Macrophage

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Macrophage
Macrophage is derived from hematopoietic stem
cells in bone marrow.
Hematopoietic stem cell (HSC)
Hematopoiesis the formation of blood cells
Myeloid pregenitor
Bone marrow
Granulocyte-monocyte progenitor
monocyte
Blood 1-6 leukocyte
macrophage
Tissue
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Macrophage
Destroy bacteria by phagocytosis.
Activate other immune function.
Phagocytose apoptotic cells
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Macrophage recognizes bacteria by Pattern
Recognition Receptors (PRRs).
PRRs recognize Pathogen-Associated Molecular
Patterns (PAMPs).
LPS (Gram negative) Lipoteichoic acids (LTA)
(Gram positive) Peptidoglycan (Gram
positive) Mannose-containing carbohydrates Flagell
in Unmethylated CpG
Bacteria
Virus
Double-stranded RNA
Fungi Zymosan
GPI-linked proteins
Parasite
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Pathogen Associated Molecular Patterns (PAMPs)
present on microbes, but not on human cells.
Distinguish foreign vs self.
invariant features of microbes.
Can be recognized by a limited number of
receptors.
essential to microbes.
Cannot escape recognition by mutation.
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Toll-like Receptor (TLR)
10 TLRs in human
TLR6/TLR2 peptidoglycan, GPI, zymosan TLR4/TLR4
LPS, LTA TLR5 flagellin TLR9 unmethylated
CpG TLR3 dsRNA
Leucine-rich repeats (LRRs)
membrane
Toll/IL-1 receptor (TIR) domain
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Activation of TLR by PAMP induces the expression
Of many genes involved in immune response.
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Activation of Toll-like Receptors by PAMP (I)
PAMP
PAMP
1
TLR
TLR
MyD88
Interaction of TLR with PAMP activates TLR.
Activated TLR interacts with MyD88.
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Activation of Toll-like Receptors by PAMP (II)
PAMP
PAMP
TLR
TLR
MyD88
MyD88 (adaptor protein)
IRAK
phosphorylatin
Autophosphorylation of IRAK.
MyD88 interacts with IRAK kinase.
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Activation of Toll-like Receptors by PAMP (III)
PAMP
PAMP
TLR
TLR
MyD88
MyD88
ubiquitination
TRAF6
ubiquitination
TRAF6
TAK-1
Activation of TRAF6 induces Autoubiquitination.
Ubiquitinated TRAF6 interacts and Activates
TAK-1.
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Activation of Toll-like Receptors by PAMP (IV)
PAMP
IKK-P
MKK-P
cytoplasm
I-?B
TLR
NF-?B
Nuclear envelope
MyD88
nucleus
NF-?B
AP-1
MKK
TAK-1
IKK
Gene expression
MKK-P
IKK-P
TAK-1 phosphorylates IKK and MKK kinases.
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TLR signaling pathway
PAMP
TLR
Phosphorylation cascade
Activated transcrption factor (NF-?B, AP-1)
Expression of genes involved in immune response
Inflammatory mediators
Antigen-presentation to T cells
Anti-microbial factors
Complement Destroy phagocytosed Bacteria.
Activates other immune functions
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Activated macrophage secrets inflammatory
cytokines
Cytokines are low-molecular weight, secreted
signaling proteins.
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Interleukin-1 (IL-1)
Interleukin-6 (IL-6)
Interleukin-8 (IL-8) (chemokines, CXCL8)
Activated macrophage secrets
Interleukin-12 (IL-12)
Tumor necrosis factor-1 (TNF-?)
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C5a, C3a, C4a increases local blood flow,
vascular permeability, and extravasation of
leukocytes.
Inflammation heat, pain, redness, swelling
Heat and redness (erythema, vasodilation)
skin
Swelling (edema)
leukocytes
C5a
extravasation
C4a
C3a
plasma
Plasma brings more complement and antibodies
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IL-1, TNF-a induces inflammation, similar to
C5a, C3a, C4a.
IL-8 (CXCL8) and C5a acts as chemoattractants To
recruit Neutrophils to the site of infection.
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IL-1, TNF-?, and IL-6 have systematic functions
1. Acute phase response
IL-1, TNF-?, IL-6
Blood circulation
Liver
Acute phase proteins
C-reactive protein
Mannose-binding lectin
Complement activation Facilitate phagocytosis
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IL-1, TNF-?, and IL-6 have systematic functions.
2. Fever
IL-1, TNF-?, IL-6 (endogenous pyrogens)
Hypothalamus
Fat, Muscle (increase energy mobilization)
Increase body temperature
Decrease bacteria replication
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Overproduction of TNF-a and IL-1 can cause
Septic shock.
