intracellular ABAs increase the mitochondrial activity and the presence of intracellular Al ions is suggested to cause an increased mitochondrial activity. Keywords: Aluminium based adjuvant, Lumogallion, Mitochondrial activity, MTT assay, Phagocytosis, ABAS, Zeolites.

Place, publisher, year, edition, pages
Bentham eBooks, 2018
Keywords
Aluminium based adjuvant, Lumogallion, Mitochondrial activity, MTT assay, Phagocytosis, ABAS, Zeolites
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:mau:diva-5015 (URN)10.2174/1874226201808010001 (DOI)26775 (Local ID)26775 (Archive number)26775 (OAI)
Available from: 2020-02-28 Created: 2020-02-28 Last updated: 2022-12-07Bibliographically approved
Svensson, A., Sandberg, T., Siesjö, P. & Eriksson, H. (2017). Sequestering of damage-associated molecular-patterns (DAMPs): a possible mechanism affecting the immune stimulating properties of aluminium adjuvants (ed.). Immunologic research, 65(6), 1164-1175
Open this publication in new window or tab >>Sequestering of damage-associated molecular-patterns (DAMPs): a possible mechanism affecting the immune stimulating properties of aluminium adjuvants
2017 (English)In: Immunologic research, ISSN 0257-277X, E-ISSN 1559-0755, Vol. 65, no 6, p. 1164-1175Article in journal (Refereed)
Abstract [en]

Aluminium based adjuvants (ABAs) have been used in human and veterinary vaccines for decades and for a long time the adjuvant properties were believed to be mediated by an antigen depot at the injection site, prolonging antigen exposure to the immune system. The depot hypothesis is today more or less abandoned, and instead replaced by the assumption that ABAs induce an inflammation at the injection site. Induction of an inflammatory response is consistent with immune activation initiated by recognition of molecular patterns associated with danger or damage (DAMPs), and the latter are derived from endogenous molecules that normally reside intracellularly. When extracellularly expressed, because of damage, stress or cell death, a sterile inflammation is induced. In this paper, we report the induction of DAMP release by viable cells after phagocytosis of aluminium based adjuvants. Two of the most commonly used ABAs in pharmaceutical vaccine formulations, aluminium oxyhydroxide and aluminium hydroxyphosphate, induced a vigorous extracellular expression of the two DAMP molecules calreticulin and HMGB1. Concomitantly, extracellular adjuvant particles adsorbed the DAMP molecules released by the cells whereas IL-1, a previously reported inflammatory mediator induced by ABAs, was not absorbed by the adjuvants. Induction of extracellular expression of the two DAMP molecules was more prominent using aluminium hydroxyphosphate compared to aluminium oxyhydroxide, whereas the extracellular adsorption of the DAMP molecules was more pronounced with the latter. Furthermore, is hypothesised how induction of DAMP expression by ABAs and their concomitant adsorption by extra cellular adjuvants may affect the inflammatory properties of ABAs.

Place, publisher, year, edition, pages
Springer, 2017
Keywords
Alarmins, Aluminium based adjuvant, DAMP, lumogallion, sterile inflammation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:mau:diva-4667 (URN)10.1007/s12026-017-8972-5 (DOI)000416918100010 ()29181774 (PubMedID)2-s2.0-85035149331 (Scopus ID)24183 (Local ID)24183 (Archive number)24183 (OAI)
Available from: 2020-02-28 Created: 2020-02-28 Last updated: 2024-02-05Bibliographically approved
Svensson, A. & Eriksson, H. (2016). Tracing aluminium adjuvants in viable cells (ed.). Atlas of Science (February 29)
Open this publication in new window or tab >>Tracing aluminium adjuvants in viable cells
2016 (English)In: Atlas of Science, no February 29Article in journal (Other academic)
Place, publisher, year, edition, pages
Atlas of Science, 2016
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:mau:diva-3968 (URN)20449 (Local ID)20449 (Archive number)20449 (OAI)
Available from: 2020-02-28 Created: 2020-02-28 Last updated: 2022-12-07Bibliographically approved
Mile, I., Svensson, A., Darabi, A., Mold, M., Siesjö, P. & Eriksson, H. (2015). Al adjuvants can be tracked in viable cells by lumogallion staining (ed.). JIM - Journal of Immunological Methods, 422, 87-94
Open this publication in new window or tab >>Al adjuvants can be tracked in viable cells by lumogallion staining
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2015 (English)In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 422, p. 87-94Article in journal (Refereed)
Abstract [en]

The mechanism behind the adjuvant effect of aluminum salts is poorly understood notwithstanding that aluminum salts have been used for decades in clinical vaccines. In an aqueous environment and at a nearly neutral pH, the aluminumsalts form particulate aggregates, and one plausible explanation of the lack of information regarding the mechanisms could be the absence of an efficientmethod of tracking phagocytosed aluminum adjuvants and thereby the intracellular location of the adjuvant. In this paper, we want to report upon the use of lumogallion staining enabling the detection of phagocytosed aluminum adjuvants inside viable cells. Including micromolar concentrations of lumogallion in the culture medium resulted in a strong fluorescence signal from cells that had phagocytosed the aluminum adjuvant. The fluorescence appeared as spots in the cytoplasm and by confocal microscopy and co-staining with probes presenting fluorescence in the far-red region of the spectrum, aluminum adjuvants could to a certain extent be identified as localized in acidic vesicles, i.e., lysosomes. Staining and detection of intracellular aluminum adjuvants was achieved not only by diffusion of lumogallion into the cytoplasm, thereby highlighting the presence of the adjuvant, but also by pre-staining the aluminum adjuvant prior to incubation with cells. Pre-staining of aluminum adjuvants resulted in bright fluorescent particulate aggregates that remained fluorescent for weeks and with only a minor reduction of fluorescence upon extensive washing or incubation with cells. Both aluminum oxyhydroxide and aluminum hydroxyphosphate, two of the most commonly used aluminum adjuvants in clinical vaccines, could be pre-stained with lumogallion and were easily tracked intracellularly after incubation with phagocytosing cells. Staining of viable cells using lumogallion will be a useful method in investigations of the mechanisms behind aluminum adjuvants' differentiation of antigen-presenting cells into inflammatory cells. Information will be gained regarding the phagosomal pathways and the events inside the phagosomes, and thereby the ultimate fate of phagocytosed aluminum adjuvants could be resolved.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Aluminum adjuvant, Lumogallion, Flow cytometry, Phagolysosome
National Category
Natural Sciences
Identifiers
urn:nbn:se:mau:diva-5095 (URN)10.1016/j.jim.2015.04.008 (DOI)000356985100010 ()25896212 (PubMedID)2-s2.0-84930754223 (Scopus ID)19498 (Local ID)19498 (Archive number)19498 (OAI)
Available from: 2020-02-28 Created: 2020-02-28 Last updated: 2024-02-05Bibliographically approved
Projects
Inflammatory induction by vaccine adjuvants with special focus on aluminium adjuvants
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-0769-9988

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