Inflammation
沈
弘
德
台北榮總教研部
本章大綱
• Leukocyte migration
• Cell-adhesion molecules
• Mediators of inflammation
• The inflammatory process
• Anti-inflammatory agents
Lymphocyte recirculation routes
* Extravasation
* Cell-adhesion molecules (CAMs)
(endothelial cells & leukocytes)
- selectins
- mucins
- integrins
- ICAMS
* Receptors bind to CAMs
General structures of the four families of cell-adhesion molecules
* Glycosylated proteins
* Interact with sialylated
carbohydrate moieties of
mucin-like molecules.
* Responsible for the initial
stickiness of leukocytes
to vascular endothelium.
* Heterodimeric proteins
* Expressed by leukocytes
* Facilitate adherence
(LAD disease)
* Contain Ig/mucin-like
domains
* Expressed on endothelial
cells
* Bind to integrin/selectin
molecules
Steps in neutrophil extravasation
Inflammatory response
↓ cytokines, inflammatory mediators
Vascular endothelium activated
Increased expression of CAMs
The neutrophil tumbles
end-over-end along
the endothelium.
Neutrophil activation
by chemoattractant
stimulus: chemokines,
PAF, C5a, C3a, C5b67,
bacterial peptides
Receptor activationinduced conformational change in the
integrin molecules →
increased affinity &
adhesion
The neutrophil
migrates through
the vessel wall into
the tissues.
Cell-adhesion molecules and chemokines involved in the
first three steps of neutrophil extravasation
rolling
activation
adhesion
Schematic cross-sectional diagram of a lymph node
postcapillary venule with high endothelium (HEV)
As many as 1.4 x 104
lymphocytes extravasate
every second through HEVs
into a single lymph node.
Each of the secondary lymphoid
organs, with the exception of
the spleen, contains HEVs.
Lymphocytes attached to the surface of a high-endothelial venule
Naïve T cell tend to home to secondary lymphoid
tissues through their HEV regions
Activation of a naïve cell
occurs within secondary
lymphoid tissue.
(Homing receptor)
(Mucin-like CAM)
Steps in extravasation of a naïve T cell through a
high endothelial venule into a lymph node
• Activation of
integrin molecules
(a homing
receptor)
• Lymphocyte-specific
chemoattractants
• G-protein-coupled
receptors
Mediators of inflammation
• Chemokines and other mediators released by tissue
mast cells, blood platelets, leukocytes and lymphocytes.
• Mediator-producing systems in plasma:
- the kinin system
- the clotting system
- the fibrinolytic system
- the complement system
• Some lipids act as inflammatory mediators
• Some cytokines are important inflammatory mediators
Chemokines
- key mediators of inflammation
Chemokines
• A superfamily of small polypeptides (90-130 aa residues)
• Major regulators of leukocyte traffic
(adhesion, chemotaxis, activation)
• Involved in inflammation, homeostatic/developmental
processes, angiogenesis, wound healing
• Induced in response to infection
→ Assembly of leukocytes at sites of infection
• > 50 chemokines, possess 4 conserved cysteine residues
(C-C subgroup, C-X-C subgroup)
• > 15 chemokine receptors (CC receptors, CXC receptors)
• The interaction between chemokines and their receptors
is of high affinity (Ka > 109) and high specificity.
Chemokines signal through receptors coupled with
heterotrimeric large G proteins
• Changes in shape of leukocytes
• Activation of integrins
• Generation of oxygen radicals
• Release of granular contents and proteases
Patterns of expression of some principal chemokine
receptors on different classes of human leukocytes
*TH1 cells: CCR1, -3, -5
TH2 cells: CCR3, -4
*Chemokine-receptor profiles mediate leukocyte activity.
Plasma enzymes act as
inflammatory mediators
Tissue damage induces formation of plasma enzyme mediators by
the kinin system, the clotting system, and the fibrinolytic system
(a plasma clotting factor)
fibrinogen
C5
C5a +C5b
mast cell degranulation
& mediators release
The complement system
• anaphylatoxins (C3a, C4a, C5a)
→ mast cell degranulation & mediators (histamine…) release
→ increase vascular permeability
induce smooth-muscle contraction
• C3a, C5a and C5b67
→ adhesion, extravasation and migration
of monocytes and neutrophils
• Influxes of fluid that carry antibody and
phagocytic cells to the site of antigen entry.
Lipids act as
inflammatory mediators
The breakdown of membrane phospholipids generates important mediators of
inflammation, including thromboxane, prostaglandins, leukotrienes, PAF
(macrophages, monocytes,
neutrophils and mast cells)
(plateletactivating
factor)
Cytokines act as
inflammatory mediators
• IL-1, IL-6, TNF-a, IL-12, and many chemokines
exhibit redundant and pleiotropic effects.
• IL-1, IL-6, TNF-a:
• IFN-g: attracting & activating macrophages
• IL-12: inducing the differentiation of
the proinflammatory TH1 subset
IFN-g: contributing to chronic inflammation by attracting and activating macrophages.
IL-12: induces the differentiation of the proinflammatory TH1 subsets.
