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Article ; Online: Comparison of the oncolytic activity of a replication-competent and a replication-deficient herpes simplex virus 1.

2024

Abstract: In 2015, the oncolytic herpes simplex virus 1 (HSV-1) T-VEC (talimogene laherparepvec) was approved for intratumoral injection in non-resectable malignant melanoma. To determine whether viral replication is required for oncolytic activity, we compared ... ...

Abstract	In 2015, the oncolytic herpes simplex virus 1 (HSV-1) T-VEC (talimogene laherparepvec) was approved for intratumoral injection in non-resectable malignant melanoma. To determine whether viral replication is required for oncolytic activity, we compared replication-deficient HSV-1 d106S with replication-competent T-VEC. High infectious doses of HSV-1 d106S killed melanoma (n = 10), head-and-neck squamous cell carcinoma (n = 11), and chondrosarcoma cell lines (n = 2) significantly faster than T-VEC as measured by MTT metabolic activity, while low doses of T-VEC were more effective over time. HSV-1 d106S and, to a lesser extent T-VEC, triggered caspase-dependent early apoptosis as shown by pan-caspase inhibition and specific induction of caspases 3/7, 8, and 9. HSV-1 d106S induced a higher ratio of apoptosis-inducing infected cell protein (ICP) 0 to apoptosis-blocking ICP6 than T-VEC. T-VEC was oncolytic for an extended period of time as viral replication continued, which could be partially blocked by the antiviral drug aciclovir. High doses of T-VEC, but not HSV-1 d106S, increased interferon-β mRNA as part of the intrinsic immune response. When markers of immunogenic cell death were assessed, ATP was released more efficiently in the context of T-VEC than HSV-1 d106S infection, whereas HMGB1 was induced comparatively well. Overall, the early oncolytic effect on three different tumour entities was stronger with the non-replicative strain, while the replication-competent virus elicited a stronger innate immune response and more pronounced immunogenic cell death.
Language	English
Publishing date	2024-03-05
Publishing country	England
Document type	Journal Article
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/imm.13775
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Article ; Online: Characterization of the visceral and neuronal phenotype of 4L/PS-NA mice modeling Gaucher disease.

Victoria Schiffer / Estibaliz Santiago-Mujika / Stefanie Flunkert / Staffan Schmidt / Martina Farcher / Tina Loeffler / Irene Schilcher / Maria Posch / Joerg Neddens / Ying Sun / Jan Kehr / Birgit Hutter-Paier

PLoS ONE, Vol 15, Iss 1, p e

2020 Volume 0227077

Abstract: Gaucher disease is caused by a deficiency in glucocerebrosidase that can result in non-neuronal as well as neuronal symptoms. Common visceral symptoms are an increased organ size, specifically of the spleen, and glucosylceramide as well as ... ...

Abstract	Gaucher disease is caused by a deficiency in glucocerebrosidase that can result in non-neuronal as well as neuronal symptoms. Common visceral symptoms are an increased organ size, specifically of the spleen, and glucosylceramide as well as glucosylsphingosine substrate accumulations as a direct result of the glucocerebrosidase deficiency. Neuronal symptoms include motor deficits and strong alterations in the cerebellum. To evaluate the effect of new compounds for the treatment of this devastating disease, animal models are needed that closely mimic the human phenotype. The 4L/PS-NA mouse as model of Gaucher disease is shown to present reduced glucocerebrosidase activity similar to human cases but an in-depth characterization of the model was still not performed. We therefore analyzed 4L/PS-NA mice for visceral alterations, motor deficits and also neuronal changes like glucocerebrosidase activity, substrate levels and neuroinflammation. A special focus was set at pathological changes of the cerebellum. Our results show that 4L/PS-NA mice have strongly enlarged visceral organs that are infiltrated by enlarged leukocytes and macrophages. Furthermore, animals present strong motor deficits that are accompanied by increased glucosylceramide and glucosylsphingosine levels in the brain, astrocytosis and activated microglia in the cortex and hippocampus as well as reduced calbindin levels in the cerebellum. The latter was directly related to a strong Purkinje cell loss. Our results thus provide a detailed characterization of the 4L/PS-NA mouse model over age showing the translational value of the model and validating its usefulness for preclinical efficiency studies to evaluate new compounds against Gaucher disease.
Keywords	Medicine ; R ; Science ; Q
Subject code	630
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Characterization of the visceral and neuronal phenotype of 4L/PS-NA mice modeling Gaucher disease.

