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T Edited by Jean-Marc Cavaillon

Cavaillon • Singer (Eds.)

he leading reference on this topic of increasing medical relevance is unique in offering
unparalleled coverage.
The editors are among the most respected researchers in inflammation worldwide and here
and Mervyn Singer
have put together a prestigious team of contributors. Starting with the molecular basis of
inflammation, from cytokines via the innate immune system to the different kinds of inflam-

Inflammation
matory cells, they continue with the function of inflammation in infectious disease before
devoting a large section to the relationship between inflammation and chronic diseases. The
book concludes with wound and tissue healing and options for therapeutic interventions.
A must have for clinicians and biomedical researchers alike.

From Molecular and Cellular Mechanisms

Jean-Marc Cavaillon is professor and was Head of the Unit “Cytokines
and Inflammation” at Institut Pasteur (Paris). He has been President to the Clinic
(1998-2000) of the “International Endotoxin and Innate Immunity
Society”, and President of the “European Shock Society” (2016-2017). He is
member of the Editorial Boards of few journals including Shock, Journal
of Infectious Diseases, and International Journal of Inflammation, and
Volume 1,2,3 and 4
has been Associate-Editor of “Cytokine” (2002-2009). He has an extensive
expertise in inflammation, innate immunity, particularly on cytokines,
bacterial endotoxins and other Toll-like receptors agonists, endotoxin
1
tolerance, activation of monocytes/macrophages and neutrophils.
He made major studies deciphering the altered immune status in sepsis
and SIRS patients, and contributed to define the reprogramming of

Inflammation
circulating leukocytes of these patients. He is the author of a book in
French on Cytokines (Masson, 1993 & 1996), and the co-author of a
book “Sepsis and non-infectious inflammation: from biology to critical
care” (Wiley VCH, 2009).

Mervyn Singer is Professor of Intensive Care Medicine at University

College London. His primary research interests are sepsis and multi-
organ failure, infection, shock and haemodynamic monitoring. Funding
for these activities primarily comes from the Wellcome Trust, Medical
Research Council and National Institute for Health Research.
He developed an oesophageal Doppler haemodynamic monitor that is
now in widespread use worldwide, the use of which has been shown in
multiple studies to improve outcomes after major surgery and reduce
length of stay. He has led on a number of important multi-centre trials
in critical care. He has authored various papers and textbooks in-
cluding the Oxford Handbook of Critical Care, now in its 3rd Edition,
and is a Council member of the International Sepsis Forum. He was
the first UK intensivist to be awarded Senior Investigator status by the
National Institute for Health Research, and to be invited to give plenary
lectures at the European and US Intensive Care Congresses.

Volume 1 of 4

ISBN 978-3-527-33899-3

www.wiley-vch.de
vi Table of Contents

2.3.4 Peptidoglycan 28
2.3.5 Fimbriae 30
2.3.6 Glycogolipids 30
2.3.7 Heat Shock Proteins 30
2.3.8 Bacterial DNA 31
2.3.9 Bacterial RNA 32
2.4 Viral PAMPs 33
2.5 Parasitic PAMPs 35
2.6 Fungal PAMPs 36
2.7 Synergy 37
References 38

3 Damage-associated Molecular Patterns 57

Jean-Marc Cavaillon
3.1 Definition 57
3.2 Necrosis versus Apoptosis 58
3.3 Receptors of Danger Signals 58
3.4 Main DAMPs 60
3.4.1 High-mobility Group Box 1 60
3.4.2 Heat Shock Protein 61
3.4.3 RNA and DNA 62
3.4.4 Mitochondria 62
3.4.5 Histones 62
3.4.6 Uric Acid Crystals 63
3.4.7 ATP 63
3.4.8 S100A8/S100A9 64
3.4.9 Interleukin-1α and Interleukin-33 64
3.4.10 Heme 65
3.4.11 Hyaluronan 65
3.4.12 Biglycan 66
3.4.13 Heparan Sulfate 66
3.4.14 Eosinophil-derived Neurotoxin 66
3.4.15 Peroxiredoxins 67
References 67

4 Bacterial Toxins 81
Marina de Bernard and Cesare Montecucco
4.1 Introduction 81
4.2 Toxins Modulating the Activity of Inflammatory Caspases and
Inflammasomes 82
4.3 Toxins Modulating the Intracellular cAMP Levels 84
4.4 Toxins Modulating MAPK Signaling 85
4.4.1 Synergy between ET and LT 86
4.5 Toxins Affecting Host Cell Motility 87
4.6 Toxins Blocking Protein Synthesis or Protein Folding 88
4.7 Conclusions 89
References 90
 Table of Contents vii

5 Venoms 99
Catarina Teixeira, Vanessa Moreira, and José María Gutiérrez
5.1 Introduction 99
5.2 Inflammation Induced by Snake Venoms 100
5.3 Inflammation Induced by Scorpion Venoms 105
5.4 Inflammation Induced by Spider Venoms 107
5.5 Inflammation Induced by Venoms of Bees, Vespids, and Ants 110
5.6 Conclusions 112
References 113

6 Hypoxia as an Inducer of Inflammation 129

Ariel Brandwein and Clifford S. Deutschman
6.1 Introduction 129
6.2 Oxygen Sensing 130
6.3 Mitochondrial Oxygen Sensing 131
6.4 The Role of Transcription Factors 132
6.4.1 Hypoxia-Inducible Factor 133
6.4.2 Nuclear Factor κB 135
6.5 The Warburg Effect 135
6.6 Acute versus Chronic Hypoxia 136
6.7 Inflammasome Activation 137
6.8 Summary and Conclusions 139
References 139

7 Vaccine Adjuvants 143

Dennis M. Klinman and Hidekazu Shirota
7.1 Introduction 143
7.2 Adjuvants Approved for Human Use 144
7.3 Aluminum Compounds: The Gold Standard 144
7.4 AS04 145
7.5 Calcium Phosphate 145
7.6 Emulsions 146
7.6.1 IFA and CFA 146
7.6.2 MF59 146
7.6.3 AS03 147
7.7 Nano/microparticles Including Liposomes and Virosomes 148
7.8 Immune Stimulating Complexes 148
7.9 Cytokines 149
7.9.1 IL-12 149
7.9.2 IL-2 149
7.9.3 IL-15 150
7.9.4 GM-CSF 150
7.10 Adjuvants that Target Toll-like Receptors 150
7.10.1 Introduction 150
7.10.2 TLR2 151
7.10.2.1 Overview 151
7.10.2.2 TLR2 ligands 151
viii Table of Contents

7.10.2.3 Clinical Activity 151

7.10.2.4 Safety 152
7.10.3 TLR3 152
7.10.3.1 Overview 152
7.10.3.2 TLR3 Ligands and Their Immunogenicity 152
7.10.3.3 Safety 153
7.10.4 TLR4 153
7.10.4.1 Overview 153
7.10.4.2 TLR4 Ligands 153
7.10.4.3 Clinical Activity 153
7.10.4.4 Safety 154
7.10.5 TLR5 154
7.10.5.1 Overview 154
7.10.6 TLR7/8 154
7.10.6.1 Overview 154
7.10.6.2 TLR7/8 Ligands and Their Preclinical Activity 155
7.10.6.3 Clinical Activity 155
7.10.6.4 Safety 155
7.10.7 TLR9 156
7.10.7.1 Overview 156
7.10.7.2 TLR9 Ligands 156
7.10.7.3 Clinical Activity 156
7.10.7.4 Safety 157
7.11 Adjuvant Combinations 157
7.12 Future Directions 157
References 158

8 Pattern Recognition Receptors 175

Lauren Whitehead and Gordon D. Brown
8.1 Introduction 175
8.2 Toll-like Receptors 176
8.2.1 Cell Surface-bound TLRs 177
8.2.2 Endosomal TLRs 178
8.2.3 TLR Signaling 179
8.2.4 MyD88-dependent Signaling Pathway 179
8.2.5 TRIF Signaling Pathway 179
8.3 C-type Lectin Receptors 181
8.3.1 DC-SIGN 181
8.3.2 Mannose Receptor 182
8.3.3 Surfactant Protein D 182
8.4 Natural Killer Gene Complex-associated CLRs 183
8.4.1 Activation Receptors 183
8.4.2 Inhibitory Receptors 185
8.4.3 CLR Signaling 186
8.5 RIG-1-like Receptors 187
8.5.1 RLR Signaling 188
8.6 NOD-like Receptors 189
 Table of Contents ix

8.6.1 NOD1 and NOD2 191

8.6.2 NOD1 and NOD2 Signaling 192
8.6.3 NLRC4 192
8.6.4 NLRPs 192
8.7 DNA-sensing Molecules 193
8.7.1 Signaling Components of DNA-sensing Molecules 194
8.7.2 Cross-talk between PRRs 195
8.8 Conclusions 195
Acknowledgments 196
References 196

