Table Of ContentHandbook of
Experimental Pharmacology
Volume
158
Editor-in-Chief
K. Starke, Freiburg i. Br.
Editorial Board
G. V. R. Born, London
M. Eichelbaum, Stuttgart
D. Ganten, Berlin
H. Herken t, Berlin
F. Hofmann, Miinchen
1. Limbird, Nashville, TN
w. Rosenthal, Berlin
G. Rubanyi, Richmond, CA
Springer-Verlag Berlin Heidelberg GmbH
The Macrophage
as Therapeutic Target
Contributors
J. M. Aerts, R. Boot, E.J. Brown, G.D. Brown, P.C. Calder,
T. J. Chambers, W. J. S. de Villiers, F. Di Virgilio, M. G. Espey,
D. Ferrari, A. Frauenschuh, T. Ganz, C. K. Glass, S. Gordon,
D.R. Greaves, A. Groener, D.N.J. Hart, P.M. Henson,
S.R. Himes, C. Hollak, D.A. Hume, Z. Johnson, G. Kraal,
R.I. Lehrer, J.D. MacMicking, J. Mahoney,
L. Martinez-Pomares, J.D. McKinney, J.L. Miller,
S. M. Moghimi, V. H. Perry, A. Proudfoot, H. Rosen,
D.R. van der Westhuyzen, N. van Rooijen, S. Vuckovic,
J.S. Welch, J.A. Willment, S. Wong, P. Yaqoob
Editor
Siamon Gordon
Springer
Professor
Siamon Gordon
Sir William Dunn School of Pathology
University of Oxford
South Parks Road
Oxford OXl 3RE
United Kingdom
e-mail: [email protected]
With 27 Figures and 9 Tables
ISBN 978-3-642-62919-8 ISBN 978-3-642-55742-2 (eBook)
DOI 10.1007/978-3-642-55742-2
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Preface
During the past decade, the rapid growth of molecular and cellular knowledge
of macrophages (M0), as a specialized host defence and homeostatic system,
has begun to offer attractive targets for therapeutic intervention. M0 playa cen
tral role in a wide range of disease processes, from genetically determined lyso
somal storage diseases, to acute sepsis, chronic inflammation and repair, tissue
injury and cell death. Under- or overactivity of M0 clearance, immune effector
functions and responses to metabolic abnormalities contribute to common dis
orders such as autoimmunity, atherosclerosis, Alzheimer's disease and major in
fections including AIDS and tuberculosis.
The discovery of tumour necrosis factor (TNF)-a and the development of
specific inhibitors that are highly effective clinically in diseases such as rheuma
toid arthritis illustrate the way scientific advances have already been translated
into practice. Development of powerful molecular genetic methods made it pos
sible to clone and express specific cytokines produced by M0 and potent
growth factors acting on M0 and other myeloid cells, such as granulocyte-mac
rophage colony-stimulating factor (GM-CSF), to modulate and boost M0 activi
ties. Specific plasma membrane receptors control cell recruitment, adhesion, en
docytosis and activation of innate and acquired immune functions. Discovery
of the Toll-like receptors has already served as a major spur to uncover signal
ling pathways that might yield future therapeutic targets. Phagocytic uptake of
apoptotic cells and micro-organisms by M0 contribute to host defences, as well
as providing a potential niche for intracellular pathogens.
Whilst the goals of therapeutic intervention based on improved understand
ing of M0 functions and their contribution to pathogenesis may seem self evi
dent, there are considerable difficulties in producing useful new agents. The M0
of the body constitute a distributed cellular system also known as the mononuc
lear phagocyte, or reticulo-endothelial system, with great heterogeneity in cell
differentiation and activation in different organs and disease states. Common
progenitors give rise to tissue M0 which differ considerably in their properties,
e.g. in the nervous system and liver, to dendritic cells, specialized for antigen
presentation to naive T lymphocytes and to osteoclasts, multinucleated cells
able to resorb living bone. Their receptors and versatile biosynthetic and secre
tory responses result in adaptation to very different micro environments. Their
VI Preface
systemic actions help to integrate many physiologic functions and pathologic
processes. It should therefore not come as a surprise if M0 contribute beneficial
as well as deleterious roles to the diseased host. They represent the classic two
edged sword. It is a formidable challenge to aim selective intervention at sub
populations of cells or subsets of their gene products without affecting their vi
tal normal functions or other cells, directly or indirectly. A further difficulty is
our present-day ignorance of basic mechanisms of M0 functions, e.g. in vaccine
development (their role as natural adjuvants or immunosuppressants) and their
complex life history in vivo. Gene ablation and transgenesis have confirmed
some hypotheses and left others open. Cell culture models are useful, but im
perfect, in not mimicking complexity within the host. Classic pharmacologic ap
proaches need to be aligned with newer knowledge of M0 gene expression and
regulation.
The present volume covers a range of subjects and provides opportunities for
a more focused M0-targeted approach. The individual chapters review selected
topics briefly, to place cellular processes and molecular targets in perspective.
