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Studies on Leukotriene B4 and Alarmins in Inflammatory Responses Department of Biochemistry and Biophysics Karolinska Institutet, Stockholm, Sweden STUDIES ON LEUKOTRIENE B4 AND ALARMINS IN INFLAMMATORY RESPONSES Min Wan 万 敏 Stockholm 2010 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. © Min Wan, 2010 ISBN 978-91-7409-767-2 Printed by 2010 Gårdsvägen 4, 169 70 Solna TO MY BELOVED FAMILY！ ���������! A theory is something nobody believes, except the person who made it. An experiment is something everybody believes, except the person who made it. -- Albert Einstein The most exciting phrase to hear in science, the one that heralds the most discoveries, is not "Eureka!", but "That's funny..." -- Isaac Asimov ABSTRACT Leukotriene B4 (LTB4) is a potent proinflammatory lipid mediator that is involved in host defense and inflammatory diseases, such as atherosclerosis. LL-37 and heparin binding protein (HBP) are cationic antimicrobial polypeptides, which belong to the alarmin family known to promote innate and adaptive immune reactions in response to tissue infection or injury. In the present thesis, the aims were to investigate the expression profile of enzymes and receptors for LT biosynthesis in atherosclerotic lesions and study the mechanisms of LTB4/LL-37 and LTB4/HBP interactions, the functions of these interactions and how anti-inflammatory lipids may interfere with the LTB4/LL-37 circuit. We found that mRNA levels of 5-lipoxygenase (5-LO), 5- lipoxygenase-activating protein (FLAP) and leukotriene A4 hydrolase (LTA4H), are significantly increased in human atherosclerotic plaques. Immunostaining confirmed abundant expression of these enzymes, colocalized in macrophages of intimal lesions. Furthermore, we have shown that in lesions of human tissues arachidonic acid may be converted into LTB4, which is blocked by a selective LTA4H inhibitor. In addition, expression of 5-LO and LTA4H, but not FLAP, is increased in patients with recent or ongoing symptoms of plaque instability. In search for the mechanisms by which LTB4 could exert a proinflammatory action within the vascular wall, we have found that LTB4 strongly promotes the release of LL- 37 and HBP from human polymorphonuclear neutrophils (PMNs) in a time- and dose- dependent manner. The induced release of LL-37 and HBP by LTB4 stimulation is mediated by the BLT1 receptor. Furthermore, protein phosphatase-1 (PP-1) inhibits the release by suppressing the BLT1-mediated exocytosis of PMN granules. LL-37 does not only exhibit potent antimicrobial activities, but the stimulation of 2+ PMNs with LL-37 also induces intracellular calcium ([Ca ]i) mobilization in a dose- dependent manner resulting in cPLA2 phosphorylation and translocation of 5-LO from the cytosol to the perinuclear membrane. Thus, LL-37 promotes the synthesis and release of LTB4 in intact or primed PMNs. This response is mediated by formyl peptide receptor like-1 (FPRL-1). Apparently, in human PMNs, positive feedback circuits exist between LTB4 and LL-37. Furthermore, this LTB4/LL-37 feedback loop is extended to functional responses, such as phagocytosis. We have also found that the two anti- inflammatory lipids, resolvin E1 (RvE1) and lipoxin A4 (LXA4) inhibit the release of LL-37 by LTB4 stimulation and the production of LTB4 by LL-37 induction, respectively. These compounds may serve as negative “brake signals” for the positive LTB4/LL-37 feedback circuit. Moreover, we have shown that postsecretory supernatants from LTB4-stimulated 2+ PMNs induce [Ca ]i mobilization in endothelial cells in vitro and enhance vascular permeability in vivo by employing a mouse model of pleurisy. Selective removal of HBP from the supernatants significantly reduces these activities, attributing a key role to HBP in LTB4-induced increase in vascular permeability. Taken together, we have provided indirect evidence that LTB4 plays a role in plaque instability and this mediator may act in synergy with LL-37 and HBP to promote vascular inflammation. These lipid-petide interactions may be regulated by endogenous anti-inflammatory lipids and offer novel opportunities for pharmacological intervention in inflammation. LIST OF PUBLICATIONS This thesis is based on the following articles, which are referred to in the text by their Roman numerals. I. Qiu H, Gabrielsen A, Agardh HE, Wan M, Wetterholm A, Wong CH, Hedin U, Swedenborg J, Hansson GK, Samuelsson B, Paulsson-Berne G, Haeggström JZ. Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. Proc Natl Acad Sci U S A. 2006,103(21), 8161-8166. II. Wan M, Sabirsh A, Wetterholm A, Agerberth B, Haeggström JZ. Leukotriene B4 triggers release of the cathelicidin LL-37 from human neutrophils: novel lipid-peptide interactions in innate immune responses. FASEB J. 2007, 21(11), 2897-2905. III. Wan M, Godson C, Agerberth B, Haeggström JZ. Leukotriene B4/LL-37 proinflammatory circuits are mediated by BLT1 and FPRL-1, and are counter-regulated by lipoxin A4 and resolvin E1. Manuscript IV. Di Gennaro A, Kenne E*, Wan M*, Soehnlein O, Lindbom L, Haeggström JZ. Leukotriene B4-induced changes in vascular permeability are mediated by neutrophil release of heparin-binding protein (HBP/CAP37/azurocidin). FASEB J. 2009, 23(6), 1750-1757. * contributed equally Related articles not included in the thesis 1. Qiu H, Johansson AS, Sjöström M, Wan M, Schröder O, Palmblad J, Haeggström JZ. Differential induction of BLT receptor expression on human endothelial cells by lipopolysaccharide, cytokines, and leukotriene B4. Proc Natl Acad Sci U S A. 2006, 103(18), 6913-6918. 2. Qiu H, Strååt K, Rahbar A, Wan M, Söderberg-Nauclér C, Haeggström JZ. Human CMV infection induces 5-lipoxygenase expression and leukotriene B4 production in vascular smooth muscle cells. J Exp Med. 2008, 205(1), 19-24. 3. Sveinbjörnsson B, Rasmuson A, Baryawno N, Wan M, Pettersen I, Ponthan F, Orrego A, Haeggström JZ, Johnsen JI, Kogner P. Expression of enzymes and receptors of the leukotriene pathway in human neuroblastoma promotes tumor survival and provides a target for therapy. FASEB J. 2009, 23(6), 1750-1757. 4. Johansson AS, Wan M, Qiu H, Sjöström M, Haeggström JZ, Palmblad J. Effects of ethanol and ethyl pyruvate on expression of leukotriene B4 (BLT) receptors on human endothelial cells. Manuscript 5. Hua X, Wan M, Su J, Cederholm A, Haeggström JZ, Frostegård J. Oxidized cardiolipin has pro-inflammatory effects which are inhibited by Annexin A5: implications for cardiovascular disease and chronic inflammation. Manuscript CONTENTS CHAPTER 1. INTRODUCTION……………………………………………....……..1 1.1 Polymorphonuclear neutrophils (PMNs)………….….………………….1 1.1.1 Granules of PMNs……………………………………………......2 1.1.2 Recruitment of PMNs to inflammatory sites……………………..4 1.1.3 Role of PMN in inflammation…………………………………....5 1.2 Lipid mediators derived from arachidonic acid…......................................6 1.2.1 Arachidonic acid …………………………….…………………...6 1.2.2 Eicosanoids…………………………….…………………............7 1.2.3 Leukotrienes…….………………………………………………..7 1.2.4 Lipoxins………….……………………………………………...18 1.3 Resolvin E1 (RvE1)…………………………………….……………...21 1.3.1 Biosynthesis of RvE1..………….…………………………........22 1.3.2 RvE1 receptors........................................................................…...23 1.3.3 Anti-inflammatory and pro-resolving properties………….…...23 1.3.4 Impact in disease models…........................................................24 1.4 Alarmins………………………………………………….………….....24 1.4.1 LL-37/hCAP18……………………………………………........25 1.4.2 Defensins…………………………………………………….....28 1.4.3 Heparin-binding protein………………………………...............29 CHAPTER 2. AIMS……………….…………………………....................................31 CHAPTER 3. METHODOLOGY……………………………….…..........................32 CHAPTER 4. RESULTS AND DISCUSSION…………………….…......................33 CHARPET 5. CONCLUSIONS………………………………………….………....43 CHAPTER 6. ACKNOWLEDGEMENTS..……………………………….…….......45 CHAPTER 7. REFERENCES…………………………………………….………....48 LIST OF ABBREVIATIONS 12-HHT 12(S)-hydroxy-heptadeca-5Z, 8E, 10E-trienoic acid 12-LO 12-lipoxygenase 15-LO 15-lipoxygenase 5-HPETE 5-hydroperoxy-eicosatetraenoic acid 5-LO 5-lipoxygenase AA Arachidonic acid AMPs Antimicrobial peptides ATL Aspirin-triggered lipoxins BLT1 Leukotriene B4 receptor 1 BLT2 Leukotriene B4 receptor 2 CMV Cytomegalovirus COPD Chronic obstructive pulmonary disease COX Cyclooxygenase cPLA2 Cytosolic phospholipase A2 CXCR2 Chemokine receptor 2 CysLT1 Cysteinyl leukotriene receptor 1 CysLT2 Cysteinyl leukotriene receptor 2 cys-LTs Cysteinyl leukotrienes DC Dendritic cell DHA Docosahexaenoic acid EC Endothelial cell EPA Eicosapentaenoic acid FLAP 5-lipoxygenase-activating protein fMLP Formyl-Met-Leu-Phe FPRL-1 Formyl peptide receptor like-1 GPCR G protein-coupled receptor HBP Heparin-binding protein hCAP18 Human cationic protein 18 HIV Human immunodeficiency virus HUVEC Human umbilical vein endothelial cell ICAM-1 Intercellular adhesion molecule-1 IL Interleukin LPS Lipopolysaccharide LT Leukotriene LTA4 Leukotriene A4 LTA4H Leukotriene A4 hydrolase LTB4 Leukotriene B4 LX Lipoxin LXA4 Lipoxin A4 MAPEG Membrane-associated proteins in eicosanoid and glutathione metabolism MAPK Mitogen activated protein kinases MMP Matrix metalloprotease PAF Platelet activating factor PG Prostaglandin PMN Polymorphonuclear neutrophil PPARα Peroxisome proliferator activated receptor α PSGL-1 P-selectin glycoprotein ligand-1 PUFA Polyunsaturated fatty acid ROS Reactive oxygen species SRS-A Slow reacting substance of anaphylaxis
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