INFLAMMATION FUNDAMENTAL MECHANISMS

Fundamental Mechanisms

Visit the link below to download the full version of this book:

https://medipdf.com/product/inflammation-fundamental-mechanisms-fundamental-mech
anisms/

Click Download Now

 b2530   International Strategic Relations and China’s National Security: World at the Crossroads

This page intentionally left blank

b2530_FM.indd 6 01-Sep-16 11:03:06 AM

10028_9789813109438_tp.indd 2 28/2/18 12:02 PM
 Published by
World Scientific Publishing Co. Pte. Ltd.
5 Toh Tuck Link, Singapore 596224
USA office: 27 Warren Street, Suite 401-402, Hackensack, NJ 07601
UK office: 57 Shelton Street, Covent Garden, London WC2H 9HE

Library of Congress Cataloging-in-Publication Data

Names: Ley, Klaus, 1957– editor.
Title: Inflammation : fundamental mechanisms / edited by Klaus Ley.
Other titles: Inflammation (Ley)
Description: New Jersey : World Scientific, 2018. | Includes bibliographical
references and index.
Identifiers: LCCN 2017058719 | ISBN 9789813109438 (hardcover : alk. paper)
Subjects: | MESH: Inflammation--physiopathology
Classification: LCC RB131 | NLM QZ 150 | DDC 616/.0473--dc23
LC record available at https://lccn.loc.gov/2017058719

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library.

Copyright © 2018 by World Scientific Publishing Co. Pte. Ltd.

All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means,
electronic or mechanical, including photocopying, recording or any information storage and retrieval
system now known or to be invented, without written permission from the publisher.

For photocopying of material in this volume, please pay a copying fee through the Copyright Clearance
Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. In this case permission to photocopy
is not required from the publisher.

For any available supplementary material, please visit

http://www.worldscientific.com/worldscibooks/10.1142/10028#t=suppl

Typeset by Stallion Press

Email: [email protected]

Printed in Singapore

XiaoLing - 10028 - Inflammation.indd 1 19-12-17 1:53:46 PM

 9x6  b3151   Inflammation: Fundamental Mechanisms

Contents

Chapter 1 TNF Superfamily in Inflammation 1

 arisol Veny, Richard Virgen-Slane
M
and Carl F. Ware
1. Introduction 1
1.1. Discovery of TNF and lymphotoxin 1
1.2. Description of TNFSF proteins 2
1.2.1. TNFSF ligands  2
1.2.2. TNF receptors superfamily 5
1.2.3. Ligand-receptor binding models 5
1.2.4. The lymphotoxin and tumor necrosis
factor network 6
1.3. Signaling pathways 8
1.3.1. The TNF-TNFR pathway  8
1.3.2. LTbR signaling and the alternative NF-kB
pathway10
2. TNFSF and inflammation 11
2.1. Acute inflammation 11
2.2. Chronic inflammation and autoimmunity 15
2.3. TNFSF signatures in human pathologies 18

b3151_FM.indd 5 06-Mar-18 10:00:07 AM

 9x6
b3151   Inflammation: Fundamental Mechanisms

vi  Inflammation: Fundamental Mechanisms

2.3.1. Rheumatoid arthritis 18

2.3.2. Inflammatory bowel disease 19
2.4. Experimental models and the TNFSF as drug targets 21
3. Targeting TNFSF in the clinic 26
3.1. TNF inhibitors 26
3.2. Other TNFSF targets 29
4. Summary 31
Acknowledgements32
References32

Chapter 2 
Complement as a Mediator of Inflammation 51
B. Paul Morgan
1. Introduction to the complement system 51
1.1. What is complement? 51
1.2. Initiation of complement activation 52
1.3. Amplification in the activation pathways 52
1.4. The amplification loop of the alternative pathway 54
1.5. Amplification at the stage of C5 cleavage 54
1.6. Assembly of the membrane attack complex 55
1.7. Active products of complement activation 55
1.8. Complement regulation 57
1.9. Complement receptors 57
2. Complement roles in health 58
2.1. Protection against infection 58
2.2. Immune complex solubilisation 58
2.3. Priming adaptive immunity 59
2.4. Regulating lipid metabolism 59
3. Complement roles in disease 60
3.1. Complement and autoimmunity 60
3.2. Complement deficiencies 61
3.3. Complement mutations and polymorphisms 63

b3151_FM.indd 6 06-Mar-18 10:00:07 AM

 9x6  b3151   Inflammation: Fundamental Mechanisms

Contents  vii

4. Complement as a driver of inflammation 64

4.1. General principles 64
4.2. Complement anaphylatoxins 65
4.3. Membrane attack complex 68
4.4. Complement and inflammasome activation 70
5. Complement inhibitors as anti-inflammatory drugs 71
5.1. Pathway blockers as anti-inflammatory drugs 71
5.2. Blocking C3a and C5a to inhibit inflammation 72
6. Summary and future prospects 73
References74