Schiffer, Victoria / Santiago-Mujika, Estibaliz / Flunkert, Stefanie / Schmidt, Staffan / Farcher, Martina / Loeffler, Tina / Schilcher, Irene / Posch, Maria / Neddens, Joerg / Sun, Ying / Kehr, Jan / Hutter-Paier, Birgit

PloS one

2020 Volume 15, Issue 1, Page(s) e0227077

Abstract	Gaucher disease is caused by a deficiency in glucocerebrosidase that can result in non-neuronal as well as neuronal symptoms. Common visceral symptoms are an increased organ size, specifically of the spleen, and glucosylceramide as well as glucosylsphingosine substrate accumulations as a direct result of the glucocerebrosidase deficiency. Neuronal symptoms include motor deficits and strong alterations in the cerebellum. To evaluate the effect of new compounds for the treatment of this devastating disease, animal models are needed that closely mimic the human phenotype. The 4L/PS-NA mouse as model of Gaucher disease is shown to present reduced glucocerebrosidase activity similar to human cases but an in-depth characterization of the model was still not performed. We therefore analyzed 4L/PS-NA mice for visceral alterations, motor deficits and also neuronal changes like glucocerebrosidase activity, substrate levels and neuroinflammation. A special focus was set at pathological changes of the cerebellum. Our results show that 4L/PS-NA mice have strongly enlarged visceral organs that are infiltrated by enlarged leukocytes and macrophages. Furthermore, animals present strong motor deficits that are accompanied by increased glucosylceramide and glucosylsphingosine levels in the brain, astrocytosis and activated microglia in the cortex and hippocampus as well as reduced calbindin levels in the cerebellum. The latter was directly related to a strong Purkinje cell loss. Our results thus provide a detailed characterization of the 4L/PS-NA mouse model over age showing the translational value of the model and validating its usefulness for preclinical efficiency studies to evaluate new compounds against Gaucher disease.
MeSH term(s)	Animals ; Cerebellum/metabolism ; Cerebellum/pathology ; Disease Models, Animal ; Female ; Gaucher Disease/genetics ; Gaucher Disease/metabolism ; Gaucher Disease/pathology ; Glucosylceramidase/genetics ; Glucosylceramidase/metabolism ; Leukocytes/pathology ; Liver/metabolism ; Liver/pathology ; Lung/metabolism ; Lung/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Movement ; Mutation ; Neurons/metabolism ; Neurons/pathology ; Phenotype ; Spleen/metabolism ; Spleen/pathology ; Thymus Gland/metabolism ; Thymus Gland/pathology
Chemical Substances	Glucosylceramidase (EC 3.2.1.45)
Language	English
Publishing date	2020-01-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0227077
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: WHO Global Situational Alert System: a mixed methods multistage approach to identify country-level COVID-19 alerts.

McMenamin, Martina / Kolmer, Jessica / Djordjevic, Irena / Campbell, Finlay / Laurenson-Schafer, Henry / Abbate, Jessica Lee / Abdelgawad, Basma Mostafa / Babu, Amarnath / Balde, Thierno / Batra, Neale / Bélorgeot, Victoria D / Brindle, Hannah / Dorji, Tshewang / Esmail, Marjam / Hammermeister Nezu, Ingrid / Hernández-García, Lucía / Hassan, Mahmoud / Idoko, Friday / Karmin, Sarah /

Kassamali, Zyleen A / Kato, Masaya / Matsui, Tamano / Duan, Mengjuan / Motaze, Villyen / Ogundiran, Opeayo / Pavlin, Boris I / Riviere-Cinnamond, Ana / Ryan, Kathleen / Schmidt, Tanja / Sedai, Tika / Van Kerkhove, Maria D / Zakaria, Teresa / Höhle, Michael / Mahamud, Abdi R / le Polain de Waroux, Olivier

BMJ global health

2023 Volume 8, Issue 7

Abstract: Background: Globally, since 1 January 2020 and as of 24 January 2023, there have been over 664 million cases of COVID-19 and over 6.7 million deaths reported to WHO. WHO developed an evidence-based alert system, assessing public health risk on a weekly ... ...

