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Myeloid Fra-1 Expression Modulates the Endotoxin Tolerance Response in Sepsis = = Myeloische Fra-1 Expression moduliert die Endotoxintoleranz wahrend einer Sepsis.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Myeloid Fra-1 Expression Modulates the Endotoxin Tolerance Response in Sepsis =/
Reminder of title:	Myeloische Fra-1 Expression moduliert die Endotoxintoleranz wahrend einer Sepsis.
Author:	Schnelzer, Anne-Christin.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
Description:	106 p.
Notes:	Source: Dissertations Abstracts International, Volume: 83-02, Section: B.
Contained By:	Dissertations Abstracts International83-02B.
Subject:	Infections. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28467679
ISBN:	9798744476403

Myeloid Fra-1 Expression Modulates the Endotoxin Tolerance Response in Sepsis = = Myeloische Fra-1 Expression moduliert die Endotoxintoleranz wahrend einer Sepsis.
Schnelzer, Anne-Christin.

Myeloid Fra-1 Expression Modulates the Endotoxin Tolerance Response in Sepsis =Myeloische Fra-1 Expression moduliert die Endotoxintoleranz wahrend einer Sepsis. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 106 p.

Source: Dissertations Abstracts International, Volume: 83-02, Section: B.

Thesis (Ph.D.)--Friedrich-Alexander-Universitaet Erlangen-Nuernberg (Germany), 2021.

This item must not be sold to any third party vendors.

Background and objective: Sepsis is a dysregulated immunological response to infection, which causes life-threatening organ failure. Since the pathophysiology of sepsis is poorly understood, no therapy targeting the patient's immune system has been successful. However, both hyper-inflammation and immunosuppression seem to be responsible for the high mortality rate.A form of septic immunomodulation occurring in macrophages is the phenomenon of endotoxin tolerance. The latter is achieved by a functional re-programming of the cells' gene transcription in response to prolonged lipopolysaccharide (LPS) exposure. This modulation of the inflammatory response leads to an immunosuppressive state, which on the one hand protects the organism from damaging hyper-inflammation but on the other hand increases the susceptibility to secondary infections.Even though their relevance in LPS-mediated inflammation is known, the role of the activator protein 1 (AP-1) transcription factor family (Fra-1, Fra-2, cFos, FosB, cJun, JunB and JunD) in the tolerance process has not been investigated much. Especially on Fra-1, no information seems to be available. Thus, the aim of this thesis was to assess the influence of Fra-1 on endotoxin tolerance.Methods: In vitro, murine wildtype and Fra-1∆Mx conditional knockout bone marrow derived macrophages (BMM) as well as human peripheral blood mononuclear cell (PBMC)-derived macrophages were assessed. Endotoxin tolerance was induced in the human and murine macrophages via LPS admission for 24 hours, leading to tolerized cells ("tolerant group"). Another group of each macrophage population was not pretreated ("endotoxin-naive group").The tolerant and the endotoxin-naive group of wildtype BMM were then stimulated with LPS for different durations and the two groups' gene expression in response to LPS was compared. Unstimulated cells served as a control. Human macrophages were stimulated and assessed accordingly. Subsequently, the effects of Fra-1 deletion on the reaction of the murine endotoxin naive and tolerant groups to LPS was evaluated. In all samples, the expression of the single AP-1 family transcription factors and of proand anti-inflammatory cytokines (e.g. interleukin 6 (IL-6) and Lipocalin 2 (Lcn2)) in response to LPS was assessed. Moreover, the murine protein levels of IL-6 and Lcn2 in cell culture supernatant were measured. For Lcn2, a chromatin immunoprecipitation (CHIP) analysis of murine macrophages was performed to detect Fra-1 binding to the Lcn2 promoter after LPS admission.In vivo, endotoxin tolerance was induced in wildtype and Fra-1∆Mx conditional knockout mice via intraperitoneal LPS injection. After three days, a second dose of LPS was admitted for two hours. In wildtype, a group of endotoxin-naive mice was stimulated with LPS for two hours as well. Unstimulated wildtype mice served as a control.Subsequently, expression of the genes examined in vitro was assessed in selected organs (lungs, livers, spleens) and in the peritoneal cells in vivo. Moreover, the CD11b+ cell fractions of the lung, liver and spleen were analysed to examine tissue macrophages. Additionally, serum level measurement of IL-6 and Lcn2, a histological analysis of the selected organs and an assessment of the cell type composition in the peritoneal cavity via flow cytometry were performed.

