The Macrophage

Contents......Page 10
Plate Section......Page 678
Contributors......Page 22
Abbreviations......Page 26
1 The biology of the macrophage......Page 30
2 Macrophage origin and kinetics......Page 32
3 Humoral control of monocytopoiesis......Page 35
4 Terminology......Page 37
5.1 Light microscopy......Page 38
5.2 Ultrastructure......Page 39
6 Histochemistry of mononuclear phagocytes......Page 42
7 Composition and metabolism......Page 43
8.1 Fc and complement receptors......Page 45
8.2 Cytokine receptors......Page 48
8.4 Macrophage lipoprotein receptors......Page 51
8.7 Adhesion receptors and migration......Page 52
8.8 Surface antigens......Page 54
9.2 Kupffer cells......Page 58
9.6 Other sites......Page 59
9.7 Relationship to Langerhans cells and other ‘professional’ antigen-presenting cells......Page 60
10.1 Phagocytosis and destruction of microorganisms......Page 61
10.2 Chemotaxis......Page 64
10.3 Antigen processing and presentation......Page 66
10.4 Secretion......Page 67
10.5 Tumor cell control......Page 76
11.1 Role in the acute phase protein response......Page 78
11.2 Role in hematopoiesis......Page 79
11.4 Role in destruction of microorganisms......Page 80
11.7 Role in atherogenesis......Page 81
11.8 Role in autoimmunity......Page 82
11.10 Role in inflammatory bowel disease......Page 83
11.12 Role in the response to environmental particles......Page 84
12 Summary......Page 85
References......Page 86
2 Molecular basis of macrophage activation: from gene expression to phenotypic diversity......Page 102
1.1 Concepts of macrophage activation......Page 103
2.1 Magnitude and physiology......Page 104
2.2 Generation of diversity......Page 106
3.2 Early injury and chemotaxis......Page 107
3.3 Microbial stimuli......Page 108
3.4 Macrophages and acquired immunity......Page 109
4 Intracellular signaling pathways in macrophage activation......Page 110
4.1 Chemoattractant signaling......Page 111
4.3 LPS/TLR signaling......Page 112
4.4 Cytokine family receptor signaling......Page 113
5.1 Transcription......Page 114
5.2 mRNA stability......Page 118
5.3 Translational control......Page 119
References......Page 120
3 Macrophages as antigen-presenting cells: relationship to dendritic cells and use in vaccination studies......Page 132
1 Introduction......Page 133
2 Origins of APCs: from the CD34[sup(+)] hemopoietic multipotent progenitor to the myelodendritic precursors......Page 134
3 Searching for the stimuli required for macrophage/DC differentiation: tuning immune responses......Page 137
4 Inside the dendritic cell system......Page 139
5 Cross-priming: processing and presentation of exogenous antigens mediated by dendritic cells in vivo......Page 143
6 Recognition of death: immunological consequences of phagocytosis of apoptotic cells......Page 146
8.1 Dendritic cell vaccination in animal tumor model systems......Page 149
8.2 Generation of human dendritic cells for cancer immunotherapy......Page 151
10 In vivo targeting of APCs: strategies to improve antigen uptake and cross-presentation in vivo......Page 152
11 Summary......Page 153
References......Page 154
4 Macrophage–virus interactions......Page 167
2.1 Phagocytosis and intracellular killing......Page 169
2.2 Antigen presentation: class I and II MHC pathways......Page 171
2.3 Viral modulation of pro-inflammatory cytokine secretion......Page 172
2.4 Viruses manipulate MP chemotactic machinery......Page 173
2.5 Type I interferons potent antiviral defenses......Page 174
3.2 Viral infection and monocyte-macrophage differentiation......Page 177
3.3 Viruses prime macrophages for subsequent immune activation......Page 181
3.4 Antibody-dependent enhancement (ADE) of viral infection......Page 183
4.1 Theiler’s murine encephalomyelitis virus (TMEV)......Page 184
4.2 Mouse hepatitis virus (JHM-MHV)-induced demyelination......Page 187
5.1 Overview......Page 188
5.2 CMV......Page 189
5.3 Human herpesvirus-8 (HHV-8), and Kaposi’s sarcoma......Page 191
6 Lentivirinae: an overview......Page 194
7 MP infection: a hallmark of ungulate lentivirus infections......Page 196
8 HIV infection of macrophages and disease pathogenesis......Page 197
8.1 HIV-1 tropism......Page 199
8.2 M-tropic virus in the transmission, persistence and progression of HIV-1 infection......Page 200
8.3 MP–HIV interactions......Page 201
8.4 Chemokine receptor polymorphisms and disease progression......Page 202
8.5 HIV-1 infection and pancytopenia......Page 203
8.6 HIV-1-associated nephropathy (HIVAN)......Page 204
8.7 HIV-1 and pulmonary interstitial pneumonitis......Page 205
8.8 HIV-1 neuropathogenesis......Page 206
8.9 HIV-2......Page 207
8.10 SIV......Page 208
8.11 Murine HIV-1 infections......Page 210