Abstract	Background: Globally, since 1 January 2020 and as of 24 January 2023, there have been over 664 million cases of COVID-19 and over 6.7 million deaths reported to WHO. WHO developed an evidence-based alert system, assessing public health risk on a weekly basis in 237 countries, territories and areas from May 2021 to June 2022. This aimed to facilitate the early identification of situations where healthcare capacity may become overstretched. Methods: The process involved a three-stage mixed methods approach. In the first stage, future deaths were predicted from the time series of reported cases and deaths to produce an initial alert level. In the second stage, this alert level was adjusted by incorporating a range of contextual indicators and accounting for the quality of information available using a Bayes classifier. In the third stage, countries with an alert level of 'High' or above were added to an operational watchlist and assistance was deployed as needed. Results: Since June 2021, the system has supported the release of more than US$27 million from WHO emergency funding, over 450 000 rapid antigen diagnostic testing kits and over 6000 oxygen concentrators. Retrospective evaluation indicated that the first two stages were needed to maximise sensitivity, where 44% (IQR 29%-67%) of weekly watchlist alerts would not have been identified using only reported cases and deaths. The alerts were timely and valid in most cases; however, this could only be assessed on a non-representative sample of countries with hospitalisation data available. Conclusions: The system provided a standardised approach to monitor the pandemic at the country level by incorporating all available data on epidemiological analytics and contextual assessments. While this system was developed for COVID-19, a similar system could be used for future outbreaks and emergencies, with necessary adjustments to parameters and indicators.
MeSH term(s)	Humans ; Bayes Theorem ; COVID-19 ; Disease Outbreaks ; Retrospective Studies ; World Health Organization ; Public Health
Language	English
Publishing date	2023-07-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2059-7908
ISSN	2059-7908
DOI	10.1136/bmjgh-2023-012241
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities.

Hayn, Manuel / Hirschenberger, Maximilian / Koepke, Lennart / Nchioua, Rayhane / Straub, Jan Hendrik / Klute, Susanne / Hunszinger, Victoria / Zech, Fabian / Prelli Bozzo, Caterina / Aftab, Wasim / Christensen, Maria Hønholt / Conzelmann, Carina / Müller, Janis Alexander / Srinivasachar Badarinarayan, Smitha / Stürzel, Christina Martina / Forne, Ignasi / Stenger, Steffen / Conzelmann, Karl-Klaus / Münch, Jan /

Schmidt, Florian Ingo / Sauter, Daniel / Imhof, Axel / Kirchhoff, Frank / Sparrer, Konstantin Maria Johannes

Cell reports

2021 Volume 35, Issue 7, Page(s) 109126

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evades most innate immune responses but may still be vulnerable to some. Here, we systematically analyze the impact of SARS-CoV-2 proteins on interferon (IFN) responses and autophagy. We show ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evades most innate immune responses but may still be vulnerable to some. Here, we systematically analyze the impact of SARS-CoV-2 proteins on interferon (IFN) responses and autophagy. We show that SARS-CoV-2 proteins synergize to counteract anti-viral immune responses. For example, Nsp14 targets the type I IFN receptor for lysosomal degradation, ORF3a prevents fusion of autophagosomes and lysosomes, and ORF7a interferes with autophagosome acidification. Most activities are evolutionarily conserved. However, SARS-CoV-2 Nsp15 antagonizes IFN signaling less efficiently than the orthologs of closely related RaTG13-CoV and SARS-CoV-1. Overall, SARS-CoV-2 proteins counteract autophagy and type I IFN more efficiently than type II or III IFN signaling, and infection experiments confirm potent inhibition by IFN-γ and -λ1. Our results define the repertoire and selected mechanisms of SARS-CoV-2 innate immune antagonists but also reveal vulnerability to type II and III IFN that may help to develop safe and effective anti-viral approaches.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Autophagosomes/immunology ; Autophagy/immunology ; COVID-19/immunology ; COVID-19/virology ; Cell Line ; Chlorocebus aethiops ; Exoribonucleases/immunology ; HEK293 Cells ; HeLa Cells ; Humans ; Immune Evasion ; Immunity, Innate ; Interferon Type I/metabolism ; Interferons/metabolism ; Receptor, Interferon alpha-beta/antagonists & inhibitors ; Receptor, Interferon alpha-beta/immunology ; SARS-CoV-2/immunology ; SARS-CoV-2/pathogenicity ; Vero Cells ; Viral Nonstructural Proteins/immunology ; Viral Proteins/immunology
Chemical Substances	Antiviral Agents ; Interferon Type I ; Viral Nonstructural Proteins ; Viral Proteins ; Receptor, Interferon alpha-beta (156986-95-7) ; Interferons (9008-11-1) ; nsp14 protein, SARS coronavirus (EC 2.1.1.56) ; Exoribonucleases (EC 3.1.-)
Language	English
Publishing date	2021-04-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2021.109126
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The Nuclear Hormone Receptor PPARγ as a Therapeutic Target in Major Diseases

Martina Victoria Schmidt / Bernhard Brüne / Andreas von Knethen

The Scientific World Journal, Vol 10, Pp 2181-

2010 Volume 2197

Abstract: The peroxisome proliferator-activated receptor γ (PPARγ) belongs to the nuclear hormone receptor superfamily and regulates gene expression upon heterodimerization with the retinoid X receptor by ligating to peroxisome proliferator response elements ( ... ...

