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Leukocyte Endothelial Interactions. Judith Berliner, Professor Departments of Biology and Medicine, UCLA. Leukocyte/endothelial interactions are a major event in the inflammatory process. Inflammation is a reaction to injury or infection. Inflammation and repair.

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slide1

Leukocyte Endothelial Interactions

Judith Berliner, Professor

Departments of Biology and Medicine, UCLA

inflammation and repair
Inflammation and repair

1. Tissue exposed to infection, toxin, trauma

2. Damaged cells rapidly produce endothelial activators

3. In some cases, venules transiently increase permeability in response to activators

4. Plasma proteins enter the tissue and react with bacteria and toxins producing more activators

inflammation and repair1
Inflammation and repair

5. Activated endothelial cells upregulate leukocyte adhesion molecules and chemotactic factors

6. Leukocytes bind to and enter the vessel wall

7. Acute: Neutrophils kill and macrophages engulf bacteria and toxins. Resolution

8. Chronic: macrophages are unable to remove source of injury. Granuloma

inflammation and repair2
Inflammation and repair

9. Cytokines and growth factors produced by injured cells stimulate replication of nearby cells. Fibrosis

10. Angiogenesis occurs in response to additional growth factors.

11. Tissue architecture is restored

activators of the endothelium to induce leukocyte ec interactions
Activators of the endothelium to induce leukocyte EC interactions

1. Bacteria

2. Toxins

3. Autoantibodies

4. Oxidized Phospholipids

5. Advanced glycosylation end products

6. Cytokines: IL-1, TNF

lipopolysaccharide

OM

peptidoglycan

IM

LIPOPOLYSACCHARIDE

lipid A

initiation of inflammation
INITIATION OF INFLAMMATION
  • RECOGNITION OF MICROBES BASED ON CONSERVED PATTERNS
    • LIPOPOLYSACCHARIDE (Gm-)
    • LIPOPEPTIDES (BACTERIA)
    • PEPTIDOGLYCAN (MOST BACTERIA)
    • FLAGELLA (MANY BACTERIA)
    • UNMETHYLATED CpG IN DNA
    • DOUBLE-STRANDED RNA (VIRAL)
toll like receptors
TOLL-LIKE RECEPTORS

single stranded

RNA

TLR8

Akira et al. Nature Rev Immun 2004

tlr specificity 2004
TLR1

Triacyl lipopeptides (Bacteria, mycobacteria)

Soluble factors (Neisseria meningitidis)

TLR2

Lipoprotein/lipopeptides (Various pathogens)

Peptidoglycan (Gram-positive bacteria)

Lipoteichoic acid (Gram-positive bacteria)

Lipoarabinomannan (Mycobacteria)

Glycolipids (Treponema maltophilum)

Porins (Neisseria)

Zymosan (Fungi)

TLR3

Double-stranded RNA (Viruses)

TLR4

Lipopolysaccharide (Gram-negative bacteria)

Taxol (Plants)

Fusion protein (Respiratory syncytial virus)

Envelope protein (Mouse mammary-tumor virus)

TLR5

Flagellin (Bacteria)

TLR6

Diacyl lipopeptides (Mycoplasma)

Lipoteichoic acid (Gram-positive bacteria)

Zymosan (Fungi)

TLR7

Imidazoquinoline (Synthetic)

Single-stranded RNA (Viruses)

TLR8

Imidazoquinoline (Synthetic)

Single-stranded RNA (Viruses)

TLR9

CpG-containing DNA (Bacteria and viruses)

TLR SPECIFICITY -2004
regulation of endothelial cell gene expression by tlr4 activation
Regulation of Endothelial Cell gene expression by TLR4 activation

1. P-Selectin and E-Selectin

2. MCP-1, IL-8, Platelet activating factor

3. ICAM-1, VCAM-1

  • Many cytokines

NFkB important in this activation

*5. Macrophages activation of TLR4 increases TNF and IL-1 that activate endothelial cells.