9 Summary......Page 211
References......Page 212
5 Macrophages in bacterial infection......Page 239
1.2 The macrophage as a safe haven for intracellular parasites......Page 241
2.1 Phenotypic differences among macrophages......Page 242
2.2 Genetic influences on macrophage antibacterial activities......Page 245
3.1 Macrophage receptors......Page 246
3.2 Opsonization......Page 247
3.3 The process of phagocytosis......Page 248
4 Bacteriocidal mechanisms of macrophages......Page 250
4.1 Oxygen-dependent microbicidal mechanisms......Page 251
4.2 Oxygen-independent microbicidal mechanisms......Page 252
5 Antibacterial secretory activities of macrophages......Page 253
5.2 Cytokine production......Page 254
6.1 Interferon-γ......Page 255
6.3 Complement......Page 257
6.4 Other factors capable of enhancing the microbicidal activity of macrophages......Page 258
7.3 Secondary or acquired abnormalities of macrophage function......Page 259
8.1 Bacterial antiphagocytic strategies......Page 260
8.2 Avoidance of phagocytosis......Page 261
8.3 Inhibition of chemotaxis......Page 262
8.5 Prevention of phagosome–lysosome fusion......Page 263
8.9 Failure to trigger a respiratory burst......Page 264
8.11 Macrophage killing (apoptosis)......Page 265
References......Page 266
6 Macrophages in parasitic infection......Page 282
1.2 Macrophages as effector cells......Page 284
1.3 Macrophages as antigen-presenting cells......Page 285
2.1 Recognition/adhesion systems......Page 287
2.2 Macrophage invasion......Page 290
2.4 Mechanisms of infection control......Page 291
2.6 GM-CSF/TNF-α-mediated lysis of T.cruzi......Page 293
2.7 Deficiency of macrophage-mediated antigen presentation......Page 294
3 Leishmania spp.......Page 295
3.1 Recognition/adhesion systems......Page 297
3.2 Macrophage invasion......Page 298
3.3 Resistance to the phagosome–lysosome fusion......Page 299
3.4 Mechanisms of infection control......Page 300
3.5 Deficiency of macrophage-mediated antigen presentation......Page 303
4 Toxoplasma gondii......Page 305
4.2 Macrophage invasion......Page 306
4.4 Mechanisms of infection control......Page 307
5 Trypanosoma brucei......Page 308
5.2 Nitric oxide-mediated immunosuppression......Page 309
5.4 Deficiency of macrophage-mediated antigen presentation......Page 310
6.2 Antibody-dependent cell-mediated cytotoxicity......Page 311
7 Summary......Page 312
References......Page 313
7 Macrophages and Alzheimer’s disease......Page 334
1 Introduction......Page 335
2.1 APP, Aβ and neuritic plaques formation......Page 336
2.3 ApoE and neuronal maintenance......Page 337
3.2 MP recruitment and activation......Page 340
4.1 Aβ primes MP......Page 341
4.2 Factors involved in MP activation......Page 342
4.3 Signal transduction pathways......Page 344
5 MP function and its relevance to AD pathogenesis......Page 346
5.2 Phagocytosis......Page 347
5.3 Secretory activities......Page 348
6.1 Neuronal signaling......Page 351
6.2 Oxidative stress......Page 354
6.3 Excitotoxicity......Page 355
6.4 Apoptosis and necrosis......Page 356
7 Laboratory and animal models for AD......Page 357
8 Summary......Page 360
References......Page 361
8 Macrophages in autoimmunity and primary immunodeficiency......Page 385
2 Role of macrophages in autoimmune disease......Page 386
2.1 Type 1 diabetes......Page 387
2.2 Multiple sclerosis and experimental autoimmune encephalomyelitis......Page 393
2.3 Rheumatic disease......Page 396
3 Role of macrophages in primary immunodeficiency disease......Page 400
4 Summary......Page 403
References......Page 404
9 Macrophages in rheumatoid arthritis......Page 420
1 Introduction......Page 421
2 Bone marrow and blood macrophage precursors in RA......Page 422
3.1 Synovial membrane histopathology......Page 423
3.2 Macrophage infiltration......Page 426
3.3 Macrophage chemoattractants in RA......Page 429
3.4 Macrophage activation and regulation......Page 430
3.6 Macrophage apoptosis in the RA synovium......Page 433
3.7 Macrophage functions in the RA synovium......Page 434
4.2 Glucocorticoid therapy......Page 439
4.3 Biological therapies......Page 440
5.1 Rheumatoid nodules......Page 441
References......Page 442
10 Macrophages in wound healing......Page 463
1 Introduction......Page 464
2 Evidence for the importance of macrophages in wound repair......Page 465
3 Monocyte recruitment into wounds......Page 466
4 Activation of macrophages in wounds......Page 468
5 The wound macrophage phenotype......Page 469
6.2 Modulation of angiogenesis by wound macrophages......Page 470
7.1 Addition of macrophages directly to the wound......Page 473
7.2 Addition of macrophage-stimulating agents or products directly to the wound......Page 474
8.1 Fetal wounds......Page 475