ISBN: 9798744476403Subjects--Topical Terms:

1621997
Infections.

Myeloid Fra-1 Expression Modulates the Endotoxin Tolerance Response in Sepsis = = Myeloische Fra-1 Expression moduliert die Endotoxintoleranz wahrend einer Sepsis.
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100 1 $a Schnelzer, Anne-Christin. $3 3564651
245 1 0 $a Myeloid Fra-1 Expression Modulates the Endotoxin Tolerance Response in Sepsis = $b Myeloische Fra-1 Expression moduliert die Endotoxintoleranz wahrend einer Sepsis.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2021
300 $a 106 p.
500 $a Source: Dissertations Abstracts International, Volume: 83-02, Section: B.
500 $a Advisor: Bozec, Aline;Schett , Georg .
502 $a Thesis (Ph.D.)--Friedrich-Alexander-Universitaet Erlangen-Nuernberg (Germany), 2021.
506 $a This item must not be sold to any third party vendors.
520 $a Background and objective: Sepsis is a dysregulated immunological response to infection, which causes life-threatening organ failure. Since the pathophysiology of sepsis is poorly understood, no therapy targeting the patient's immune system has been successful. However, both hyper-inflammation and immunosuppression seem to be responsible for the high mortality rate.A form of septic immunomodulation occurring in macrophages is the phenomenon of endotoxin tolerance. The latter is achieved by a functional re-programming of the cells' gene transcription in response to prolonged lipopolysaccharide (LPS) exposure. This modulation of the inflammatory response leads to an immunosuppressive state, which on the one hand protects the organism from damaging hyper-inflammation but on the other hand increases the susceptibility to secondary infections.Even though their relevance in LPS-mediated inflammation is known, the role of the activator protein 1 (AP-1) transcription factor family (Fra-1, Fra-2, cFos, FosB, cJun, JunB and JunD) in the tolerance process has not been investigated much. Especially on Fra-1, no information seems to be available. Thus, the aim of this thesis was to assess the influence of Fra-1 on endotoxin tolerance.Methods: In vitro, murine wildtype and Fra-1∆Mx conditional knockout bone marrow derived macrophages (BMM) as well as human peripheral blood mononuclear cell (PBMC)-derived macrophages were assessed. Endotoxin tolerance was induced in the human and murine macrophages via LPS admission for 24 hours, leading to tolerized cells ("tolerant group"). Another group of each macrophage population was not pretreated ("endotoxin-naive group").The tolerant and the endotoxin-naive group of wildtype BMM were then stimulated with LPS for different durations and the two groups' gene expression in response to LPS was compared. Unstimulated cells served as a control. Human macrophages were stimulated and assessed accordingly. Subsequently, the effects of Fra-1 deletion on the reaction of the murine endotoxin naive and tolerant groups to LPS was evaluated. In all samples, the expression of the single AP-1 family transcription factors and of proand anti-inflammatory cytokines (e.g. interleukin 6 (IL-6) and Lipocalin 2 (Lcn2)) in response to LPS was assessed. Moreover, the murine protein levels of IL-6 and Lcn2 in cell culture supernatant were measured. For Lcn2, a chromatin immunoprecipitation (CHIP) analysis of murine macrophages was performed to detect Fra-1 binding to the Lcn2 promoter after LPS admission.In vivo, endotoxin tolerance was induced in wildtype and Fra-1∆Mx conditional knockout mice via intraperitoneal LPS injection. After three days, a second dose of LPS was admitted for two hours. In wildtype, a group of endotoxin-naive mice was stimulated with LPS for two hours as well. Unstimulated wildtype mice served as a control.Subsequently, expression of the genes examined in vitro was assessed in selected organs (lungs, livers, spleens) and in the peritoneal cells in vivo. Moreover, the CD11b+ cell fractions of the lung, liver and spleen were analysed to examine tissue macrophages. Additionally, serum level measurement of IL-6 and Lcn2, a histological analysis of the selected organs and an assessment of the cell type composition in the peritoneal cavity via flow cytometry were performed.