Part Two Inflammatory Cells 217

9 Monocytes and Macrophages 219

Irina N. Shalova, Shilpi Saha, and Subhra K. Biswas
9.1 Introduction 219
9.2 Origin and Differentiation 219
9.3 Activation and Polarization 221
9.4 Functions 222
9.4.1 Cytokine Production and Inflammation 223
9.4.2 Phagocytosis 224
9.4.3 Antigen Presentation 226
9.4.4 Migration 227
9.4.5 Immunoregulation 228
9.4.6 Vascular Functions 229
9.5 Molecular Pathways and Mechanisms Regulating Response 230
9.5.1 Signaling Pathways 230
9.5.2 Epigenetic Regulation 232
9.5.3 Micro-RNAs 234
9.6 Conclusions 235
Acknowledgment 235
References 236

10 Neutrophils 253
Salvatore Cuzzocrea
10.1 Characteristics 253
10.2 Hematopoiesis 254
10.3 Adhesion and Migration 255
10.3.1 Traffic and Margination 255
10.3.2 Adhesion to the Endothelial Wall 256
10.3.3 Transendothelial Migration 257
10.4 Phagocytosis and Degranulation 258
10.4.1 Phagocytosis 258
10.4.2 Degranulation 259
10.5 Cytokine Synthesis 260
10.5.1 TNF-α 260
x Table of Contents

IL-1 and IL-1 Receptor Antagonist 260

10.5.2
IL-8 as a Model of Chemokines 261
10.5.3
10.5.4
Modulation of Cytokine Expression and Production by
Neutrophils 261
10.6 Neutrophil Apoptosis 261
10.7 Neutrophils in Pathology 262
10.7.1 Bacterial Infection 263
10.7.2 Tissue Injury-induced Inflammation: Ischemia-reperfusion
Injury 263
10.7.3 Crystal-induced Inflammation 263
10.7.4 Cytokine-induced Inflammation: Rheumatoid Arthritis 263
10.7.5 Autoimmunity Against Neutrophil Components:
Antineutrophil Cytoplasmic Antibodies and Vasculitis 264
10.7.6 Genetic Disorders of Neutrophil Regulations: Hereditary
Periodic Fever Syndromes 264
10.7.7 Cystic Fibrosis: Neutrophil-mediated Tissue Damage and
Concomitant Persistence of Infection 265
10.8 Conclusions 265
References 266

11 Mast Cells: Master Drivers of Immune Responses against

Pathogens 273
W.X. Gladys Ang and Soman N. Abraham
11.1 Introduction 273
11.2 Biology of Mast Cells 273
11.3 Role of Mast Cells in Immune Surveillance 275
11.3.1 Strategic Peripheral Location 275
11.3.2 Direct Recognition of Pathogens 275
11.3.3 Indirect Recognition of Pathogens 276
11.3.4 Activation by Endogenous Danger Signals 276
11.3.5 Degranulation and Secretory Responses to Pathogens 277
11.4 Mast Cells in Innate Immunity 278
11.4.1 Direct Bactericidal Activity of Mast Cells 278
11.4.2 Resistance to Exo- and Endotoxins 278
11.4.3 Induction of Immune Cell Trafficking to Sites of
Infection 279
11.5 Mast Cells in Adaptive Immunity 279
11.5.1 Mast Cells as Effectors of Adaptive Immunity 279
11.5.2 Recruitment of DCs and Effector T Cells to Sites of
Infection 280
11.5.3 Recruitment of Dendritic Cells and T Cells to Draining Lymph
Nodes 280
11.5.4 Antigen Presentation 280
11.6 Enhancement of Immunity by Boosting Mast Cell Activity 281
11.6.1 Mast Cell Activators as Novel Vaccine Adjuvants 281
11.6.2 Synthetic Mast Cell Granules 281
 Table of Contents xi

11.7 Potentially Detrimental Roles of Mast Cell Activation during Immune

Responses 282
11.7.1 Overactivation of Mast Cells 282
11.7.2 Negative Modulation of Immunity by Mast Cells 283
11.8 Concluding Remarks 283
Acknowledgments 284
References 284

12 Dendritic Cells in Inflammatory Disease 289

Bart N. Lambrecht, Martin Guilliams, and Hamida Hammad
12.1 What Defines a Dendritic Cell? 289
12.2 Dendritic Cell Subsets 290
12.3 Dendritic Cells and T-cell Polarization 291
12.4 Dendritic Cells in Allergic Inflammation 292
12.4.1 Dendritic Cells are Necessary and Sufficient for Induction of
Th2 Immunity 292
12.4.2 Different Subtypes of DCs Induce Th2 Immunity 293
12.4.3 Dendritic Cells are Also Required for Effector Th2 Immune
Responses to Allergens 294
12.4.4 DCs Get Activated Directly after Exposure to Allergen 295
12.4.5 Lung DCs Activated Indirectly by Epithelial Cells 296
12.5 Inflammatory DCs’ Role in Human Allergy 298
12.6 Dendritic Cells in Autoimmune Inflammatory Disease 298
12.7 Conclusions 299
References 300

13 Roles for NK Cells and ILC1 in Inflammation and Infection 315

Christian A.J. Vosshenrich and James P. Di Santo
13.1 Introduction 315
13.2 Distinguishing Group 1 ILC and NK Cells 316
13.3 NK Cell and ILC1 Activating and Inhibitory Receptors 317
13.3.1 Natural Cytotoxicity Receptors 317
13.3.2 NKG2D 318
13.3.3 DNAX Accessory Molecule-1 (DNAM-1, CD226) 318
13.3.4 MHC Class I-specific Receptors and NK Cell
“Education” 318
13.3.5 Are ILC1s “Educated” Similar to Convention NK Cells? 319
13.4 Evidence for Distinct Subsets of NK Cells and ILC1 319
13.5 Effector Functions of NK Cells and ILC1 320
13.6 NK Cells and Group 1 ILCs in Inflammation and Infection 322
13.6.1 Mouse Cytomegalovirus 322
13.6.2 Influenza Virus 323
13.6.3 NK Cells and Other Viral Infections 324
13.6.4 Salmonella 324
13.6.5 Listeria monocytogenes 325
13.6.6 Mycobacteria and Other Bacteria 325
13.7 NK Cell and ILC1 Memory 326
xii Table of Contents

13.8 Concluding Remarks: NK and ILC1 as Partners in a Type 1

Network 327
References 329

14 Group 2 and 3 Innate Lymphoid Cells: New Actors in Immunity

and Inflammation 341
Nicolas Serafini and James P. Di Santo
14.1 ILCs: A New Family of Innate Effector Cells 341
14.2 ILC2 and ILC3 Heterogeneity and Homeostasis 342
14.3 ILC2 in Acute and Chronic Inflammation 345
14.4 ILC3 in Acute and Chronic Inflammation 348
14.5 Therapeutically Harnessing ILC2 and ILC3 351
14.6 Concluding Remarks 352
References 353

15 Th9 Cells: From the Bench to the Bedside and Back Again 365
Benjamin J. Ulrich, Matthew M. Hufford, and Mark H. Kaplan
15.1 The History of T Helper Cells 365
15.2 Introduction to Th9 Cells 367
15.2.1 Development 367
15.2.2 Additional Th9-inducing Cytokines 368
15.2.3 Th9-inducing Cell Surface Ligands 369
15.2.4 The Function of Th9 Cells 369
15.3 Th9 Cells in Disease: The Helpful and Unhelpful 371
15.3.1 Tumor Immunity 372
15.3.2 Helminth Immunity 372
15.3.3 Inflammatory Bowel Disease 373
15.3.4 Allergic Inflammation 374
15.3.5 Dermatitis 376
15.3.6 Food Allergy 377
15.4 Targeting Th9 Cells Therapeutically 377
15.4.1 Th9 Differentiation 377
15.4.1.1 Cytokines and Costimulators Required for
Differentiation 377
15.4.1.2 Transcription Factors for Differentiation 379
15.4.1.3 Factors Required for Promotion of Th9 Biology 380
15.4.2 Th9-associated Effector Molecules 381
15.5 Summary and Future Directions 382
References 382

16 Th17 Cells 395

Mélissa Noack and Pierre Miossec
16.1 Introduction 395
16.2 Differentiation of Th17 Cells 396
16.2.1 Th17 Cell Differentiation in Mice 396
16.2.2 Th17 Cell Differentiation in Humans 397
16.2.3 Pathogenic Th17 Cells 398
 Table of Contents xiii

16.2.4 Circulating versus Tissue Phenotypes 398

16.3 Cytokines and Chemokines Related to Th17 Cells 399
16.3.1 Major Cytokines and Chemokines Produced by Th17
Cells 399
16.3.1.1 IL-17A (IL-17)/IL-17F 399
16.3.1.2 IL-21 400
16.3.1.3 IL-22 400
16.3.1.4 CCL20 400
16.3.2 Major Cytokines Acting on Th17 Cells 401
16.3.2.1 IL-23 401
16.3.2.2 IL-27 401
16.4 Th17 and Inflammatory Diseases 401
16.4.1 Psoriasis 402
16.4.2 Arthritic Diseases 402
16.4.3 Multiple Sclerosis 403
16.4.4 Inflammatory Bowel Diseases 403
16.5 Mechanisms in Chronic Inflammation 403
16.5.1 Differentiation, Recruitment, and Maintenance of Th17
Phenotype during Chronic Inflammation 403
16.5.2 Secretion of IL-17 and its Activity 404
16.6 Plasticity of Th17 Cells 405
16.7 Clinical Targeting of Th17 Cells 407
16.8 Conclusions 408
Acknowledgment 408
References 408

