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Prof. Dr. Med. Detlef Zillikens “The Role of Leukotriene

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Prof. Dr. Med. Detlef Zillikens “The Role of Leukotriene From the Clinic of Dermatology of the University of Lübeck Director: Prof. Dr. med. Detlef Zillikens “The Role of Leukotriene B4 and Its Receptor BLT1 in Pathogenesis of Autoantibody-Induced Skin Inflammation” Dissertation for Fulfillment of Requirements for the Doctoral Degree of the University of Lübeck from the Department of Natural Sciences Submitted by Tatiana Sezin, MSc. from Haifa, Israel Lübeck 2016 Dedicated to my family II First referee: Prof. Dr. med. C. Sadik Second referee: Prof. Dr. rer. nat R. Manz Chairman: Prof. Dr. rer. nat G. Sczakiel Date of oral examination: 12.05.2016 Approved for printing: 23.05.2015, Lübeck III ABSTRACT Recruitment of leukocytes into the skin is a hallmark of skin inflammation, but the molecular mechanisms mediating early leukocyte recruitment into the skin are still poorly understood. In this study we set out to elucidate the mechanisms of early leukocyte recruitment into the skin in autoantibody-induced skin inflammation using a mouse model of epidermolysis bullosa acquisita (EBA). EBA is a prototypical example of an autoimmune blistering skin disease caused by autoantibodies (AAbs) directed to collagen 7 (COL7). The localization of AAbs at the basement membrane zone of the skin leads to recruitment of neutrophils, release of reactive oxygen species (ROS) and matrix metalloproteinases, inducing dermal-epidermal separation in the skin. Our findings describe a novel role for the lipid mediator LTB4 and its high affinity receptor BLT1 in directing neutrophils recruitment into the skin in antibody-transfer EBA mouse model. Accordingly, deficiency in 5- lipoxygenase, a key enzyme in the biosynthesis of leukotrienes (LTs), or in BLT1, confers dramatic resistance to disease. Thus, while WT mice developed severe clinical and histopathological signs of EBA, 5-lipoxygenase- (Alox5-/-) and BLT1-deficient (Ltb4r1-/-) mice did not develop signs of EBA, neither clinically, nor histopathologically. Although anti-Col7 antibodies expectedly bound to basal membrane in these knockout mice, their skin remained devoid of neutrophils, suggesting a severe defect in neutrophil recruitment into the skin in these animals. -/- Moreover, intradermal injection of exogenous LTB4 into Alox5 mice restored disease, indicating that LTB4 is the only LT essential for development of skin inflammation in antibody-transfer EBA. In addition, generation of bone marrow chimera (BMC) mice confirmed that 5-LO and BLT1 expression on radiosensitive hematopoietic cells is required for AAb-induced skin inflammation. Consequently, neutrophil- and eosinophil- depletion studies further confirmed that neutrophil, but not eosinophils, significantly contribute to development of skin inflammation in EBA. Accordingly, adoptive transfer of either WT or Ltb4r1-/- neutrophils into the dermis of Ltb4r1-/- mice restored disease. These findings, combined with data from cryosection and ROS-release assay suggest that LTB4 is required to recruit neutrophils into the skin, but is dispensable for induction of dermal-epidermal separation and the release of ROS. Furthermore, negligible signs of EBA present in Ltb4r1-/- BMC mice, transplanted with equal populations of WT and Ltb4r1-/- donor bone marrow cells, further indicate that the numbers of BLT1+ neutrophils are IV absolutely critical for induction of skin inflammation in EBA mouse model. Lastly, the requirement for LTs in initiation of skin inflammation is stimulus specific. Thus, using Alox5-/- mice we did not find contribution of LTs to the course of Aldara- induced psoriasiform dermatitis that is elicited by a topical application of the TLR7/TLR8 agonist imiquimod. Altogether, our results hint at a role of LTB4/BLT1 as critical gatekeeper of neutrophil egress into the skin in organ-specific, autoantibody-induced inflammation and propose LTB4/BLT1 as promising pharmacological targets for the treatment of autoimmune blistering skin diseases. V Zusammenfassung Die Einwanderung von Leukozyten in die Haut ist ein Kennzeichen der Entzündung der Haut. Allerdings sind die molekularen Mechanismen, die die frühe Einwanderung der Leukozyten in die Haut vermitteln, bisher nur ungenügend verstanden. Das Ziel dieser Studie war es die Mechanismen der frühen Leukozyteneinwanderung in die Haut in Autoantikörper-induzierter Hautentzündung am Beispiel eines Mausmodels für Epidermolysis bullosa acquisita (EBA) aufzuklären. EBA ist ein prototypisches Beispiel für eine blasenbildende Autoimmundermatose, welche durch Autoantikörper (AAk) gegen Typ VII Kollagen (COL7) versursacht wird. Die Anlagerung der AAk an die Basalmembran der Haut führt zur Einwanderung von Neutrophilen, Freisetzung von reaktiven Sauerstoffspezies (ROS) und Matrixmetalloproteinasen und induziert dadurch dermale-epidermale Spaltbildung in der Haut. Unsere Ergebnisse beschreiben eine neue Rolle für die Lipidkomponente LTB4 und ihren Hochaffinitätsrezeptor BLT1 bei der Steuerung der Neutrophilenrekrutierung in die Haut im Antikörpertransfer- induzierten EBA-Mausmodel. Folglich führt das Fehlen der 5-Lipoxygenase (5-LO), einem Schlüsselenzym in der Biosynthese der Leukotriene (LT), oder von BLT1 zu einer eindeutigen Krankheitsresistenz. Während Wildtyp (WT)-Mäuse daher ausgeprägte klinische und histopathologische Anzeichen für EBA entwickelten, zeigten 5-Lipoxygenase (Alox5-/-)- und BLT1 (Ltb4r1-/-)-defiziente Mäuse keine Anzeichen von EBA, weder klinisch noch histopathologisch. Obwohl Anti-Col7- Antikörper wie erwartet an die Basalmembran in diesen Knock-out-Mäuse gebunden haben, blieb ihre Haut frei von Neutrophilen, was auf eine schwerwiegende Störung in der Neutrophilenrekrutierung in die Haut dieser Tiere hinweist. Zudem konnte -/- durch die intradermale Injektion von exogenem LTB4 in Alox5 -Mäuse die Krankheit ausgelöst werden. Dies ist ein Hinweis darauf, dass LTB4 das einzig essenzielle LT für die Entwicklung der Hautentzündung in Antikörpertransfer- induzierter EBA ist. Zusätzlich bestätigte die Entwicklung von Knochenmarkschimären (BMC)-Mäusen, dass die 5-LO- und BLT1-Expression auf radiosensitiven hämatopoetischen Zellen für die AAk-induzierte Hautentzündung benötigt wird. Daraufhin, bestätigten auch Neutrophilen- und Eosinophilen- Depletionsstudien, dass Neutrophile, aber nicht Eosinophile, signifikant zur VI Entwicklung der Hautentzündung in EBA beitragen. Daher führte der adoptive Transfer von entweder WT oder Ltb4r1-/--Neutrophilen in die Dermis von Ltb4r1-/-- Mäusen zu erneuter Erkrankung. Diese Erkenntnisse zusammen mit Daten aus dem Gefrierschnitt- und ROS-Freisetzungs-Assay weisen darauf hin, dass LTB4 notwendig ist um Neutrophile in die Haut zu rekrutieren, aber entbehrlich ist für die Induktion der dermalen-epidermalen Spaltbildung und die Freisetzung von ROS. Darüberhinaus, deuten kaum ausgeprägte Krankheitsanzeichen von EBA in Ltb4r1-/-- BMC-Mäusen, welche mit gleich großen Populationen von WT- und Ltb4r1-/-- Spenderknochenmarkzellen transplantiert wurden, dass die Anzahl der BLT1+- Neutrophilen unbedingt entscheidend für die Induktion der Hautentzündung im EBA-Mausmodel ist. Schließlich ist die Notwendigkeit für LT zu Beginn der Hautentzündung Stimulus-spezifisch. Daher konnte in der Aldara-induzierten psoriasiformen Dermatitis, welche durch die topische Applikation des TLR7/TLR8- Agonisten Imiquimod ausgelöst wird, keine Beteiligung von LT an der Krankheitsentstehung durch die Verwendung von Alox5-/--Mäuse nachgewiesen werden. Zusammengefasst, deuten unsere Ergebnisse daraufhin, dass LTB4/BLT1 eine Rolle als wichtiger Kontrollpunkt bei der Auswanderung der Neutrophilen in die Haut in der Organ-spezifischen, Autoantikörper-induzierten Entzündung spielt und LTB4/BLT1 als vielversprechendes pharmakologisches Ziel für die Behandlung von blasenbildenden Autoimmundermatosen ausweist. VII TABLE OF CONTENTS Page ABSTRACT IV ZUSSAMENFASSUNG VI CONTENTS VIII LIST OF FIGURES XII LIST OF TABLES XIII ABBREVIATIONS XIV 1. INTRODUCTION 1 1.1 Autoimmunity & Autoimmune Diseases 1 1.2 Skin structure and function 2 1.3 Autoimmune bullous skin diseases 6 1.4 Epidermolysis bullosa acquisita (EBA) 7 1.5 Experimental models of EBA 9 1.7 Eicosanoids 15 1.8 Leukotrienes 16 1.9 LTB4 / BLT1 19 1.10 The role of LTB4 and BLT1 in initiation of inflammation 21 1.11 Aims of the present study 24 2. MATERIALS & METHODS 25 2.1 Materials 25 2.2 Mice 25 2.3 Methods Part I: Antibody transfer EBA mouse model 25 2.3.1 Induction of antibody transfer EBA mouse model 25 2.3.1.1 Scoring disease severity in antibody transfer EBA 26 2.3.1.2 Generation of affinity purified rabbit anti-murine Col7c IgG 27 2.3.1.3 Expression of recombinant NC-1 peptide and immunization of rabbits 28 VIII 2.3.1.4 Affinity column chromatography for purification of total rabbit IgG 28 2.3.1.5 Expression of recombinant mCol7c-His tag protein 29 2.3.1.6 Generation of mCol7c affinity chromatography column 30 2.3.1.7 Purification of specific rabbit anti-mCol7c IgG 31 2.3.1.8 Sodium dodecyl sulfate polyacrylamide gel electrophoresis 31 2.3.2 Skin histopathology 32 2.3.2.1 Hematoxylin & eosin staining (H&E) 32 2.3.2.2 Immunofluorescence microscopy 33 2.3.2.3 Direct immunofluorescence (DIF) microscopy 33 2.3.2.4 Indirect immunofluorescence (IIF) microscopy 33 2.3.3 Immunohistochemistry 34 2.3.3.1 Ly6G staining 35 2.3.3.2 F4/80 & Siglec-F staining 35 2.3.4 Bone marrow chimera 35 2.3.4.1 Isolation of murine bone marrow 36 2.3.4.2 Generation of “crisscross” bone marrow chimera 37 2.3.4.3 Generation of mixed bone marrow chimera 38 2.3.4.4 Ly6G CD45.1/ CD45.2 immunohistochemistry 38 2.3.5 Flow
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