8.2 Aging......Page 476
8.5 Trauma, hemorrhage and sepsis......Page 477
References......Page 478
11 Macrophages in tumor biology......Page 486
1 Introduction......Page 487
2 Macrophage differentiation in a tumor spheroid—a model for TAM ontogeny......Page 488
3 Chemotaxis—regulation of monocyte infiltration into the tumor site......Page 490
4 The cytokine network within the tumor microenvironment—regulation of tumor growth......Page 491
5 Tumor-associated macrophages and their pivotal role in angiogenesis......Page 492
5.1 The support of angiogenesis by TAMs......Page 493
5.2 The inhibition of angiogenesis by TAMs......Page 494
6.1 Recognition of tumor cells by macrophages......Page 495
6.2 Mechanisms of cytotoxicity by macrophages......Page 496
6.4 Inhibition of tumor cytotoxicity......Page 498
7 Regulation of a specific immune response by TAMs......Page 499
8.1 Adoptive immunotherapy with human macrophage cells......Page 500
8.2 Use of monocyte-derived cells to present antigen......Page 502
9 Summary......Page 503
12 Macrophages in cardiovascular disease......Page 519
2.1 The normal artery......Page 520
2.2 The atherosclerotic artery......Page 521
2.3 The role of macrophages in atherosclerosis......Page 523
3.1 Morphology of macrophage foam cells in plaque......Page 525
3.2 Protein expression by atherosclerotic lesion macrophages......Page 526
3.3 Lipid composition of foam cell macrophages and cell-rich plaques......Page 527
4.1 Sources of cholesterol......Page 529
5.1 The likely importance of LDL oxidation in atherosclerosis......Page 532
5.2 Macrophage-mediated oxidation of LDL......Page 533
5.3 Inhibitory actions of macrophages in LDL oxidation......Page 535
5.4 Likely role of macrophages in LDL oxidation in vivo......Page 536
6.1 Macrophage-derived inflammatory mediators......Page 537
6.3 PPAR-α and PPAR-γ......Page 538
7.1 Routes for cholesterol disposal in foam cells......Page 539
7.2 Properties of cholesterol acceptors for macrophages......Page 540
7.3 Mechanisms for cholesterol export from macrophages......Page 541
7.4 Plasma membrane determinants of cholesterol export......Page 543
References......Page 545
13 Macrophages in the central nervous system......Page 552
1 Introduction......Page 553
2.1 Origin......Page 554
2.2 Morphology, phenotype and distribution......Page 555
2.3 Kinetics......Page 559
2.4 Functions......Page 561
3.1 Choroid plexus......Page 562
3.3 Perivascular macrophages......Page 563
4 Response of microglia to injury......Page 564
References......Page 570
14 Macrophages in reproductive biology......Page 577
2.1 Macrophages in folliculogenesis and steroidogenesis......Page 578
2.2 Macrophages in follicular atresia and regression of the corpus luteum......Page 581
3.1 Cytology and classification......Page 583
3.2 Endometriosis and peritoneal macrophages......Page 584
4 Macrophages in Fallopian tubes......Page 586
4.1 Macrophages in the oviductal lumen......Page 587
4.2 Macrophages in the endosalpingeal stroma and smooth muscle layer......Page 588
5 Endometrial/decidual macrophages......Page 589
5.1 Decidual macrophages and immunoregulation......Page 590
6 Villous macrophages (Hofbauer cells)......Page 592
6.2 Origin......Page 593
6.3 Function......Page 594
7  Summary......Page 598
References......Page 599
15 Macrophages in gene therapy: cellular targets and gene delivery vehicles......Page 606
2 Methods used for gene transfer to macrophages......Page 607
2.1 Viral methods......Page 608
2.2 Non-viral methods......Page 610
3.1 Malignant tumors......Page 613
3.2 Arthritic joints......Page 614
3.5 Atherosclerosis......Page 615
3.8 Liver disease......Page 616
4.1 Malignant tumors......Page 617
4.4 Use of macrophages to synthesize/deliver therapeutic viruses......Page 618
4.5 Homing of macrophages to diseased sites after ex vivo manipulation......Page 619
5 Summary......Page 621
References......Page 622
16 Use of mathematical models to simulate and predict macrophage activity in diseased tissues......Page 628
1 Introduction......Page 629
2 The role of mathematical modeling in Medicine......Page 630
3 Macrophage dynamics in tumors......Page 631
3.1 Antitumor effects and imunotherapy......Page 632
3.2 Macrophage infiltration into solid tumors......Page 638
4.1 Macrophage–HIV interactions......Page 649
4.2 HIV–T cell interactions......Page 651
5 Topics ripe for mathematical modeling......Page 652
5.3 Arthritis......Page 653
6 Discussion......Page 654
References......Page 657
Appendix: some mathematical details......Page 661
A......Page 664
B......Page 665
C......Page 666
F......Page 667
H......Page 668
L......Page 669
M......Page 670
P......Page 672
R......Page 673
T......Page 674
V......Page 675
Z......Page 676