17 Platelets 419
Jack Levin
17.1 Introduction 419
17.2 Expression of Toll-like Receptors 422
17.3 Interactions between Platelets and Bacteria 422
17.4 Interactions between Platelets and White Blood Cells 423
17.5 Platelet Integrins 424
17.6 Role of Platelets in Immune Responses 425
17.7 Platelets and Inflammatory Disorders 425
17.8 Malaria 426
17.9 Systemic Lupus Erythematosus 426
17.10 Conclusions 426
References 427

18 Epithelial Cells 437

Jill M. Hoffman and Charalabos Pothoulakis
18.1 Introduction 437
18.2 The Intestinal Epithelium: An Archetypal Epithelial Barrier 438
18.3 Choosing a Cell Fate: The Absorptive Lineage 438
18.4 Choosing a Cell Fate: The Secretory Lineage 439
18.4.1 Goblet Cells 439
 Table of Contents xv

20.4 IL-1β 486

20.4.1 Historical Background 486
20.5 Systemic Effects of IL-1β in Humans 487
20.5.1 Transcription, Translation, and Synthesis of IL-1β 487
20.5.2 Regulation of IL-1β Production 487
20.5.3 The NLRP3 Inflammasome-dependent Processing and
Secretion of IL-1β 488
20.5.4 P2X7 and the Activation of the Inflammasome 489
20.5.5 Noncaspase-1 Processing of IL-1β 489
20.5.6 Effects in Mice Deficient in IL-1β 490
20.6 IL-18 and IL-18-binding Protein 490
20.6.1 Processing of the IL-18 Precursor by Caspase-1 491
20.6.2 Signal Transduction by IL-18 491
20.6.3 Role of IL-18 in the Production of IFNγ 492
20.6.4 IL-18, IL-17, and Gamma/delta T-Cell Activation 492
20.7 IL-18 and Inflammation 493
20.7.1 Proinflammatory Properties of IL-18 493
20.7.2 IL-18 in Heart Disease 494
20.8 IL-18 as a Protective Cytokine 495
20.9 IL-18-binding Protein 495
20.9.1 Background on IL-18BP 495
20.9.2 The Concept of Free IL-18 496
20.9.3 Regulation of IL-18BP 496
20.9.4 Viral IL-18BP 497
20.9.5 Hemophagocytic Lymphohistiocytosis and Macrophage
Activation Syndrome 497
20.9.6 IL-18 in the Hemophagocytic Syndromes 497
20.10 IL-33 498
20.10.1 The Discovery of IL-33 498
20.10.2 Processing of IL-33 498
20.10.3 IL-33 Shares with IL-1 the Coreceptor IL-1R3 499
20.10.4 Nuclear Function of IL-33 499
20.10.5 Role of IL-33 in Human Disease 500
20.11 IL-36 500
20.11.1 IL-36 Background 500
20.11.2 Role of IL-36 in Disease 500
20.12 IL-37 501
20.12.1 Background of IL-37 501
20.12.2 The IL-37 Signaling Complex: Requirement for IL-1R5
and IL-1R8 501
20.12.3 Binding Studies 502
20.12.4 The IL-37, IL-18Rα, and IL-1R8 Complex 502
20.12.5 Production of IL-37 503
20.12.6 Processing and Release 503
20.12.7 Effects of Recombinant IL-37 504
20.13 Disease Models in IL37-tg Mice 504
20.13.1 IL37-tg Mice 504
xvi Table of Contents

20.13.2 Experimental Colitis 505

20.13.3 Ischemic and Damage Models 505
20.13.4 Spinal Cord Injury 505
20.13.5 Metabolic Syndrome 505
20.13.6 Aging in IL37-tg Mice 506
20.13.7 Translocation of IL-37 to the Nucleus 506
20.13.8 Requirement for Smad3 507
20.13.9 A Role for IL-37 in Human Disease 507
20.14 IL-38 508
20.14.1 The Functional Role of IL-1 Family Member 10, Recently
Renamed IL-38 508
References 509

21 TNF Superfamily 529

Salvatore Cuzzocrea
21.1 Introduction 529
21.2 TNFα 530
21.3 TNFα: Biological Roles 530
21.4 Mechanisms of Action 531
21.5 Characterization of the TNFα Gene and Molecule 532
21.6 TNF Receptors and the TNF Receptor Superfamily 532
21.6.1 TL1A 533
21.6.2 FasL 534
21.6.3 LIGHT 534
21.6.4 DcR3 535
21.6.5 TRAIL 535
21.6.6 TWEAK 535
21.6.7 BAFF-R–BAFF 536
21.6.8 OX40–OX40L 536
21.6.9 GITR–GITRL 537
21.7 TNF Family: Role on Inflammatory Bowel Diseases 537
21.8 Role in Neuronal Inflammation 538
21.9 Conclusions 540
References 541

22 Interleukin-17 A-E 549

Giovanni Monteleone, Irene Marafini, and Edoardo Troncone
22.1 Introduction 549
22.2 Cell Sources of IL-17 Cytokines 549
22.3 IL-17 Receptor: Structure and Biology 550
22.4 Production and Role of IL-17 Cytokines in Normal and Inflamed
Intestine 551
22.5 IL-17 Blockers are Not Therapeutic in CD 553
22.6 IL-17 Cytokines in Psoriasis 553
22.7 Anti-IL-17 Therapy in Psoriasis 554
22.8 IL-17A in Psoriatic Arthritis 555
22.9 IL-17A in Rheumatoid Arthritis 556
22.10 Clinical Findings 556
 Table of Contents xvii

22.11 IL-17B, IL-17C, and IL-17D 557

22.12 IL-25 (IL-17E) 557
22.13 Conclusions 559
References 559

23 IL-6 Superfamily 573

Toshio Tanaka, Masashi Narazaki, and Tadamistu Kishimoto
23.1 Introduction 573
23.2 IL-6 and its Family of Cytokines 573
23.2.1 Biological Activity and Signaling System of IL-6 573
23.2.2 Original Members of IL-6 Family of Cytokines 575
23.2.3 New Members of IL-6 Family of Cytokines 575
23.2.4 Receptor Components of IL-6 Family of Cytokines 575
23.2.5 Soluble Forms of Receptors of IL-6 Family of Cytokines 577
23.2.6 Redundant and Nonredundant Functions of IL-6 Family of
Cytokines 578
23.3 Clinical Application of Members of IL-6 Family of Cytokines and Their
Inhibitors 578
23.3.1 Clinical Application of Members of IL-6 Family of
Cytokines 578
23.3.2 Clinical Application of Inhibitors of Members of IL-6 Family of
Cytokines 579
23.3.3 Present Status and Prospects of IL-6 Blockade Therapy 579
23.4 Concluding Remarks 582
References 582

24 Type I and II Cytokine Superfamilies in Inflammatory Responses 587

William F. Carson IV and Steven L. Kunkel
24.1 Introduction 587
24.2 Cytokine–Receptor Interactions 588
24.3 Cytokine Superfamilies 589
24.3.1 Type I Superfamily 589
24.3.2 Common Gamma Chain 589
24.3.2.1 IL-2 590
24.3.2.2 IL-4 590
24.3.2.3 IL-7 591
24.3.2.4 IL-9 591
24.3.2.5 IL-15 592
24.3.2.6 IL-21 592
24.3.3 Common Beta Chain 592
24.3.3.1 IL-3 593
24.3.3.2 IL-5 593
24.3.3.3 GM-CSF 594
24.3.4 IL-12 Subfamily 594
24.3.4.1 IL-12 594
24.3.4.2 IL-23 595
24.3.4.3 IL-27 595
24.3.4.4 IL-35 596
xviii Table of Contents

Orphan Type I Cytokines 596

24.3.5
24.3.5.1 IL-13 597
24.3.5.2 IL-14 597
24.3.5.3 IL-32 597
24.3.5.4 IL-34 597
24.3.5.5 G-CSF 598
24.3.5.6 M-CSF 598
24.3.6 Type II Superfamily 598
24.3.7 Interferons 599
24.3.7.1 Type I: IFN-α, -β, and Variants 599
24.3.7.2 Type II: IFNγ 600
24.3.7.3 Type III: IFNλ-1, -2, and -3 600
24.3.8 IL-10 Subfamily 600
24.3.8.1 IL-10 601
24.3.8.2 IL-19 601
24.3.8.3 IL-20 602
24.3.8.4 IL-22 602
24.3.8.5 IL-24 602
24.3.8.6 IL-26 603
24.4 Summary: Cytokine Networks in Cellular Immunity 603
References 604

25 Chemokines and Chemotaxis 619

Osamu Yoshie and Kouji Matsushima
25.1 Introduction 619
25.2 Chemokine and Chemokine Receptor Nomenclature Systems 626
25.3 Extravasation of Leukocytes: The Multistep Model 626
25.4 Inflammatory Chemokines and Homeostatic Chemokines 627
25.5 The Structure of Chemokines 630
25.6 Chemokine Receptors 632
25.7 The Two-step Model of Chemokine Receptor Activation 633
25.8 Signal Transduction 634
25.9 Atypical Chemokine Receptors 635
25.10 Organ Development and Chemokines 636
25.11 The Primary Lymphoid Organs and Chemokines 636
25.12 The Secondary Lymphoid Organs and Chemokines 637
25.13 Memory/effector T Cells and Chemokine Receptors 639
25.14 Mucosal Immunity and Chemokines 640
25.15 Skin Immunity and Chemokines 641
25.16 Clinical Applications 642
References 643