These are grouped broadly. Section I deals with general issues of cell differentia
tion, routes of delivery and of M0-specific gene targeting, with particular em
phasis on the living host. Section II deals with selected plasma membrane recep
tors, uptake processes, regulation of cellular responses and different categories
of secretory products. Finally, Sect. III considers specialized cell types, environ
ments and examples of cell-pathogen interactions. Overall, the volume should
provide a broad sample of the state of the art. Useful reviews and references in
the literature are cited within individual chapters.
I would like to acknowledge the excellent assistance of Christine Holt, and of
the editorial staff at Springer-Verlag.
Oxford, Spring 2003 Siamon Gordon
List of Contributors
(their addresses can be found at the beginning of their respective chapters)
Aerts, J.M. 193 Johnson, Z. 269
Boot, R. 193 Kraal, G. 55
Brown, E.J. III
Brown, G.D. 459 Lehrer, R.I. 265
Calder, P.e. 173
MacMicking, J.D. 409
Chambers, T.J. 353
Mahoney, J. 253
Martinez-Po mares, L. 67
de Villiers, W. 147
McKinney, J.D. 409
Di Virgilio, F. 131
Miller, J.L. 385
Moghimi, S.M. 41
Espey, M.G. 227
Perry, V.H. 373
Ferrari, D. 131
Proudfoot, A. 269
Frauenschuh, A. 269
Rosen, H. 3
Ganz, T. 295
Glass, C.K. 209
van der Westhuyzen, D.R. 147
Gordon, S. 89, 385, 459
van Rooijen, N. 55
Greaves, D.R. 89
Vuckovic, S. 337
Groener, A. 193
Hart, D.N.J. 337 Welch, J.S. 209
Henson, P.M. 305 Willment, J.A. 459
Himes, S.R. 11 Wong, S. 67
Hollak, C. 193
Hume, D.A. 11 Yaqoob, P. 173
List of Contents
Part 1. General
The Macrophage as a Validated Pharmaceutical Target. . . . . . . . . . . . . . . . . . .. 3
H. Rosen
Transcription Factors that Regulate Macrophage Development
and Function ..... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 11
D.A. Hume and S.R. Himes
Exploitation of Macrophage Clearance Functions In Vivo . . . . . . . . . . . . . . .. 41
S.M. Moghimi
Reaching the Macrophages: Routes of Delivery. . . . . . . . . . . . . . . . . . . . . . . .. 55
G. Kraal and N. van Rooijen
Antigen Presenting Cells and Vaccine Design . . . . . . . . . . . . . . . . . . . . . . . . .. 67
L. Martinez-Pomares and S. Wong
Macrophage-Specific Gene Targeting In Vivo. . . . . . . . . . . . . . . . . . . . . . . . . .. 89
D.R. Greaves and S. Gordon
Part 2. Macrophage Targets in Inflammation
Integrins of Macrophages and Macrophage-Like Cells 111
E.]. Brown
Macrophage Targets in Inflammation: Purinergic Receptors ............. 131
F. Di Virgilio and D. Ferrari
Macrophage Lipid Uptake and Foam Cell Formation ................... 147
w.J.S. de Villiers and D.R. van der Westhuyzen
Dietary Fatty Acids and Macrophages ............................... 173
P.e. Calder and P. Yaqoob
Macrophages as Therapeutic Targets in Lysosomal Storage Disorders ...... 193
e.
J.M. Aerts, Hollak, R. Boot, and A. Groener
X List of Contents
Nuclear Receptors as Regulators of Macrophage Homeostasis
and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 209
J.S. Welch and c.K. Glass
Relationships between Reactive Oxygen Species and Reactive
Nitrogen Oxide Species Produced by Macrophages. . . . . . . . . . . . . . . . . . . .. 227
M.G. Espey
Proteases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 253
J.A. Mahoney
Targeting the Chemokine System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 269
Z. Johnson, A. Frauenschuh, and A. Proudfoot
Antimicrobial Peptides ..... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 295
T. Ganz and R.I. Lehrer
Macrophage Phospholipid Products. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 305
P.M. Henson
Part 3. Modulation of Specialised Macrophage Activities
Dendritic Cells Versus Macrophages as Antigen-Presenting Cells:
Common and Unique Features. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 337
S. Vuckovic and D.N.]. Hart
The Osteoclast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 353
T.J. Chambers
Macrophages in the Central and Peripheral Nervous System ............. 373
V.H. Perry
Innate Recognition of Viruses by Macrophage and Related Receptors:
Potential Ligand for Antiviral Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 385
s.
J.L. Miller and Gordon
Macrophage Immunity and Mycobacterium Tuberculosis. . . . . . . . . . . . . . .. 409
J.D. MacMicking and J.D. McKinney
Detection and Control of Fungi by Macrophages:
The Role of Carbohydrates and Antifungal Agents . . . . . . . . . . . . . . . . . . . .. 459
s.
J.A. Willment, Gordon, and G.D. Brown
Subject Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 479
Part 1
General