Abstract	The peroxisome proliferator-activated receptor γ (PPARγ) belongs to the nuclear hormone receptor superfamily and regulates gene expression upon heterodimerization with the retinoid X receptor by ligating to peroxisome proliferator response elements (PPREs) in the promoter region of target genes. Originally, PPARγ was identified as being essential for glucose metabolism. Thus, synthetic PPARγ agonists, the thiazolidinediones (TZDs), are used in type 2 diabetes therapy as insulin sensitizers. More recent evidence implied an important role for the nuclear hormone receptor PPARγ in controlling various diseases based on its anti-inflammatory, cell cycle arresting, and proapoptotic properties. In this regard, expression of PPARγ is not restricted to adipocytes, but is also found in immune cells, such as B and T lymphocytes, monocytes, macrophages, dendritic cells, and granulocytes. The expression of PPARγ in lymphoid organs and its modulation of macrophage inflammatory responses, lymphocyte proliferation, cytokine production, and apoptosis underscore its immune regulating functions. Moreover, PPARγ expression is found in tumor cells, where its activation facilitates antitumorigenic actions. This review provides an overview about the role of PPARγ as a possible therapeutic target approaching major, severe diseases, such as sepsis, cancer, and atherosclerosis.
Keywords	Technology ; T ; Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2010-01-01T00:00:00Z
Publisher	Hindawi Limited
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The nuclear hormone receptor PPARγ as a therapeutic target in major diseases.

Schmidt, Martina Victoria / Brüne, Bernhard / von Knethen, Andreas

TheScientificWorldJournal

2010 Volume 10, Page(s) 2181–2197

Abstract: The peroxisome proliferator-activated receptor γ (PPARγ belongs to the nuclear hormone receptor superfamily and regulates gene expression upon heterodimerization with the retinoid X receptor by ligating to peroxisome proliferator response elements (PPREs) ...

Abstract	The peroxisome proliferator-activated receptor γ (PPARγ belongs to the nuclear hormone receptor superfamily and regulates gene expression upon heterodimerization with the retinoid X receptor by ligating to peroxisome proliferator response elements (PPREs) in the promoter region of target genes. Originally, PPARγ was identified as being essential for glucose metabolism. Thus, synthetic PPARγ agonists, the thiazolidinediones (TZDs), are used in type 2 diabetes therapy as insulin sensitizers. More recent evidence implied an important role for the nuclear hormone receptor PPARγ in controlling various diseases based on its anti-inflammatory, cell cycle arresting, and proapoptotic properties. In this regard, expression of PPARγ is not restricted to adipocytes, but is also found in immune cells, such as B and T lymphocytes, monocytes, macrophages, dendritic cells, and granulocytes. The expression of PPARγ in lymphoid organs and its modulation of macrophage inflammatory responses, lymphocyte proliferation, cytokine production, and apoptosis underscore its immune regulating functions. Moreover, PPARγ expression is found in tumor cells, where its activation facilitates antitumorigenic actions. This review provides an overview about the role of PPARγ as a possible therapeutic target approaching major, severe diseases, such as sepsis, cancer, and atherosclerosis.
MeSH term(s)	Animals ; Atherosclerosis/drug therapy ; Atherosclerosis/metabolism ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/metabolism ; Humans ; Models, Biological ; Neoplasms/drug therapy ; Neoplasms/metabolism ; PPAR gamma/agonists ; PPAR gamma/metabolism ; Receptors, Cytoplasmic and Nuclear/agonists ; Receptors, Cytoplasmic and Nuclear/metabolism ; Sepsis/drug therapy ; Sepsis/metabolism ; Thiazolidinediones/therapeutic use
Chemical Substances	PPAR gamma ; Receptors, Cytoplasmic and Nuclear ; Thiazolidinediones
Language	English
Publishing date	2010-11-04
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2075968-X
ISSN	1537-744X ; 1537-744X
ISSN (online)	1537-744X
ISSN	1537-744X
DOI	10.1100/tsw.2010.213
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Article: Antioxidant signaling via Nrf2 counteracts lipopolysaccharide-mediated inflammatory responses in foam cell macrophages