26 Lipid Mediators in Inflammation 651

Shuh Narumiya, Takehiko Yokomizo, and Junken Aoki
26.1 Introduction: Biosynthesis, Degradation, and Receptors of Lipid
Mediators 651
26.2 PGs in Inflammation 654
 Table of Contents xix

26.2.1 PGs in Acute Inflammation 654

26.2.2 PGs in Chronic Inflammation 657
26.2.2.1 PGs Act as Cytokine Amplifiers and Form Positive
Feedback Loops of Inflammation Through Induction
of COX-2 657
26.2.2.2 PGs in Autoimmune and Allergic Inflammation 659
26.2.2.3 PGs in Th1/Th17-mediated Autoimmune
Inflammation 660
26.2.2.4 PGs in Th2-mediated Allergic Inflammation 661
26.2.2.5 PGs in Tissue Remodeling (Fibrosis, Angiogenesis,
Lymphangiogenesis, etc.) 663
26.2.3 Anti-inflammatory Actions of PGs 663
26.3 LTs in Inflammation 664
26.3.1 LT Receptors 664
26.3.2 LTB4 and BLT1 in Acute and Chronic Inflammation 664
26.3.3 Roles of BLT2 in Inflammation and Tissue Homeostasis 665
26.3.4 CysLTs in Acute and Chronic Inflammation 666
26.3.5 Lysophospholipid, Lysophosphatidic Acid, and Sphingosine
1-Phosphate 667
26.3.6 Receptor for LPA and S1P 668
26.3.6.1 Receptors for LPA 668
26.3.6.2 Receptor for S1P 671
26.3.7 Synthetic Pathways and Enzymes for LPA and S1P 671
26.3.7.1 Synthetic Pathways and Enzymes for LPA 671
26.3.7.2 Synthetic Pathways for S1P 673
26.3.8 Degradation Pathway for LPA and S1P 674
26.3.9 Pathophysiological Roles of LPA and S1P in
Inflammation 674
26.3.9.1 Role of LPA and S1P in Angiogenesis 674
26.3.9.2 Fibrosis 675
26.3.9.3 Neuropathic Pain 676
26.3.9.4 Roles of S1P and LPA in Lymphocyte
Circulation 676
26.4 Concluding Remarks 677
References 677

27 Free Radicals in Inflammation 695

Andrew Cumpstey and Martin Feelisch
27.1 Introduction 695
27.2 What Are Free Radicals? 696
27.3 Oxidative Stress and the Redox Code 697
27.4 Free Radical Production: The Mitochondrion 699
27.5 Reactive Oxygen Species 700
27.5.1 Superoxide 700
27.5.2 Hydrogen Peroxide, Hydroxyl Radical, and Oxidative
Damage 701
27.6 Reactive Nitrogen Species 702
xx Table of Contents

27.6.1 Nitric Oxide 702

27.6.2 Enzymatic and Nonenzymatic Production of Nitric Oxide 703
27.6.3 Nitrogen Dioxide, Peroxynitrite, and RNS Metabolism 704
27.6.4 RNS as Anti-infectious Agents 705
27.7 Reactive Sulfur Species 706
27.7.1 Thiyl and Other Sulfur-Based Radicals 706
27.7.2 Hydrogen Sulfide 707
27.7.3 Could RSS have been Mistaken for ROS? 708
27.8 Making Redox Regulation Work: ROS, RNS, and RSS Acting in Concert
at the Level of Thiols 709
27.9 Antioxidants/Free Radical Scavengers 710
27.9.1 Dietary Antioxidants 710
27.9.2 Endogenous Antioxidants 711
27.9.3 Cells Respond to Oxidative Stress through Increased
Antioxidant Gene Expression 712
27.9.4 Antioxidants: Harmful or Beneficial? 712
27.10 The Redox Code in Health and Disease 713
27.10.1 Inflammation and the Innate Immune Response 713
27.10.2 Aging 713
27.10.3 Diabetes Mellitus 714
27.10.4 Cardiovascular Disease: Atherosclerosis 715
27.10.5 Ischemia Reperfusion Injury 715
27.11 Looking to the Future: Newly Discovered Signaling Roles, the Reactive
Species Interactome, and an Increasing Need to Assess the Role of Free
Radicals in Personalized Medicine 716
27.11.1 Prognostic Markers in an Increasingly Personalized World of
Medicine 717
27.11.2 The Reactive Species Interactome 717
27.12 Conclusions: Free Radicals, the Reactive Species Interactome, and Its
Importance to the Inflammatory Response 718
References 719

28 Proteases 727
Celine Deraison, Chrystelle Bonnart, and Nathalie Vergnolle
28.1 Introduction 727
28.2 Host Proteases and Inhibitors: Origin and Distribution 727
28.2.1 Inflammatory Cells 728
28.2.2 Resident Cells 728
28.2.3 Protease Inhibitors 729
28.3 Host Protease’s Functions in Inflammation 731
28.3.1 Antimicrobial Functions 732
28.3.2 Inflammatory Mediator Processing 732
28.3.3 Junction Molecule Degradation 733
28.3.4 Mucus and Surfactant Protein Cleavage 734
28.3.5 Immunoglobulin Cleavage 734
28.3.6 Immunoproteasome, Antigen Presentation, and
Processing 735
 Table of Contents xxi

28.3.7 Matrix Remodeling 736

28.3.8 Receptor Activation 736
28.3.9 Apoptosis or Anoikis 738
28.3.10 Coagulation and Fibrinolysis 739
28.3.11 Kinin–Kallikrein System 740
28.3.12 Complement System Activation 741
28.3.13 Inflammasome 742
28.4 Microbial Proteases and Inflammation 742
28.4.1 Effects on Barrier Function 744
28.4.2 Effects on Vascular Permeability 745
28.4.3 Effects on Complement Proteins 746
28.4.4 Effects on Cytokine/Chemokine Production 746
28.5 Proteases as Targets in Inflammatory Pathologies 747
28.5.1 Gut 747
28.5.2 Airways 748
28.5.3 Skin 750
28.5.4 Joints 751
28.5.5 Pancreatitis 752
28.5.6 Traumatic Brain Injury 752
28.6 Conclusions 753
List of Abbreviations 754
Acknowledgments 755
References 755

29 Psychiatric Disorders and Inflammation 767

Robert Dantzer
29.1 Introduction 767
29.2 Association Studies between Inflammation and Psychiatric
Disorders 768
29.3 Mechanisms of the Association between Inflammation and Psychiatric
Disorders 770
29.4 Other Causal Factors for the Relationship between Inflammation and
Psychiatric Disorders 774
29.5 Relations between Inflammation and Neuropathology 775
29.6 Conclusions 776
Acknowledgments 777
References 777

30 Complement System 785

Peter A. Ward and Claudia Kemper
30.1 Introduction 785
30.2 Pathways of Complement Activation 785
30.2.1 Complement Activation 785
30.2.2 Complement Regulation 787
30.3 Activation Products of Complement 787
30.4 Receptors for Complement Activation Products 788
30.4.1 Opsonin Receptors 788
xxii Table of Contents

30.4.2 Anaphylatoxin Receptors 789

30.5 Role of Complement in Innate and Adaptive Immunity 790
30.5.1 Complement, Innate Immunity, and Acute Inflammation 790
30.5.2 Complement, Adaptive Immunity, and Chronic
Inflammation 792
30.5.2.1 Humoral Immunity 792
30.5.2.2 T-cell Immunity 792
30.6 Evidence for Intracellular Activation of Complement 793
30.7 Roles of C5a, C5aRs, and C3aR in Inflammatory Disorders 795
30.7.1 Acute Respiratory Distress Syndrome (ARDS) 795
30.7.2 Sepsis 795
30.7.3 Acute Lung Injury 796
30.7.4 Biological Roles of C3a and C5a Receptors 798
30.8 Role of Complement in Selected Human Diseases 799
30.8.1 Vasculitis 799
30.8.2 Examples of Complement-related Glomerulopathies in
Humans 799
30.8.2.1 Membranous Glomerulonephritis 799
30.8.2.2 C3 Glomerulonephritis 799
30.8.2.3 Hemolytic Uremic Syndrome and Related
Disorders 801
30.8.2.4 Systemic Lupus Erythematosus and Lupus
Nephritis 802
30.9 Strategies to Block Complement Activation and Complement Activation
Products 802
30.9.1 Compstatin 802
30.9.2 C1 Esterase Inhibitor 802
30.9.3 C5 Blocking Antibodies 803
30.9.4 C5a Antibodies 803
30.10 Conclusions for Role of C3aR and C5aR 804
Acknowledgments 804
References 804