Chapter 3 
Lipids and Inflammation 79
 alerie B. O’Donnell, Robert C. Murphy
V
and Garret A. FitzGerald
1.
Introduction 79
2.
Lipids and inflammation in obesity  80
3.
Circulating plasma lipids and inflammation 82
4.
Specific lipid classes in inflammation 84
4.1. Eicosanoids and related lipids  84
4.1.1. COX enzymes, products, and their receptors  84
4.1.2. Inhibition of COXs 87
4.1.3. COX metabolites in inflammation 87
4.1.4. LOX enzymes, products, and their receptors  89
4.1.5. LOX metabolites in inflammation  91
4.1.6. Transcellular generation of eicosanoids  92
4.1.7. Endocannabinoids and inflammation 94
4.1.8. Isoprostanes and inflammation  96
4.2. Phospholipids in inflammation  96
4.2.1. Aminophospholipid translocation
in inflammation  97
4.2.2. Oxidized phospholipids in inflammation 97

b3151_FM.indd 7 06-Mar-18 10:00:07 AM

 9x6
b3151   Inflammation: Fundamental Mechanisms

viii  Inflammation: Fundamental Mechanisms

4.2.3. Lysophospholipids (LP) and

phosphatidic acid (PA)  100
4.2.4. Phosphoinositides 101
4.3. Ceramides/sphingolipids 103
5. Lipid receptors in inflammation: PPAR and LXR 105
5.1. Peroxisome proliferator-activated receptors (PPAR) 105
5.2. Liver X receptor (LXR) 107
6. Lipidomics of inflammation: Analysis of bioactive lipids 107
7. Summary 109
References109

Chapter 4 Reactive Oxygen Species 125

Ulla G. Knaus
1. Introduction 125
2. Reactive oxygen species 126
2.1. Superoxide 127
2.2. Hydrogen peroxide 128
2.3. Hydroxyl radical 129
2.4. Hypochlorous acid 129
2.5. Oxidative protein modification  130
3. Oxidant–antioxidant balance 131
4. ROS sources 135
4.1. H2O2 as secondary enzymatic product 135
4.2. Prokaryotic H2O2 136
•–
4.3. O2 as secondary enzymatic product —
Mitochondrial electron transport chain 137
•–
4.4. O2 and H2O2 as primary enzymatic
product — NADPH oxidases 139
4.4.1. NOX/DUOX structural organization 140
4.4.2. NOX2 assembly and activation 143
4.4.3. Regulation of other NOX/DUOX family
members146
4.4.4. ROS deficiency due to NADPH oxidase
variants including CGD 147

b3151_FM.indd 8 06-Mar-18 10:00:07 AM

 9x6  b3151   Inflammation: Fundamental Mechanisms

Contents  ix

5. ROS in immunity and inflammation 148

5.1. Mitochondrial ROS in immunity and inflammation  148
5.2. NOX2-derived ROS in immunity and inflammation 150
6. Outlook 152
Acknowledgments153
Glossary of Acronyms and Abbreviations 153
References155

Chapter 5 Leukocyte Adhesion 171

Klaus Ley and Zhichao Fan
1. Leukocyte adhesion molecules 172
1.1. Integrins 172
1.1.1. Endothelial ligands for integrins 180
1.1.2. ECM ligands for integrins 181
1.2. Selectins 181
1.3. Leukocyte ligands for selectins 182
1.4. Immunoglobulin adhesion molecules 183
2. Biomechanics of leukocytes adhesion under flow 184
3. Adhesion cascade 186
3.1. Deviations from the adhesion cascade 187
4. Leukocyte subsets 188
5. Leukocyte adhesion in lymphatics 190
6. Leukocyte adhesion to thrombi 190
7. Defects in leukocyte adhesion 191
References192