Kuhn, Anne-Marie / Tzieply, Nico / Schmidt, Martina Victoria / von Knethen, Andreas / Namgaladze, Dmitry / Yamamoto, Masayuki / Brüne, Bernhard

Free Radical Biology and Medicine. 2011 May 15, v. 50, no. 10

2011

Abstract: Inflammatory conditions and oxidative stress contribute to the development of atherosclerosis. Nuclear factor E2-related factor 2 (Nrf2) is a redox-sensitive transcription factor known for its antioxidant, anti-inflammatory, and, thus, cell-protective ... ...

Abstract	Inflammatory conditions and oxidative stress contribute to the development of atherosclerosis. Nuclear factor E2-related factor 2 (Nrf2) is a redox-sensitive transcription factor known for its antioxidant, anti-inflammatory, and, thus, cell-protective properties. Its role in effecting a deactivated state of oxidized low-density lipoprotein (oxLDL)-generated foam cell macrophages (FCMs), a prevailing cellular phenotype of atherosclerotic lesions, has not been investigated yet. In this study RAW264.7- or mouse peritoneal macrophage-derived FCMs showed reduced mRNA expression of proinflammatory cytokines such as IL-1β and IL-6 and an attenuated production of reactive oxygen species (ROS), as analyzed by hydroethidine in response to lipopolysaccharide (LPS) and compared to LPS-treated control macrophages. In peritoneal FCMs from Nrf2⁻/⁻ mice (C57BL/6J), the LPS-induced proinflammatory response was restored. OxLDL induced heme oxygenase (HO)-1, which was Nrf2-dependent, and inhibition of HO-1 activity in FCMs using zinc protoporphyrin-IX allowed the cells to regain a proinflammatory phenotype. Mechanistically, oxLDL attenuated ROS-dependent activation of CCAAT/enhancer binding protein (C/EBP) family members in FCMs, thereby reducing cytokine expression. Thus, in FCMs the Nrf2/HO-1 axis intervenes in LPS signaling. ROS production is impaired, C/EBP transactivation is reduced, and consequently the expression of proinflammatory mediators is attenuated, thereby shaping a desensitized FCM phenotype. This macrophage phenotype may be important for the progression of atherosclerosis.
Keywords	antioxidants ; atherosclerosis ; binding proteins ; foam cells ; gene expression ; heme oxygenase (biliverdin-producing) ; inflammation ; interleukin-1beta ; interleukin-6 ; lipopolysaccharides ; low density lipoprotein ; messenger RNA ; mice ; oxidative stress ; phenotype ; reactive oxygen species ; transcription factors ; transcriptional activation ; zinc
Language	English
Dates of publication	2011-0515
Size	p. 1382-1391.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	807032-5
ISSN	1873-4596 ; 0891-5849
ISSN (online)	1873-4596
ISSN	0891-5849
DOI	10.1016/j.freeradbiomed.2011.02.036
Database	NAL-Catalogue (AGRICOLA)

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Article: PPARγ stabilizes HO-1 mRNA in monocytes/macrophages which affects IFN-β expression

von Knethen, Andreas / Neb, Holger / Morbitzer, Virginie / Schmidt, Martina Victoria / Kuhn, Anne-Marie / Kuchler, Laura / Brüne, Bernhard

Free Radical Biology and Medicine. 2011 July 15, v. 51, no. 2

2011

Abstract: NADPH oxidase activation in either RAW264.7 cells or peritoneal macrophages (PM) derived from PPARγ wild-type mice increased reactive oxygen species (ROS) formation, caused PPARγ activation, heme oxygenase-1 (HO-1) induction, and concomitant IFN-β ... ...