31 Heat Shock Proteins 813

Willem van Eden, Femke Broere, and Ruurd van der Zee
31.1 The Molecules (HSP Families) 813
31.2 Biological Function of HSPs (Chaperones) 813
31.2.1 The Markers of Cellular Stress 813
31.2.2 Molecular Basis of the Heat Shock Response 814
31.2.3 Triggers for the Heat Shock Response 815
31.2.4 The Chaperone Functions of HSP Families 816
31.2.5 HSP70 as a Prominent Peptide Donor for the MHCII
Ligandome 817
31.3 The Immunology of HSPs 817
31.3.1 Immunodominance of Prokaryotic HSP 817
31.3.2 Cross-reactivity with Self-HSP 818
31.4 HSPs Protect in Models of Inflammatory Disease 819
xiv Table of Contents

18.4.2 Paneth Cells 441

18.4.3 Enteroendocrine Cells 441
18.5 The Epithelium: The Sum is Greater than its Parts 442
18.6 Epithelial Homeostasis: Maintaining the Balance 443
18.6.1 Wnt Signaling 443
18.6.2 Notch Signaling 444
18.6.3 Inflammation-induced Alterations in Epithelial Cells 445
18.7 Concluding Remarks 447
References 447

19 Inflammation: The Role of Endothelial Cells 457

J. Steven Alexander, D. Neil Granger, and Norman R. Harris
19.1 Introduction 457
19.2 Vasomotor Dysfunction 458
19.2.1 Mechanism of Vascular Smooth Muscle Contraction/
relaxation 459
19.2.2 Endothelial Cell-dependent Vasoactivity 459
19.2.3 Endothelium-dependent Vasoactivity in IBD 460
19.2.3.1 Leukocyte– and Platelet–endothelial Cell
Adhesion 461
19.2.3.2 Enhanced Thrombosis 463
19.2.3.3 Angiogenesis/vasculogenesis 465
19.2.3.4 Junctional and Vascular Permeability 468
19.3 Conclusions 470
References 471

Volume II
Part Three Inflammatory Mediators 477

20 IL-1 Superfamily and Inflammasome 479

Charles A. Dinarello
20.1 Introduction 479
20.1.1 The IL-1 Family of Cytokines and the Innate Immune
System 479
20.1.2 The Family of IL-1 of Receptors 481
20.1.3 The IL-1 Family Consensus Sequence 481
20.1.4 The IL-1 Family as Therapeutics 482
20.2 IL-1α 483
20.2.1 Historical Background 483
20.2.2 Systemic Effects of IL-1α in Humans 483
20.2.3 IL-1α is a Dual-function Cytokine 484
20.3 Cell Sources, Production, and Secretion 484
20.3.1 Large Amounts of Constitutive IL-1α in Healthy and Disease
Cells 484
20.3.2 IL-1α as a Growth Factor 485
20.3.3 Membrane IL-1α 485
20.3.4 Studies in IL-1α-deficient Mice 486
 Table of Contents xxiii

31.5 HSP as Inflammatory Mediators 821

31.5.1 HSP are DAMPs? 821
31.6 HSP are DAMPERs of Inflammation 821
31.6.1 Effects of HSP on Mediators of Inflammation 822
31.6.2 HSP are Targets for a Default Regulatory Immune
Response 822
31.6.3 HSP and Tregs 823
31.6.4 HSP Coinducing Substances 823
31.7 The Clinical use of HSP in Chronic Inflammatory Diseases 824
31.7.1 HSP Peptides and Proteins 824
31.7.2 TolDC Loaded with HSP Peptides 824
References 825

Volume III
Part Four Inflammation and Host Response 831

32 Inflammation and Coagulation 833

Marcel Levi MD PhD
32.1 Introduction 833
32.2 Incidence of Inflammation-associated Coagulopathy 833
32.3 Clinical Relevance of the Interaction between Inflammation and
Coagulation 834
32.4 Pathogenetic Pathways in the Coagulopathy of Sepsis 835
32.4.1 Initiation of Inflammation-induced Activation of
Coagulation 835
32.4.2 Role of Platelets in Inflammation-induced Coagulation 836
32.4.3 Downregulation of Physiological Anticoagulant and
Fibrinolytic Pathways during Inflammation 837
32.4.4 Antithrombin and Inflammation 837
32.4.5 Activated Protein C and Inflammation 838
32.4.6 Thrombomodulin and Inflammation 840
32.4.7 TFPI and Inflammation 841
32.5 Modulation of Inflammation by Coagulation in vivo 841
32.5.1 Extracellular DNA, Histones, and Neutrophil Extracellular
Traps 842
32.6 Injured Endothelium and Microparticles 843
32.7 Systemic versus Localized Responses 843
32.8 Organ-specific Responses by Endothelial Cells 844
32.9 Diagnostic Approach to the Inflammation-induced
Coagulopathy 845
32.10 Supportive Treatment of Coagulation Abnormalities during Severe
Inflammation 847
References 849