Neutrophil Extracellular Traps

Chapter 6  205
Tobias A. Fuchs, Abdul Hakkim and
Constantin F. Urban
1. Introduction 205
1.1. Introduction of neutrophils 206
1.2. Discovery of NETs 207
2. Architecture and composition of NETs 208

b3151_FM.indd 9 06-Mar-18 10:00:07 AM

 9x6
b3151   Inflammation: Fundamental Mechanisms

x  Inflammation: Fundamental Mechanisms

3. Formation of NETs 211

3.1. Suicidal NETosis 211
3.2. Vital NETosis 216
4. Induction of NETosis 217
5. Regulation of NETosis 219
5.1. Reactive oxygen species 219
5.2. Neutrophil elastase 220
5.3. Peptidylarginine deminase 4 220
6. Clearance of NETs 221
7. General Functions of NETs 222
8. Functions of NETs in disease 223
9. Antimicrobial NETs 224
9.1. Viral infections 228
9.2. Bacterial infections 229
9.3. Fungal infections 234
9.4. Parasitic infections 239
10. Cytotoxic NETs 241
10.1. Cytotoxic activity of NETs 242
10.2. Infection 243
10.3. Sterile inflammation 244
11. Prothrombotic NETs 246
11.1. Endothelium 247
11.2. Platelets 248
11.3. Red blood cells 248
11.4. Coagulation 249
11.5. Thrombolysis 249
11.6. Animal models of thrombosis 250
11.7. Patients with thrombosis 251
12. Immunogenic NETs 251
12.1. NETs in systemic lupus erythematosus and vasculitis 253
12.2. NETs in rheumatoid arthritis 256
12.3. NETs in other autoimmune diseases 256

b3151_FM.indd 10 06-Mar-18 10:00:08 AM

 9x6  b3151   Inflammation: Fundamental Mechanisms

Contents  xi

13. Anti-inflammatory NETs 257

14. Conclusions 258
Acknowledgments  259
References259

Chapter 7 Sepsis277
J amison J. Grailer, Matthew J. Delano
and Peter A. Ward
1. Introduction 277
1.1. Epidemiology of sepsis 277
1.2. History of experimental and clinical sepsis studies 278
2. Brief overview of pathophysiology 278
2.1. Hyperinflammation 278
2.2. Immunosuppression 279
2.3. Long-term defects associated with sepsis 280
3. Cellular and molecular consequences of sepsis 280
3.1. Redox imbalance 280
3.2. Defective Ca2+ homeostasis 281
3.3. PARP1, PARP2 activation 281
3.4. Mitochondrial dysfunction 282
3.5. Apoptosis of lymphoid cells and immunosuppression 282
3.6. Extracellular histones 283
4. Role of complement in sepsis 283
4.1. Complement activation in sepsis 283
4.2. Role of C5a and its receptors in experimental sepsis 284
4.3. Role of complement and extracellular histones
in sepsis 285
5. Current concepts, problems, and controversies
in animal sepsis models 286
5.1. Heterogeneity of animal models of sepsis 287
5.2. Endotoxemia studies 289
5.3. Use of rodents versus larger animals 289

b3151_FM.indd 11 06-Mar-18 10:00:08 AM

 9x6
b3151   Inflammation: Fundamental Mechanisms

xii  Inflammation: Fundamental Mechanisms

6. Current concepts, problems and controversies in

human sepsis studies 290
6.1. Concerns about current clinical classifications
of human sepsis 290
6.2. Failure in clinical trials, including recent clinical
trials using antagonists of toll-like receptors 290
6.3. Concerns about clinical trial endpoints 292
6.4. The influence of age and co-morbidities
in human sepsis 292
6.5. Genomic analysis of septic humans 293
6.6. Human sepsis biomarkers 293
7. The current outlook on treatment of sepsis 294
References 295

Granulomatous Inflammation
Chapter 8  303
 Marc Hilhorst, Gene Hunder, Jörg Goronzy
and Cornelia Weyand
1. Introduction 303
1.1. Architecture of the granuloma 305
1.2. Basic principles of the granulomatous inflammation 306
2. Granulomatous inflammation of infectious origin 309
2.1. Bacterial triggers 309
2.1.1. Tuberculosis 309
2.1.2. Leprosy 312
2.2. Other bacterial triggers 313
2.3. Fungal triggers 313
2.3.1. Histoplasmosis 313
2.3.2. Other fungal pathogens 314
2.4. Viral triggers 314
2.4.1. Hepatitis viruses 314
2.4.2. Other viruses that can cause
granulomatous inflammation 315