The inflammatory process
The inflammatory process
• acute inflammatory response (neutrophils, 1010/day)
- localized inflammatory response
(redness, swelling, heat, pain)
- systemic acute-phase response
• chronic inflammation (antigen persists) (macrophages)
- IFN-g
- TNF-a
- fibrosis (scar formation)
- granuloma formation
• chronic inflammatory diseases
The major local manifestations of acute inflammation
Leukocyte emigration and
accumulation in the site of injury.
extravasation of
plasma fluid and
proteins
vascular dilation (erythema & warmth)
A localized acute inflammatory response
• redness & heat
vasodilation - an increase in vascular diameter
an increase in the volume of blood in the area
& a reduction in the flow of blood
• swelling
an increase in vascular permeability
leakage of fluid from the blood vessels
an accumulation of fluid in the tissue (edema)
extravasation of leukocytes
• activation of the kinin, clotting, fibrinolytic
and complement (C53a, C4a, C5a) systems
Macrophages:
- arrive about 5-6 hours after an inflammatory response begins
- exhibit increased phagocytosis
- exhibit increased release of mediators, cytokines and
lytic enzymes that contribute to the inflammatory response
(IL-1, IL-6, TNF-a)
Overview of the cells and mediators involved in a local
acute inflammatory response
(tissue damage)
*Tissue repair: TGF-b, proliferation of fibroblasts, deposition of extracellular matrix
The inflammatory process
• acute inflammatory response (neutrophils, 1010 x 10/day)
- localized inflammatory response
(redness, swelling, heat, pain)
- systemic acute-phase response
• chronic inflammation (antigen persists) (macrophages)
- IFN-g
- TNF-a
- fibrosis (scar formation)
- granuloma formation
• chronic inflammatory diseases
Overview of the organs and mediators involved in a
systemic acute-phase response
(inhibits the growth
of pathogens)
The acute-phase response produces molecules that bind
pathogens but not host cells.
On vertebrate cells, these mannose
residues are covered by other sugar groups,
especially by sialic acid while avoiding
complement activation on host cell
surfaces.
C/EBP is expressed constitutively in liver hepatocytes and
promotes transcription of albumin and transthyretin genes
During an inflammatory response
Comparison of the structure and function of C/EBP and NF-IL6
*Both transcription factors are dimeric proteins containing a leucine-zipper domain and
a basic DNA-binding domain.
*Both proteins bind to the same nucleotide sequence in the promoter or enhancer of
the genes encoding various liver proteins.
Outcome of acute inflammation
The inflammatory process
• acute inflammatory response (neutrophils, 1010 x 10/day)
- localized inflammatory response
(redness, swelling, heat, pain)
- systemic acute-phase response
• chronic inflammation (antigen persists) (macrophages)
- IFN-g
- TNF-a
- fibrosis (scar formation)
- granuloma formation
• chronic inflammatory diseases
A prolonged DTH response can lead to formation of a granuloma
Lytic enzymes released from
activated macrophages in a
granuloma can cause extensive
tissue damage.
Roles of IFN-g and TNF-a in
chronic inflammation
Summary of pleiotropic activity of interferon gamma (IFN-g)
*Activated macrophages secrete TNF-a.
TNF-a acts synergistically with IFN-g to initiate a chronic inflammatory response.
Biological activities of TNF-a
(endotoxin)
*Endotoxin induces macrophages to produce TNF-a, which then
acts to destroy the tumor.
Transgenic mouse (top) bearing a TNF-α transgene
becomes anorectic and severely wasted
The inflammatory process
• acute inflammatory response (neutrophils, 1010 x 10/day)
- localized inflammatory response
(redness, swelling, heat, pain)
- systemic acute-phase response
• chronic inflammation (antigen persists) (macrophages)
- IFN-g
- TNF-a
- fibrosis (scar formation)
- granuloma formation
• chronic inflammatory diseases
*HEV-like regions: sites of lymphocyte extravasation into the inflamed tissue.
*IFN-g and TNF-a may play a role in the induction of HEV-like regions along the vasculature.
Leukocyte-adhesion deficiency (LAD) in humans and cattle
- A rare autosomal recessive disease
- omphalitis (a swelling and reddening around
the stalk of the umbilical cord)
- Patients suffer recurrent and often chronic bacterial infections
(inability of their leukocytes to undergo adhesion-dependent
migration into sites of inflammation)
- An absence of CD18 (an essential component of
a number of integrins)
Anti-inflammatory agents
Anti-inflammatory agents
• Antibody therapies reduce leukocyte extravasation
- to block the activity of various adhesion molecules
(anti-ICAM-1 + anti-LFA-1)
• Corticosteroids are powerful anti-inflammatory drugs
- reduction in the numbers and activity of immune-system cells
- prevents NF-kB activation
- reduces the phagocytic and killing ability of macrophages
and neutrophils
- reduces chemotaxis
- reduces expression of class II MHC molecules and
IL-1 production by macrophages
- reduces the release of lysosomal enzymes
• NSAIDs combat pain and inflammation
Corticosteroids
• lipophilic
• can cross the plasma membrane
• form receptor-hormone complex in the cytosol
• transported to the nucleus
• bind to specific regulatory DNA sequences
• induce increased transcription of the NF-kB inhibitor (I-kB)
• binding of I-kB to NF-kB in the cytosol
• prevent the translocation of NF-kB into the nucleus
• prevent NF-kB activation of a number of genes
(genes involved in T cell activation and cytokine production)
Inhibition of cyclooxygenase 1 and 2 by NSAIDs
*Cox-2-specific NSAIDs – inhibit inflammation and do not cause damage to the GI tract
Inflammation
• redness
• swelling
• heat
• pain
• immune-system cells
• mediators
Sequence of leukocyte events in inflammation
(shown here for neutrophils)