33 Fever: Mediators and Mechanisms 861

Joachim Roth
33.1 Introduction 861
Another random document with
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 “It has indeed,” said the men present, looking at her with
affectionate pride. They had all known her from her birth, and loved
her almost as well as their own children, and somehow they were
glad to have her back amongst them.
“Are you ready?” asked Loïs.
“Yes, we are quite ready,” answered Father Nat. Loïs ate the
supper they hastened to place before her, and then told them
something of the day’s journey.
“We saw no one on the road,” she said; “it seems difficult to
imagine such danger is threatening us.”
“Nevertheless, I have heard sounds in the forest which tell me
plainly the Indians are not far off,” said Nathaniel.
“Now,” said Loïs, rising, “I will lie down and sleep for an hour;
there is yet time.”
“Do,” said Father Nat, and Loïs went to her own room and knelt
beside her white bed and prayed, as she had done all the years of
her life, from childhood to womanhood. Then, throwing herself on her
bed, she slept.
 CHAPTER XIX
THE ATTACK
The lights were extinguished; the inhabitants of the Marshes were
apparently sunk in slumber. It was near upon midnight, but the moon
was shining so brightly that it seemed almost as if it were daylight.
Loïs had risen, and, standing in the darkness at a window of an
upper room at Omega Marsh, looking down into the valley, was
almost tempted to think she must have been mistaken, that her
interview with Nadjii was an evil dream, the scene was so peacefully
lovely. The church spire rose in the midst of the surrounding houses.
She knew every one of them; their inhabitants had been familiar to
her since her childhood, from the old grandfather to the toddling child
she had helped to carry on the road that morning. By the light of the
moon and stars she saw the outline of the hills, and farther on the
mountain ridges; whilst the river gleamed here and there as it wound
through the meadows. But what riveted her gaze was that dark,
impenetrable forest. What did it conceal? She knew full well that all
around the garden men belonging to the village lay on the ground
watching, even as she was watching. Would to God it might be in
vain! but Nadjii had spoken, and Loïs had implicit confidence in the
Indian woman.
Suddenly, without warning, a loud shout arose. Then Loïs knew
the enemy was at hand, and in the space of a few seconds the
settlement was surrounded. The Indians poured down into the valley
like a flock of locusts. Nat had issued the order that no man was to
stir until the savages should have passed the boundaries, and then
to fire on them simultaneously. Up towards the Marshes they
swarmed, never doubting that the inhabitants were sleeping; but they
were soon undeceived—a murderous fire came pouring down upon
them. Shrieks, howls of pain and anger, filled the air, and the dark
figures, with their waving headgears, leapt the barriers, striking out to
the right and left with their murderous hatchets.
 To Loïs, as she shrank back, it was as if all the devils of hell had
been suddenly let loose. Steadily the fire continued; but so
numerous were the assailants, that even as they fell others poured in
over them, filling up the gaps. The settlement was surrounded on all
sides. The besieged were not long in perceiving this, for the
triumphant yells of the red men were heard on every side.
“They are too many for us, Marcus,” said Father Nat; “they are
murdering our people wholesale down yonder. Good Heavens! they
are setting fire to the barns; they’ll burn the village down!”
“I’m afraid they will,” said Marcus. Even whilst speaking they had
not ceased firing. With a score of other men they were crouching
behind the trees in the garden, just in front of Omega Marsh. Other
groups were scattered here and there, protecting the homestead.
The dead and wounded lay around, but the assailants still came on,
the circle narrowing as they pressed forward.
“Where is Loïs?” asked Father Nat.
“Here,” she answered; and raising her gun, she fired over his
shoulder at an Indian, who had leapt to within a yard of them.
“We must back into the house and bar the doors,” she said; “it is
our only chance.”
“I think she’s right,” said the minister, and slowly they began to
move backwards. A yell of delight from the savages greeted this
retrograde movement, and one leapt forward, and, raising his
tomahawk, would have brought it down on Father Nat’s head, if a
thrust from a knife had not made the uplifted arm drop helpless, and
with a shriek of agony the man sprang back. At the same moment
Loïs felt herself lifted from the ground and carried into the house.
With a sudden rush the others followed her. To bolt and bar the
doors and windows of the ground floor was the work of a few
seconds. Some of the men had ascended to the first story, and were
firing from the windows upon the savages.
“We can only hold out a certain time,” said John Cleveland; “and
even that depends upon their being kind enough not to set fire to the
place.”
It seemed very unlikely that the Indians would refrain from doing
so. The village was burning; and by the light of the flames the terrible
fight which was going on below and around was clearly visible.
It was evident they had some reason for not setting fire to the
homestead, probably the desire of taking the inhabitants alive for the
purpose of torturing them “Father Nat” more especially, their anger
being directed against Roger. The house was strongly built, the
doors and windows secured by heavy iron bars, and so far the
savages had been kept at bay by the incessant firing of the
beleaguered. Suddenly they appeared to retreat, making a rush
round to the back of the house. At the same moment Nadjii stood by
the side of Loïs.
“See!” she whispered. “Roger;” and even as she spoke, running
swiftly up the hill with shouts of “Hurrah, hurrah!” they saw the well-
known red shirts of the Rangers.
“Saved,” said Father Nat, turning round quickly. “My brave lad!” He
had hardly uttered the words when he was felled to the earth, and
the room was filled with savages, yelling, hewing to the right hand
and to the left. The settlers were grouped together in a corner of the
room, keeping the savages at bay with their guns and rifles.
The last thing Loïs saw was Nadjii, who, thrusting her behind her,
with blood flowing down her own half-naked body, held aloft a
glittering steel knife stained with gore.
The sun rose upon a scene of utter devastation. The village of
Marshwood lay in ruins; upwards of one hundred men had been
killed, or, worse still, were missing.
Almost the only house which stood uninjured was Alpha Marsh;
evidently the Indians had their reasons for respecting it. Their own
loss was immense. The sudden appearance of the Rangers had
been totally unexpected. When the savages had forced an entrance
at the back and had swarmed into the house, Roger and his men
took them in the rear and cut them to pieces, at the same time as
they were being fired on by the besieged; retreat was therefore
impossible, and they perished to a man. A few threw themselves out
of the windows in the hope of escaping, but were either killed in the
fall or bayoneted by their opponents stationed below; the same thing
went on throughout the village. In less than an hour after the
Rangers appeared, the Indians were swept away, leaving their dead
and wounded to the mercy of the conquerors.
 Of the group of men who had defended Omega Marsh only a few
escaped unwounded. When the fight was at an end, and Roger
forced his way over the dead into the room where the besieged had
taken refuge, an awful sight met his eyes. Father Nat lay apparently
killed, Loïs was close beside him senseless, and almost covering
them with her naked body, gashed with wounds, lay Nadjii.
The scene was one of indescribable horror. For a second Roger’s
spirit failed him. The survivors, faint and exhausted, hardly believing
they were saved, still stood with their weapons in their hands.
Marcus, badly wounded himself, was striving to get at Loïs, but the
Indian woman’s body had to be moved first, and he had no strength
left. Stern and agonised was Roger’s face, as John Cleveland,
clasping his hand, said, with a sob in his voice,—
“He knew you had come to the rescue. A minute sooner and you
would have saved him.”
“Are you sure he is dead?” said Roger, in a hoarse voice, as he
helped Marcus to move Nadjii and Loïs; and then he raised his father
in his arms. Apparently dead he certainly was; but the face was so
swollen and disfigured by a ghastly wound on the forehead that it
was impossible to say positively.
“He and the women had better be carried over to Alpha Marsh,”
he said; “the flames are spreading below. I must go and help my
men.”
At that moment Loïs opened her eyes, and consciousness came
back to her immediately. She sat up and looked around.
“Oh, Roger!” she exclaimed; and for the first time for years he did
not turn away from her, but asked,—
“Are you hurt, Loïs?”
She tried to rise. John Cleveland gave her his hand.
“No,” she answered, “I think not; it is their blood,” and she
shivered, pointing to her blood-stained garments.
“Alpha Marsh is uninjured; we are going to carry Father Nat
there.”
“And she?” said Loïs, looking down at Nadjii.
“If you wish it,” answered Roger, turning away.
 And so Nathaniel was laid in the best chamber of Alpha Marsh,
and Nadjii in Loïs’ own bedroom.
Nokomis, the Huron woman who had served Nathaniel ever since
he rescued her from another tribe of Indians, who had slain her son
and her husband, came out of hiding, and with a few other women,
some old, some sick, who had refused to leave the settlement, set to
work to tend the wounded.
“He no dead, she no dead,” said Nokomis, after washing the blood
from Father Nat’s head and body, and, with Loïs’ help, performing
the same office for Nadjii. “But,” she added, shaking her head, “they
both die; no meda[5] save her.”
[Footnote 5: Medicine-man.]
“But you are as good as a meda,” said Lois. “You know of herbs
and salves, Nokomis; you must try what you can do.”
“For my Nosa[6] perhaps,” she said, as she bound up the ghastly
wound which had lain Father Nat’s head open; “but for the Nadjii,
she dead;” and yet as Loïs bent over the dark face, and held a
feather to her lips, she knew that Nadjii still lived.
[Footnote 6: Master.]
“Oh, Nokomis,” she said, tears running down her face, “she tried
to save us all; if I am living it is because she stood between me and
death. She has a brave heart.”
“She is a chief’s daughter,” answered Nokomis, with certain
dignity; “but she must die; her hour is come.”
Suddenly a thought struck Loïs; her pale face flushed.
The child—where had Nadjii left the child?
 CHAPTER XX
“LIGHTEN OUR DARKNESS.”
“How did you know they were coming against us?” said Minister
Cleveland. “We heard a fortnight ago that you were up on the shores
of Lake Champlain.”
“I was not far from there,” answered Roger. “We have had a hard
time of it lately, harassed on all sides by the French, the Canadians,
and Indians. I had drawn my men off, to give them a few days’ rest;
for in our last skirmish we had lost several men, and others had been
wounded. I was lying half-asleep and half-awake at the foot of a tree
one night, when I became conscious of some one creeping round
from behind. In a second I was on foot, and at the same moment an
Indian youth rose up before me. I seized him, and knew at once he
was an Iroquois. I had seen him before; he was Nadjii’s half-brother.
“‘What are you doing here?’ I asked.
“‘Nadjii tell me come,’ he answered, in his native dialect. ‘Find the
“Brave Heart,”’ she said, ‘and tell him to be near the old Nosa before
the moon is at its full.’
“‘There’s mischief brewing against the Marshes then?’ I asked.
“‘I do not know; Nadjii say come,’ he answered.
“‘Where is she? and where is the white chief, her husband?’ I
asked.
“‘Nadjii watch the white maiden. The white chief with the white
men up at the City on the Rock.’
“Then I knew that Charles was with General Montcalm, and that a
tribe, probably the one I had escaped from, was about to attack the
Marshes out of revenge.
“‘It is well,’ I answered. ‘You stay with me. If you speak truly, good;
if you deceive us——’ and I made a well-known sign of punishment.
He only smiled, and sat down on the ground in token of consent.
 “An hour later we were on our way; but it is a long journey, and we