b3151_FM.indd 12 06-Mar-18 10:00:08 AM

 9x6  b3151   Inflammation: Fundamental Mechanisms

Contents  xiii

2.5. Other infectious triggers 315

2.5.1. Schistosomiasis 315
2.5.2. Leishmaniasis 318
3. Immune-related, idiopathic granulomatous inflammation 319
3.1. Vasculitis 319
3.1.1. Small-vessel vasculitis 319
3.1.2. Large-vessel vasculitis 322
3.1.2.1. Giant cell arteritis 322
3.1.2.2. Takayasu’s arteritis 325
3.2. Sarcoidosis 326
3.3. Crohn’s disease 327
3.4. Primary biliary cirrhosis 329
3.5. Common variable immune deficiency 330
4. Granulomatous inflammation associated with
environmental and iatrogenic triggers 331
4.1. Berylliosis 331
4.2. Silicosis 332
4.3. Foreign bodies and topical medication 333
4.4. Other triggers 334
4.4.1. Chronic granulomatous disease 334
4.4.2. Granuloma annulare 335
5. Conclusions 336
References336

Index357

b3151_FM.indd 13 06-Mar-18 10:00:08 AM

 9x6  b3151   Inflammation: Fundamental Mechanisms

Chapter 1

TNF Superfamily
in Inflammation
Marisol Veny*, Richard Virgen-Slane*
and Carl F. Ware*

1. Introduction
1.1. Discovery of TNF and lymphotoxin
Studies of the tumor necrosis factor superfamily (TNFSF) can be
traced back to the 1800s, when it was found that acute inflammation
induced by bacterial extracts could trigger necrosis of tumors. Nearly
two centuries later, activated lymphocytes in culture were shown to
produce a cytotoxic factor for tumor cells,1 named Lymphotoxin
(LT)2 and macrophages secreted a cytotoxin that caused hemorrhagic
necrosis of tumors, named Tumor Necrosis Factor (TNF).1–3
Although these host-derived anti-tumor factors were greeted with
great enthusiasm, knowledge of their true physiologic functions
awaited advances in protein chemistry and molecular biology.

* Infectious and Inflammatory Diseases Center, Sanford Burnham Prebys Medical

Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.

b3151_Ch-01.indd 1 06-Mar-18 7:38:34 AM

 9x6
b3151   Inflammation: Fundamental Mechanisms

2  M. Veny, R. Virgen-Slane & C. F. Ware

The cloning of the genes for LT4–6 and TNF7–10 revealed signifi-
cant shared sequence homology.4,11,9 Additionally, the recombinant
proteins displayed similar biological activities4,9 and bound the same
two cell surface receptors, now referred to as TNFR1 and TNFR2.12–17
Thus, LT and TNF were recognized as the founding members of a
superfamily of homologous ligands, and their specific cell surface
receptors forming the TNF receptor superfamily. The similarities in
TNF and LT and their receptors suggested redundancy of function.18
This outlook changed with the discovery of two important differ-
ences in the properties of TNF and LT. The first key difference,
which prompted the renaming of LT (also called TNFb) to LTa, was
its interaction to form a novel ligand with lymphotoxin-b (LTb)
forming a heterotrimeric complex LTa1b2.1,9 Later, a receptor spe-
cific for LTa1b2, but not TNF, was discovered and named the LTb
receptor (LTbR).20 The second major finding was that mice deficient
in either one of the genes LTa, LTb, or LTbR fail to develop lymph
nodes and other secondary lymphoid organs.21–23
Several more receptors (Table 1) and ligands (Table 2) were dis-
covered as members of these superfamilies, revealing the scope of
these ligand–receptors in animal physiology. Among the receptors
critical for immune responses include CD27,24 CD40,25 CD30,26
OX40,27 4-1BB,28 and Fas.29 Members of the TNFRSF also play
important roles in the physiology of skin, bone, and nervous system,
and orthologous genes were found in the genomes of large DNA
viruses including poxvirus30 and herpesviruses.

1.2 Description of TNFSF proteins

1.2.1. TNFSF ligands
With the exception of TL1A31 and FasL,32 the expression of TNFSF
ligands is restricted to cells of the immune system, including den-
dritic cells (DC), activated lymphocytes, and myeloid cells.
TNF-related cytokines are type II transmembrane proteins with
short cytoplasmic tails (15–25 amino acids) and larger extracellular
regions (~150 amino acids). They contain a signature b-sheet sand-
wich, known as the TNF homology domain, which facilitates

b3151_Ch-01.indd 2 06-Mar-18 7:38:34 AM

 9x6  b3151   Inflammation: Fundamental Mechanisms

TNF Superfamily in Inflammation   3

Table 1.  TNFSF receptors.