520 $a Hintergrund und Ziele: Sepsis bezeichnet eine dysregulierte Immunantwort auf einen Infekt, die zu einem lebensbedrohlichen Organversagen fuhren kann. Da die Pathophysiologie der Sepsis zum grosten Teil noch unverstanden ist, existieren bisher keine effektiven Therapieoptionen, die das Immunsystem als Ziel haben. Jedoch scheinen sowohl Hyperinflammation als auch Immunsuppression die hohe Mortalitat mitzuverursachen.Eine in Makrophagen vorkommende Form der septischen Immunmodulation ist die Endotoxintoleranz. Sie bezeichnet eine funktionelle Umprogrammierung der Gentranskription als Antwort auf eine andauernde Stimulation mit Endotoxinen (=Lipopolysaccharid (LPS)). Diese genetische Modulation fuhrt zu einem eher immunsuppressiven Zustand, der einerseits die uberschiesende, organschadigende Entzundungsreaktion eindammt, andererseits jedoch die Anfalligkeit des Organismus fur Sekundarinfektionen erhoht.Obwohl ihre Relevanz fur die LPS-vermittelte Entzundungsreaktion bekannt ist, gibt es nur wenige Studien zur Bedeutung der Aktivator Protein 1 (AP-1) Transkriptionsfaktorenfamilie (Fra-1, Fra-2, cFos, FosB, cJun, JunB und JunD) fur die Toleranzreaktion. Insbesondere zum AP-1 Protein Fra-1 scheint es keine Daten zu geben. Daher war es Ziel dieser Arbeit, den Einfluss von Fra-1 auf die Endotoxintoleranz zu untersuchen.Methoden: Die Endotoxintoleranzreaktion wurde in einem murinen und humanen in vitro Modell, sowie in einem murinen in vivo Modell untersucht.In vitro wurden Knochenmarksmakrophagen (KMM) von Wildtyp- und Fra-1∆Mx Mausen sowie aus humanen peripheren mononuklearen Blutzellen differenzierte Makrophagen verwendet. Die Zellen wurden fur 24 Stunden mit LPS stimuliert, um Endotoxintoleranz zu induzieren (Endotoxin-tolerante Gruppe). Eine weitere Gruppe von Makrophagen wurde jeweils nicht vorbehandelt (Endotoxin-naive Gruppe).Die Endotoxin-naiven und -toleranten Gruppen von murinen Wildtyp KMM wurden daraufhin jeweils fur unterschiedlich Zeitraume mit LPS stimuliert und bezuglich ihrer Genexpression in Antwort auf LPS verglichen. Mit den humanen Makrophagen wurde genauso verfahren. Unstimulierte Zellen dienten jeweils als Kontrolle. Im Folgenden wurden die Effekte der Fra-1 Deletion auf die murine Endotoxin-naive und -tolerante Gruppe untersucht.In allen Modellen wurde die Genexpression der einzelnen AP-1 Transkriptionsfaktoren sowie von pro- und anti-inflammatorischen Proteinen (z.B.: Interleukin 6 (IL-6) und Lipocalin 2 (Lcn2)) nach LPS-Exposition gemessen. Zudem wurden in den Mausmodellen die Konzentrationen von IL-6 und Lcn2 im Zellkulturuberstand bestimmt. Fur Lcn2 wurde eine Chromatin-Immunoprazipitation (CHIP) in murinen Makrophagen durchgefuhrt, um festzustellen, ob Fra-1 nach LPS-Stimulation an den Lcn2-Promoter bindet.In vivo wurde Endotoxintoleranz durch intraperitoneale LPS-Injektion in Wildtyp- und Fra-1∆Mx Mause induziert. Nach drei Tagen erfolgte eine zweite LPS-Stimulation fur zwei Stunden. Eine Gruppe von Endotoxin-naiven Wildtypmausen wurde ebenfalls fur zwei Stunden mit LPS stimuliert. Unstimulierte Mause dienten als Kontrolle.Daraufhin wurde die Expression der in vitro untersuchten Gene in ausgewahlten Organen (Lunge, Leber und Milz) und in peritonealen Zellen gemessen. Zusatzlich wurde die Genexpression in den CD11b-positiven Zellen der Lunge, Leber und Milz untersucht, um spezifischere Informationen uber die Reaktion der in diesen Organen vorhandenen Makrophagen zu erhalten. Auserdem erfolgte eine Bestimmung der Serumkonzentrationen von IL-6 und Lcn2. Die ausgewahlten Organe wurden auch histologisch untersucht; die peritonealen Zellen wurden mittels Durchflusszytometrie naher charakterisiert.Ergebnisse: Die humanen Makrophagen sowie die murinen Wildtyp-KMM zeigten generell eine gesteigerte AP-1 Expression nach einfacher LPS-Stimulation unbehandelter Zellen.
590 $a School code: 0575.
650 4 $a Infections. $3 1621997
650 4 $a Pathogens. $3 3540520
650 4 $a Sepsis. $3 3560733
650 4 $a Mortality. $3 533218
650 4 $a Cytokines. $3 687114
650 4 $a Inflammation. $3 662994
650 4 $a Genotype & phenotype. $3 3561790
650 4 $a Apoptosis. $3 600650
650 4 $a Feedback. $3 677181
650 4 $a Blood. $3 641576
650 4 $a Kinases. $3 3558077
650 4 $a Proteins. $3 558769
650 4 $a Patients. $3 1961957
650 4 $a Spleen. $3 3561759
650 4 $a Gene expression. $3 643979
650 4 $a Dendritic cells. $3 1001571
650 4 $a Liver. $3 3564653
650 4 $a Immune system. $3 689864
650 4 $a Biomarkers. $3 2205735
650 4 $a Bone marrow. $3 1621080
650 4 $a Antigens. $3 700737
650 4 $a Stem cells. $3 767761
650 4 $a Tuberculosis. $3 808530
650 4 $a Transcription factors. $3 669191
650 4 $a Bioinformatics. $3 553671
650 4 $a Genetics. $3 530508
650 4 $a Immunology. $3 611031
650 4 $a Cellular biology. $3 3172791
650 4 $a Morphology. $3 591167
650 4 $a Laboratories. $3 531588
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710 2 $a Friedrich-Alexander-Universitaet Erlangen-Nuernberg (Germany). $3 3564652
773 0 $t Dissertations Abstracts International $g 83-02B.
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