had to keep clear of the Indians. The nearer we got to Marshwood,
the more we became aware of their presence. We had to take a
circuitous path, which delayed us and made us late.”
“Yes,” said the minister; “but for that poor creature dying upstairs,
we should all of us have been murdered in cold blood.”
This conversation had taken place in Alpha kitchen, where, late at
night, the two men found themselves alone for the first time: the call
upon both of them from within and without had been incessant. They
had not only to attend to the living, but had to arrange for the
removal of the dead bodies of the killed—no light task.
Father Nat had shown unmistakable signs of life, but was still
insensible. A messenger had been despatched to the nearest town
for a doctor, and was expected to return next day; in the meanwhile
Nokomis had brewed herbs, and, with Loïs, done what she could for
the sufferers. Now Loïs was watching beside Nadjii. It was midnight,
and still they had no news of the child. Where had the mother hidden
it when she came to the rescue? With Marcus’ help Loïs had
searched the house and outhouses, and assured herself it was not
there. It lay probably in the forest in the trunk of some tree.
Evidently having become possessed of the secret of the tribe,
Nadjii had travelled alone with her child through the forest, crossing
rivers and rapids as only an Indian woman could, to reach the
Marshes in time and warn the inmates. On the night of the attack she
must have lain the child to sleep in some hidden place; but where? It
would surely die if its mother could not tell.
Nadjii was wounded unto death, and Loïs knew it; a few hours at
most and she would cease to live, carrying her secret away with her,
and her child’s hope of life! Loïs, as she knelt beside Nadjii, seemed
to hear the wailing of the infant, the helpless cry for mother’s milk
and mother’s kisses. “O Father, have mercy on the innocent babe,”
she prayed; “let it not die this terrible death! My poor Nadjii has been
faithful and true, and has laid down her life for her husband’s people,
moved by the great love she bears him.”
Truly love, the great purifier, entering this poor heathen’s heart,
had taught her many things, lightening her darkness! To her, though
she knew it not, had been revealed the primary laws of love,
obedience, and self-sacrifice! Her husband had bidden her watch
over Loïs and his mother, and report to him if harm threatened them;
and she had done what she could—she had laid down her life for
them. All these thoughts crowded through Loïs’ mind as she knelt
and prayed. She had all the early Puritan’s faith in prayer. No
conflicting doubts troubled her. God would surely hear her!
“Spare the child, O God!” she repeated again and yet again, her
clasped hands stretched out over the body of the dying mother. Her
eyes were closed, her pale face raised, she was as one wrestling
with God. Suddenly a word fell on her ear, “Nenemoosha.”[7] She
turned quickly and looked at the Indian woman. Her eyes were open,
and from out the swollen lips came in a voice almost inaudible the
same word repeated, “Nenemoosha.” Tears sprang to Loïs’ eyes.
She understood the meaning; and, bending over Nadjii, said, “Tell
me where he is and I will fetch him.” The answer came, but in quick
Indian words; and though Loïs understood a few, she could not
follow her.
[Footnote 7: Sweetheart.]
“Wait! I will fetch some one,” she said; but before leaving Nadjii
she gave her a cordial and damped the cloth that was bound round
her head, whispering, “Never fear, Nadjii; we will find Nenemoosha.”
Then she left her, smiling back at her as she went, though her heart
was very sore. She had thought to fetch Nokomis, but the old Indian
had been called away from Father Nat’s bedside to tend another
wounded man, and had left an ancient village crone in charge.
Hastily Loïs ran into the kitchen, where John Cleveland the minister
and Roger were together.
“Roger,” said Loïs, going up to him, “Nadjii, the squaw, has
spoken, but I cannot understand her; you must come. She left her
and his child somewhere in the forest when she came to our rescue.
You must go for it. Come!”
Roger started back from her, anger flashing from his eyes.
“A child of such a brood! Better let it die, Loïs. Would you nurture
a viper in your bosom?” he said.
“It is my brother’s child, and its mother is dying for me!” said Loïs
passionately, and she burst into tears.
 A great struggle was visible in the hunter’s face. He hated this
Indian woman, who, to his mind, had helped to decoy his friend. Why
should he save her child?
“She is dying; fetch the child for her, Roger, and then I will depart
with it, and you shall see our faces no more!” and Loïs threw herself
on her knees before him. “By our old love,” she murmured. He
turned away and strode up to the room where he knew they had laid
Nadjii. Loïs and the minister followed.
All the soul of the dying woman was reflected in her eyes. When
she saw Roger she strove to lift herself, but Loïs sprang to her side
and laid her hand upon her, saying,—
“Tell him where to find Nenemoosha. He will go for him,” she said.
Nadjii lay motionless, wounded from head to foot, tortured with
awakening agony.
Loïs moistened her lips, and smiled down on her dark sister as an
angel might.
Then Nadjii spoke, quickly, gaspingly, looking at Roger. When she
ceased, he bowed his head and left the room.
“Shall you be able to find it?” asked the minister.
“Yes,” answered Roger. “She has hidden it in the trunk of a tree
about a mile distant, and she has marked the trees leading to the
one where the child lies by an arrow cut in the bark; if it be still there
I shall find it;” and he strode out of the house.
In less than an hour he came back, but his arms were empty.
“They have stolen it,” he said to Loïs, who met him. “She had
made a bed of leaves for it, and I saw where it had been; but I also
saw the track of a man’s foot round the tree, and the hands of a man
had touched the child’s resting-place. It is gone.”
“What shall I say to her?” said Loïs, wringing her hands and
weeping.
“You will not need to say anything,” answered the minister; “she is
even now passing away. Come.”
They re-entered the room, and truly they knew that death was
there before them. The veil was slowly being drawn across things
earthly for the poor Indian woman; her eyes were already dim, her
senses failing. The minister knelt down and prayed that the departing
soul might awaken in another world to new knowledge and new light;
and even as he prayed the answer came. A flash of light shot from
Nadjii’s eyes, and a cry went up from her lips, “Jesus! Nenemoosha!”
and she looked straight before her, as if she saw a vision; and so
looking, the light died out of her face, and Nadjii slept.
 CHAPTER XXI
AT THE HELM
After his repulse from Ticonderoga, General Abercromby made no
marked effort to retrieve his position; his troops were disheartened,
and fearing another attack by the French, he hastened to retire down
Lake St. George, and to protect himself in an intrenched camp. In
October, after the taking of Louisburg, General Amherst joined him;
but it was then too late in the year to renew active service. Montcalm
with his army withdrew for the winter to Montreal, and the English
returned to Albany.
The English were, however, slowly gaining ground. Fort
Duquesne, after immense labour and many hardships, was wrested
by Brigadier-General Forbes from the French, and re-baptised, in
honour of the great statesman, Pittsburg. Fort Frontenac was also
captured, and this was more especially important as it gave the
English a footing on Lake Ontario. And so the year 1758 came to a
close, and the nations knew, both at home and abroad, that the great
contest was likely to be fought out during the ensuing year; but whilst
the land lay under its white covering of snow, with ice-bound rivers,
there was peace, or rather a cessation of hostilities, and the leaders
at home and abroad looked around to see who were the men most
fitted to place at the helm.
Pitt had for some time past had his eye on a man who had already
distinguished himself at the siege of Louisburg, James Wolfe. After
the taking of that fortress he had desired to push on at once to
Quebec; but he was overruled by the other generals, and a far more
disagreeable task was allotted to him. It was considered necessary
to destroy all the French settlements on the Gulf of St. Lawrence,
and he was deputed to carry out the order.
It is difficult for us now to realise the extent of misery this decision
entailed; certainly it was more especially repugnant to a sensitive,
humane nature such as Wolfe’s. It meant laying waste hundreds of
pleasant homesteads, driving their inhabitants forth shelterless! The
wailing of women and children, the low, bitter curses of the men—all
this had to be borne with apparent stoicism. Always delicate, already
suffering from the disease to which he was to succumb, Wolfe’s
health entirely broke down under the severe mental and moral strain,
and it was found necessary to grant him a prolonged leave of
absence. He immediately set sail for England, hoping in the quiet of
his home and his much-loved mother’s society to recruit his
shattered health. His was a peculiar nature, a strange mixture of
tenderness and passion; loving and sensitive beyond measure, yet
at times strangely fierce and stern. His mother was wont to say he
was a living barometer, his spirits rising and falling with every change
of weather.
With such a character it was hardly possible for him to have been
what we generally term a happy man; there were too many
contradictions in his nature. When still quite young he either was, or
imagined himself to be, in love; the result was a bitter
disappointment, and for some time afterwards he plunged into a life
of dissipation. At the early age of twenty-three he was already
lieutenant-colonel (he had entered the army at fourteen), and was
sent in garrison to Inverness. Here he remained five years, a great
favourite with both his men and fellow-officers, but so entirely
isolated from society that, as he expressed it himself, “He feared lest
he should become a ruffian.” Once more he went to the other
extreme, like a pendulum, and for six months took up his residence
in Paris, devoting himself to the study of the French language and to
the acquirement of every social accomplishment.
He was, we are told by those who knew him most intimately,
possessed of only moderate abilities; but his diligence and
perseverance were so remarkable that he accomplished anything he
set his heart upon. Effeminacy was hateful to him; he was essentially
a high-principled man, with a strong sense of duty, ever faithful to his
ideal of what a true soldier ought to be—“always ready to meet the
fate we cannot shun, and die gracefully when my hour comes,” he
said on one occasion, and truly he carried this axiom out through life
unto death!
 In personal appearance he might almost have been considered an
ugly man. He had a retreating forehead and chin; his nose was
upturned, and formed with other features the point of an obtuse
triangle. His mouth was by no means shaped to express resolution.
The redeeming point in his face was his eyes; they were clear,
bright, and piercing, full of spirit. His hair was red, and, according to
the custom of the time, tied in a queue, and he always wore a black
three-cornered hat. His physique denoted less than ordinary
strength. He is represented with narrow shoulders, slender body,
long thin limbs cased in scarlet frock-coat with broad cuffs and ample
skirts, which reached down to his knees. Such was the outward
seeming and character of the man who played so conspicuous a part
in a war which ultimately gave to England one of her richest and
most loyal colonies.
It was with a sense of relief that after the capture of Louisburg
Wolfe set sail for England. His experiences of the last few months
had impressed him so painfully that he hoped never to return to
Canada. He had strong domestic tastes, his affection for his mother
was the dominant passion of his life, and he had been but a few
weeks in England when he proposed to and was accepted by a Miss
Lowther; and so life seemed to be dawning for him in roseate hues.
He was only thirty-three years of age, and was beloved both at home
and abroad; his delicate health was the only shadow on his horizon,