TNF Receptor Superfamily

Chromosomal location

Gene Name/Alias Human Mouse Gene Symbol

TNFR1, p55-60 12p13.2 ch6 (60.55 cM) TNFRSF1A
TNFR2, p75-80 1p36 3-36.2 ch4 (75.5 cM) TNFRSF1B
LTβR 12p13 ch6 (60.4 cM) LTβR
OX40 1p36 ch4(79.4 cM) TNFRSF4
CD40 20q12-q13.2 ch2 (97.0 cM) CD40
FAS, CD95 10q24.1 ch19(23.0 cM) TNFRSF6
DcR3 20q13 unknown TNFRSF6B
CD27 12p13 ch6 (60.35) TNFRSF7
CD30 1p36 ch4 (75.5 cM) TNFRSF8
4-1BB 1p36 ch4 (75.5 cM) TNFRSF9
TRAILR-1, DR4 8p21 unknown TNRSF10A
TRAIL-R2, DR5 8p22-p21 ch14(D1) TNFRSF10B
TRALLR3, DcRl 8p22-p21 ch7 (69.6 cM) TNFRSF10C
TRAILR4, DcR2 8p21 ch7 (69.6 cM) TNFRSF10D
RANK, TRANCE-R 18q22.1 ch1 TNFRSF11A
OPG, TR1 8q24 ch15 TNFRSF11B
FN14 16p13.3 ch17 TNFRSF12A
TRAMP, DR3, LARD 1p36.3 ch4 (E1) TNFRSF25
TACI 17p11.2 ch11 TNFRSF13B
BAFFR 22q13.1-q13.31 ch15 TNFRSF13C
HVEM, HveA, ATAR 136.3-p36.3 ch4 TNFRSF14
P75NTR, NGFR 17q12-q22 ch11 (55.6 cM) TNFRSF16
BCMA 16pl3.1 ch16(B3) TNFRSF17
AITR, GITR 1p36.3 ch4(E) TNFRSF18
RELT 11q13.2 unknown TNFRSF19L
TROY, TAJ 13q12.11-q12.3 ch14 TNFRSF19
EDAR 2q11-q13 ch10 EDAR1
EDA2R Xq11.1 chX EDA2R
DR6 6p12.2-21.1 ch17 TNFRSF21
IGFLR1,Tmem149 19q13.12 ch7 IGFLR1

b3151_Ch-01.indd 3 06-Mar-18 7:38:34 AM

 9x6
b3151   Inflammation: Fundamental Mechanisms

4  M. Veny, R. Virgen-Slane & C. F. Ware

Table 2.  TNFSF ligands.

TNF Superfamily

Chromosomal location

Gene Name/Alias Human Mouse Gene Symbol

TNF 6p21.3 ch17 (19.06 cM) TNFSF1A
LTα 6p21.3 ch17 (19.06 cM) TNFSF1B
LTβ 6p21.3 ch17 (19.06 cM) TNFSF3
OX40-L 1q25 ch1 (84.90 cM) TNFSF4
CD40-L,CD154 Xq26 chX (18.0 cM) TNFSF5
Fas-L 1q23 ch1 (85.0 cM) TNFSF6
CD27-L, CD70 19p13 ch17(20.0 cM) TNFSF7
CD30-L,CD153 9q33 ch4 (32.20 cM) TNFSF8
4-1BB-L 19p13 ch17(20.0 cM) TNFSF9
TRAIL 3q26 ch3 TNFSF10
RANK-L, TRANCE 13q14 ch14 (45.0 cM) TNFSF11
TWEAK 17p13 ch11 TNFSF12
APRIL/TALL2 17p13.1 ch13 TNFSF13
BAFF, BLYS, TALL1 13q32-q34 ch8 (3 cM) TNFSF13B
LIGHT 19p13.3 ch17(D-E1) TNFSF14
TL1A 9q33 ch4 (31.80 cM) TNFSF15
GITRL, AITRL 1q23 unknown TNFSF18
EDA1 Xq12-q13.1 chX (37.0 cM) EDA1
EDA2 Xq12-q13.1 cX(37.0 cM) EDA2

trimer formation and receptor binding. The ligands have highly

conserved tertiary structures,33–37 despite only limited sequence
homology (<35%). Linker regions between the b stands are varia-
ble and form specific contacts with the receptors. Many TNFSF
ligands can form homotrimers, and some also assemble as hetero-
trimers; examples of the latter group are LTa with LTb19 and
APRIL with BAFF.38 Alternatively spliced variants of TNFSF
ligands produce molecules with additional functionalities. These
include the fusion of TWEAK and APRIL to form TWE-PRIL39 and
the cytosolic form of LIGHT.40

b3151_Ch-01.indd 4 06-Mar-18 7:38:34 AM