Abstract	NADPH oxidase activation in either RAW264.7 cells or peritoneal macrophages (PM) derived from PPARγ wild-type mice increased reactive oxygen species (ROS) formation, caused PPARγ activation, heme oxygenase-1 (HO-1) induction, and concomitant IFN-β expression. In macrophages transduced with a dominant negative (d/n) mutant of PPARγ (RAW264.7 AF2) as well as PPARγ negative PM derived from Mac-PPARγ-KO mice, NADPH oxidase-dependent IFN-β expression was attenuated. As the underlying mechanism, we noted decreased HO-1 mRNA stability in RAW264.7 AF2 cells as well as PPARγ negative PM, compared to either parent RAW264.7 cells or wild-type PM. Assuming mRNA stabilization of HO-1 by PPARγ we transfected macrophages with a HO-1 3′-UTR reporter construct. The PPARγ agonist rosiglitazone significantly up-regulated luciferase expression in RAW264.7 cells, while it remained unaltered in RAW264.7 AF2 macrophages. Deletion of each of two AU-rich elements in the 3′-UTR HO-1 decreased luciferase activity in RAW264.7 cells. Using LPS as a NADPH oxidase activator, PM from Mac-PPARγ-KO mice showed a decreased HO-1 mRNA half-life in vitro and in vivo compared to PPARγ wild-type mice. These data identified a so far unappreciated role of PPARγ in stabilizing HO-1 mRNA, thus, contributing to the expression of the HO-1 target gene IFN-β.
Keywords	agonists ; genes ; half life ; heme oxygenase (biliverdin-producing) ; interferon-beta ; luciferase ; macrophages ; messenger RNA ; mice ; monocytes ; mutants ; reactive oxygen species
Language	English
Dates of publication	2011-0715
Size	p. 396-405.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	807032-5
ISSN	1873-4596 ; 0891-5849
ISSN (online)	1873-4596
ISSN	0891-5849
DOI	10.1016/j.freeradbiomed.2011.04.033
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Antioxidant signaling via Nrf2 counteracts lipopolysaccharide-mediated inflammatory responses in foam cell macrophages.

Kuhn, Anne-Marie / Tzieply, Nico / Schmidt, Martina Victoria / von Knethen, Andreas / Namgaladze, Dmitry / Yamamoto, Masayuki / Brüne, Bernhard

Free radical biology & medicine

2011 Volume 50, Issue 10, Page(s) 1382–1391

Abstract	Inflammatory conditions and oxidative stress contribute to the development of atherosclerosis. Nuclear factor E2-related factor 2 (Nrf2) is a redox-sensitive transcription factor known for its antioxidant, anti-inflammatory, and, thus, cell-protective properties. Its role in effecting a deactivated state of oxidized low-density lipoprotein (oxLDL)-generated foam cell macrophages (FCMs), a prevailing cellular phenotype of atherosclerotic lesions, has not been investigated yet. In this study RAW264.7- or mouse peritoneal macrophage-derived FCMs showed reduced mRNA expression of proinflammatory cytokines such as IL-1β and IL-6 and an attenuated production of reactive oxygen species (ROS), as analyzed by hydroethidine in response to lipopolysaccharide (LPS) and compared to LPS-treated control macrophages. In peritoneal FCMs from Nrf2-/- mice (C57BL/6J), the LPS-induced proinflammatory response was restored. OxLDL induced heme oxygenase (HO)-1, which was Nrf2-dependent, and inhibition of HO-1 activity in FCMs using zinc protoporphyrin-IX allowed the cells to regain a proinflammatory phenotype. Mechanistically, oxLDL attenuated ROS-dependent activation of CCAAT/enhancer binding protein (C/EBP) family members in FCMs, thereby reducing cytokine expression. Thus, in FCMs the Nrf2/HO-1 axis intervenes in LPS signaling. ROS production is impaired, C/EBP transactivation is reduced, and consequently the expression of proinflammatory mediators is attenuated, thereby shaping a desensitized FCM phenotype. This macrophage phenotype may be important for the progression of atherosclerosis.
MeSH term(s)	Animals ; Antioxidants/metabolism ; Cells, Cultured ; Heme Oxygenase-1/metabolism ; Inflammation/chemically induced ; Inflammation/immunology ; Lipopolysaccharides/immunology ; Lipopolysaccharides/pharmacology ; Lipoproteins, LDL/metabolism ; Macrophages/drug effects ; Macrophages/immunology ; Mice ; Mice, Inbred C57BL ; NF-E2-Related Factor 2/deficiency ; NF-E2-Related Factor 2/genetics ; NF-E2-Related Factor 2/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction
Chemical Substances	Antioxidants ; Lipopolysaccharides ; Lipoproteins, LDL ; NF-E2-Related Factor 2 ; Reactive Oxygen Species ; oxidized low density lipoprotein ; Heme Oxygenase-1 (EC 1.14.14.18)
Language	English
Publishing date	2011-05-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	807032-5
ISSN	1873-4596 ; 0891-5849
ISSN (online)	1873-4596
ISSN	0891-5849
DOI	10.1016/j.freeradbiomed.2011.02.036
Database	MEDical Literature Analysis and Retrieval System OnLINE

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