but it was hoped that perfect rest and good nursing would restore
that. Therefore, throughout that winter Wolfe remained at home,
perfectly happy, ignoring the fact that William Pitt’s eagle eye had
already marked him out, and that his name was destined to be
handed down to posterity among those men who have deserved well
of their country.
But, whilst physically Wolfe was being thus strengthened for the
fray, his great opponent was losing heart. Throughout that winter
Montcalm recognised more than ever the many discordant elements
by which he was surrounded.
The Governor’s jealousy had increased; he took every opportunity
in his power for disparaging Montcalm, even going the length of
demanding from the Court at Versailles that he should be recalled.
But indifferent as the French king and his ministers were to the real
interests of Canada, they were still sufficiently clear-sighted to know
that General Montcalm was the right man in the right place, and to a
certain extent to appreciate the services he had rendered the state.
They therefore raised his rank to that of lieutenant-general, as also
his officers Bourlamaque and Levis, who were made colonel and
major-general.
But in his own heart Montcalm knew that when the Forts of
Niagara, Crown Point, and Duquesne fell into the hands of the
English, the end could not be far off. Little by little he was becoming
isolated and cut off on the St. Lawrence, the British holding the
command of the seas. He was possessed, however, of great military
genius, and displayed to the last extraordinary skill in defending the
French possessions.
During the winter the social life at Montreal was wholly in
contradiction to the General’s feelings, so that he withdrew himself
entirely from society, remaining in his own quarters, occupied with
combining plans for the spring campaign, which he foresaw would
decide the fate of Canada. This conduct was of itself a cause of
complaint against him, being a reproach to Bigot and his associates,
in whose palace at Quebec every night high revelry reigned. Supper
parties, dances, and masquerades were of nightly occurrence; and
worse still, gambling was carried to such a pitch that the results had
in many cases to be hushed up.
Mercèdes lived in her rooms at the Intendance, ignorant of what
was going on below. Like her father, retiring more and more from
public life, seldom seen except on her way to church or on her visits
to the poor, without knowing it she was a sort of hostage for her
father. Probably she would not have been allowed to remain so
entirely in the background but for Madame Péan’s open protection.
That lady reigned supreme in the gay world at Quebec, and she
would not suffer her protégée to be annoyed. “She is in my charge;
she shall not be molested,” she was wont to say when it was hinted
by the government officials that it would strengthen their arguments
against Montcalm if his daughter could be persuaded to join in their
revelries.
“It is quite useless,” Madame Péan declared; “she would not
understand our ways. You would scare her quite away.”
 But one night the revelry had attained even wilder proportions
than usual. A sumptuous supper succeeded a masquerade ball.
Towards morning the guests dispersed, and only about twenty
intimates remained. Some one suddenly said,—
“What a joke it would be if we were to surprise Monsieur de
Vaudreuil and General Montcalm at Montreal!”
There was a general laugh.
“Why not do so?” said Intendant Bigot. “We could be there in three
days’ sleighing. If it would afford the ladies any pleasure, they have
but to command. I am their humble servant.”
“It would cost a fortune,” said Madame Péan.
“You are growing economical, my dear,” retorted Madame Marin;
“there is the king’s exchequer! I vote we do it, and we will take
Mademoiselle Mercèdes with us to see her father. This gentle
attention will soften the old bear, and he will not have the heart to
reproach us. What do you say to my plan, Monsieur Bigot?”
“Only what I said before, that if you ladies wish it we will start at
midday, reach Pointe-aux-Trembles in time for supper, sleep there,
and go on the next day to St. Anne. Our next halt might be at the Isle
des Castors, where Rigaud would entertain us, and finally Montreal.
If you will decide at once, I will despatch couriers to have everything
in readiness. What are your wishes, Madame?” he added,
addressing himself to Madame Péan, whose beauty and
accomplishments always ensured her the first place in every project
for the general amusement.
“I am willing,” she said carelessly.
“And you will persuade Mademoiselle Mercèdes to join us?”
insisted Madame Marin.
“If she knows she is likely to see her father she will not refuse,”
answered Madame Péan. “She will go in my sleigh.”
“I wish you joy!” said one of her lady friends. “What you see in that
little dull thing, to have her always about with you, is more than I can
imagine. Why, I saw you out sleighing with her and that Indian
hunter, Charles Langlade, last week, near the village of Beauport.
Are you trying to make a match of it?”
 “I wish I could,” answered Madame Péan; “but you know as well
as I do he has his Indian squaw. Now, good-night, or rather good-
morning; I am off to get a few hours’ sleep.”
There was a general leave-taking, and it was agreed they should
all meet at midday on the morrow; and so the ladies retired, but the
gentlemen remained in consultation as to ways and means.
“I intend it to be a grand affair,” said Bigot ostentatiously. “We will
spare no expense, eh, Marin?”
“Certainly not! Why should we? It is necessary for the good of the
country. You require to see Vaudreuil; De Martet and Varin have to
look after the army and navy supplies. We are going on the king’s
service, therefore the king must pay. Long live the King!”
“Long live our Gracious Master the King!” they all shouted in high
spirits, and forthwith began arranging for the projected excursion.
The light of the dim November morning was slowly creeping into the
palace when they separated to snatch a brief repose.
 CHAPTER XXII
HOME NEWS
“Go to Montreal and see my dear father? You do not really mean
it!” exclaimed Mercèdes, clapping her hands in sheer childish delight.
“Indeed I do. We are starting in a few hours,” said Madame Pèan,
smiling. “Can you be ready?”
“Ready? I should think so indeed! I have nothing to do,” said
Mercèdes. “I suppose Marthe will stay here. You will not mind being
alone for a few days, shall you?” she said, turning to her nurse.
“No, Mademoiselle, assuredly not. Go and amuse yourself; your
life is dull enough, and yet the General——”
“Oh, Marthe!” interrupted Mercèdes reproachfully. “Do you think I
would care to go if it were not to see my father, and perhaps have
news of the dear ones at Candiac? It is so long since I heard from
them.”
“Of course, of course,” said Madame Péan. “I will take good care
of her, Marthe; and only think how delighted the General will be to
see his daughter.”
“I hope the General will be satisfied,” answered Marthe doubtfully;
“but he particularly desired I should never leave Mademoiselle, and
you know he does not approve——”
“That is enough, Marthe; I will take all responsibility on myself;
and, after all, Mademoiselle is in my charge, and you know, I think,
by this time, that I love her dearly.” Then turning to Mercèdes,
Madame Péan continued, “You will be ready by twelve o’clock,
dearest. Mind you have plenty of furs and wraps of all sorts. It is
freezing hard; it is grand weather. Fancy sleighing from Quebec to
Montreal! It will be something to say one has accomplished such a
feat! Now, good-bye; come down to my rooms when you are ready.
Adieu, Marthe. You need not be anxious about your nursling.” And
she left them.
 Two years and a half had elapsed since Mercèdes first set foot in
Canada, and from a mere girl she had developed into a woman. She
was small and slender, and still looked very young; indeed, though
she was now eighteen years of age, she was but little altered. She
had more colour, and was healthier in appearance, which, with her
bright dark eyes and soft smile, made her almost good-looking. She
and Marthe had settled down to their quiet way of living, and by
degrees had been nearly forgotten by the outside world. The
General had ceased to worry about her, and was only too glad when
he visited Quebec, which he did not do sometimes for several
months at a time, to find Mercèdes, with her ready sympathy and
warm affection. It was the only real relaxation he knew of; and many
a happy hour was passed in those little rooms overlooking the
convent. By degrees they had come to a sort of tacit agreement that
she should not enter the convent until the war was ended. If the truth
must be told, Mercèdes experienced a sense of relief when this was
decided; she had grown to love Canada, for the defence of which her
father was giving the best years of his life, and all the genius with
which nature had endowed him.
She had made many excursions in the neighbourhood of Quebec,
sometimes in company with Madame Péan, sometimes alone with
Marthe, and was never tired of admiring the lovely scenery. The
village of Beauport, with its whitewashed dwellings, situated on the
curving shore of the river St. Charles, and stretching down to the
rocky gorge of Montmorenci, charmed her. The fields on either side
were studded with huts and Indian wigwams. In the short summer
and early autumn the varied colour of the trees lent great brilliancy to
the landscape. The hills, which had shrunk almost out of sight on
one hand, looking like a long purple line against the horizon, drew
suddenly so near the shore that at one point they seemed to rise
almost out of the water.
In the winter the scene was changed, but she loved it still; the
joyous sleigh bells, making music as the sleighing parties flew
through the villages and hamlets lying beneath their snowy shroud,
filled the girl’s heart with gladness, and she realised to the full the joy
of living. And so time had passed quickly with her, and she had been
happy, with the quiet, unreasoning happiness of the young, to whom
the past has brought little sadness, and upon whom the future smiles
with all the enchanting fascination of unbounded hope. And then
Mercèdes was not given to anticipate trouble. Her strong religious
sentiments gave her a calm faith which never deserted her, and next
to God she believed in her father. The struggle might be long, might
be difficult, but assuredly he would come forth a conqueror.
It was with feelings of unmitigated delight that she prepared for
her journey; but her astonishment was great when she became
aware of the proportions the party had assumed. When the hour for
their departure came, no less than twenty sleighs were drawn up
along the length of the street. Crowds gathered to see them start; but
amidst the general laughter and mirth some bitter speeches were
overheard, such as, “The Intendant, M. Bigot, was going to Montreal
to see the Governor and the General. It was a strange necessity that
he must needs have such a goodly company of ladies and
gentlemen to escort him.”
But when M. Bigot appeared with Mercèdes and Madame Péan,
there was a respectful silence. It was the great General’s daughter
he was conducting; of course it must be all right. Thus the effect he
had anticipated was attained; and he took his place beside the ladies
in high spirits, bowing and smiling on the people, addressing one or
two by name, and thus by word and manner propitiating them; so
that he drove off with the good wishes of those who at first had
seemed hostile, and to the friendly cry of “Bon voyage.”
The three days’ journey resembled a royal progress. Couriers had
been sent on in advance, and at each resting-place the most
elaborate preparations had been made for the reception of the
company. Mercèdes was bewildered. She was the object of the most
marked attention; she had never been so surrounded, so courted in
her life. When they reached Montreal, almost the whole population
turned out to see them; but from amidst the crowd murmurs of
discontent were rife at such unnecessary display on the part of the
Government, when the people were oppressed by taxes, and the
most ordinary articles of daily consumption were at famine prices.
Anger, and even threats, were not lacking. Mercèdes was startled by
the cold severity of her father’s manner when he became aware of
her presence.