activators of the endothelium to induce leukocyte ec interactions1
Activators of the endothelium to induce leukocyte EC interactions

1. Bacteria

2. Toxins – Hydrogen Peroxide

3. Autoantibodies – Rheumatoid Arthritis

4. Oxidized Phospholipids - Atherosclerosis

5. Advanced glycosylation end products – Diabetes

6. Cytokines – TNF, IL-1

activators of the endothelium to induce leukocyte ec interactions2
Activators of the endothelium to induce leukocyte EC interactions

1. Bacteria

2. Toxins – Hydrogen Peroxide,Silica

3. Autoantibodies – FC receptor

4. Oxidized Phospholipids – CD 36

5. Advanced glycosylation end products – RAGE

6. Cytokines – TNF, IL1 - TNF and IL-1 receptors

rolling molecules
Rolling Molecules

Selectins and their ligands

Integrins and their ligands

selectins
SELECTINS
  • SELECTINS--LEUKOCYTE AND ENDOTHELIAL PROTEINS THAT MEDIATE CELL ADHESION TO CARBOHYDRATES
    • P-SELECTIN, ON ENDOTHELIA AND PLATELETS, UPON ACTIVATION RAPIDLY TRANSFERRED TO CELL MEMBRANE
    • L-SELECTIN, ON LEUKOCYTES, EXPRESSED CONSTITUTIVELY, BECOME MORE ADHESIVE IN STIMULATED LEUKOCYTES BUT SHED WITHIN MINUTES OF ACTIVATION
    • E-SELECTIN, ON ENDOTHELIA, INDUCED WITHIN HOURS BY INFLAMMATORY MEDIATORS
slide25

Regulation of Chemokines Levels and Activity

Attachment to GAGs- localizes activity

Cleavage by metalloproteinases

Formation of homo and heterodimers

m-RNA Degradation

Protein Degradation

effects of chemotactic factors on leukocyte activation
Effects of chemotactic factors on leukocyte activation

1. Chemotactic factors bind to GPCR

2. This leads to integrin activation

3. Integrin activation causes arrest followed by spreading and migration

structure and function of integrins
Structure and Function of Integrins

Integrins are heterodimers (formed by  and chains) receptors located on the surface of cells. The  subunit contains the RGD-binding site. Calcium is required for integrin binding activities. The cytoplasmic end is associated with cytoskeletal proteins.

FAK

leukocyte transmigration
Leukocyte transmigration

1. Leukocyte migrates to EC junction

2. Leukocyte activates transient endothelial retraction

3. Leukocyte extends pseudopod into junctions

4. Leukocyte binds to homotypic molecules on EC and moves across monolayer

5. Leukocyte produces proteases and migrates across basement membrane in response to chemotactic factors

phagocytosis and killing
PHAGOCYTOSIS AND KILLING

PHAGOCYTIC KILLING:

-BY GRANULE CONTENTS

-BY REACTIVE OXYGEN PRODUCTS

EXTRACELLULAR

KILLING

neutrophils arsenal
NEUTROPHILS: ARSENAL
  • REACTIVE OXYGEN PRODUCTS
  • NUTRIENT-BINDING PROTEINS
  • PROTEASES
  • LYSOZYME
  • MICROBICIDAL PEPTIDES
    • DEFENSINS
    • CATHELICIDINS
slide45

Diseases Associated with Inflammation and Angiogenesis

Cancer

Rheumatoid Arthritis

Atherosclerosis

Diabetic Retinopathy

slide47

Sources of Inflammatory Molecules in Tumors

Extrinsic Pathway – Inflammation due to infection of cell injury

Intrinsic Pathway – Oncogene Activation

Both lead to increased macrophages in tumors

slide48

Macrophage Phenotypes and Cancer

M1M2

Markers: IL12, TNF, IL6,ROS IL-4, IL-10, TGFB

Functions: Attract lymphocytes Decrease lymphocyte entry

Activate lymphocytes Decrease in lymphocyte activation

Kill tumor cells Increase in angiogenesis

Increase tumor cell growth