Endotoxin (LPS) from Gram-negative bacteria (e.g.
E. coli)
Blood circulation
Massive macrophage activation in liver and spleen
Overproduction of TNF-? and IL-1
Dilation of blood vessels and massive leakage of
fluid into tissues throughout the
body. Widespread blood clotting (disseminated
intravascular coagulation).
Septic Shock
Multiple organ failure
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Macrophage (and mast cell) also produces lipid
mediators of inflammation
Membrane phospholipids
Arachidonic acid
Cycloexygenese pathway
Lipoxygenase pathway
Prostaglandin
Leukotriene
Inflammation
Vasadilation, increased blood vessel
permeability, Neutrophil recruitment
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Phagocytosis is mediated by phagocytic
receptors and opsonin receptors.
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Phagocytic Receptors
1. Scavenger Receptors (SRs)
Bind to many microbial ligands (LPS, LTA, etc).
2. Macrophage Mannose Receptor (MR)
Bind to mannose-containing microbial
carbohybrates.
3. ?-Glucan Receptor
Bind to glycan in microbial cell walls.
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Opsonin Receptors
1. Complement receptors (CRs)
Opsonin C3b or its cleavage products (iC3b)
bacteria
Complement receptor (CR CR1, CR3, CR4)
Macrophage
2. Immunoglobulin Fc receptors
Opsonin antibody
bacteria
Immunoglobulin Fc receptor
Macrophage
3. Collectin receptors
Opsonin collectins (oligomeric C-type lectins)
binds to bacterial carbohydrates.
Mannose binding lectin (MBL) binds to mannose
containing carbohybrate.
4. Pentraxin receptors
Opsonin C-reactive proteins (CRP) binds to
phosphocholine in LPS.
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Phagocytosis (I)
Initiated by phagocytic receptors or opsonin
receptors.
PAMP (LPS, peptidoglycan, etc) Opsonin (C3b, Ab,
etc)
Phagocytic receptors (Scavenger receptors,
etc) Opsonin receptors (CRs, Ig Fc receptors, etc)
macrophage
PAMP-Phagocytic Receptor
1. Ligand-receptor interaction
Opsonin-Opsonin Receptors
macrophage
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Phagocytosis (II)
pseudopodia
2. Engagement and clustering of receptors
Actin polymerization
Intracellular signals
macrophage
Local actin polymerization
Pseudopodia formation
phagosome
3. Phagosome formation
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Phagocytosis (III)
lysosome
4. Fusion of phagosome with lysosome to form
Phagolysosome.
phagosome
phagolysosome
Bacteria is degraded within the phagolysosome.
Macrophage activation
Arginine, O2, NAPDH
O2
Nitric oxide synthetase (NOS)
Oxidase
Respiratory burst
.-
NO
O2
Nitric oxide
Superoxide anion
Highly toxic to bacteria
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(No Transcript)
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Phagocytosis (IV)
5. Present part of the degraded peptide to T
cells.
6. Exocytose degraded material
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Recognition of Bacteria by Macrophage
Toll-like Receptors (TLRs)
Scavenger Receptors (SRs)
Phagocytic Receptors
Macrophage mannose receptor (MR)
?-Glucan receptors
Complement Receptors (CRs)
Immunoglobulin Fc Receptors
Opsonin Receptors
Collectin Receptors
Pentraxin Receptors
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Pathogen Associated Molecular Patterns (PAMPs)
LPS (Gram negative) Lipoteichoic acids (LTA)
(Gram positive) Peptidoglycan (Gram
positive) Mannose-containing carbohydrates Flagell
in Unmethylated CpG
Bacteria
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Bacteria
phagocytosis
Macrophage
Lipid mediator
cytokines
Infammation
T cell activation
Acute phase Response
Other immune function
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Opsonization
lysis
phagocytosis
Bacteria
T cell activation
Macrophage
Complement
inflammation
Acute phase reaction
Mast cell
Neutrophils
Other immune functions
C-reactive protein MBL
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Damage to blood vessel also induces inflammation
Blood vessel damage
Activation of Hageman factor
Blood clotting system
Kinin system
Proteolytic cascade
Bradykinin
Fibrin degradation product
Inflammation
Vasodilatin, increased vascular permeability, Pain
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Relevant parts in the Textbook
Macrophage page 38-41. PRRs page
69-72. Cytokines page 276-281. Septic shock
page 291-292. Opsonization page
314. Inflammation page 348-353.