Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
SIGNALING IN THE INNATE IMMUNE SYSTEM PRR SIGNALING
Tímea Berki and Ferenc BoldizsárSignal transduction
Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
TÁMOP-4.1.2-08/1/A-2009-0011
PAMPsThe microbe-specific molecules that are recognized by a given Pattern Recognition Receptor (PRR) are called Pathogen-Associated Molecular Patterns (PAMPs):• Bacterial carbohydrates (e.g. lipopolysaccharide or
LPS mannose)• Nucleic acids (e.g. bacterial or viral DNA or RNA),• Bacterial peptides (flagellin, ax21)• Peptidoglycans• Lipotechoic acids (from Gram positive bacteria)• N-formylmethionine, lipoproteins and fungal glucans• Endogenous stress signals are called DAMPs (danger-
associated molecular patterns) and include uric acid
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Endocytic Pattern-Recognition Receptors • Mannose receptors of phagocytes are C-type lectins
bind mannose-rich glycans with mannose or fructose as the terminal sugar that are commonly found in microbial glycoproteins and glycolipids.
• Scavenger receptors bind to bacterial cell wall components such as LPS, peptidoglyan and teichoic acids and stressed, infected, or injured cells. Scavenger receptors include CD36, CD68, and SRB-1.
• Opsonin receptors bind microbes to phagocytes.• N-formyl Met receptors bind N-formyl methionine,
the first amino acid produced in bacterial proteins.
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Signaling Pattern-Recognition Receptors • Cell surface /Extracellular TLRs: TLR1, TLR2, TLR4,
TLR5, and TLR6 • Signaling PRRs found in the membranes of the
endosomes /phagolysosomes: TLR3, TLR7, TLR8, and TLR9
• Signaling PRRs found in the cytoplasm: NOD1, and 2 (CARD-containing proteins)
TÁMOP-4.1.2-08/1/A-2009-0011Signaling PRRs found in the membranes of the endosomes/phagolysosomes• TLR-3, 7 and 8 bind single- or double-stranded viral
RNA • TLR-9 binds unmethylated cytosine-guanine
dinucleotide sequences (CpG DNA)• Most of the TLRs that bind to viral components
trigger the synthesis of interferons that block viral replication within infected host cells
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Toll-like receptors (TLRs)• They are single, membrane-spanning, non-catalytic
receptors that recognize structurally conserved molecules derived from microbes
• They receive their name from their similarity to the protein coded by the Toll gene identified in Drosophila in 1985 by Christiane Nüsslein-Volhard. The gene in question, when mutated, makes the Drosophila flies look unusual, or 'weird'. The researchers were so surprised that they spontaneously shouted out in German "Das ist ja toll!" which translates as "That´s wild!"
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Toll-like receptors-pattern recognition
Peptidoglycan (G+)Lipoprotein
Lipoarabinomannan (Mycobacteria)LPS (Leptospira)
LPS (Porphyromonas)GPI (Trypanosoma cruzi)
Yymosan (Yeast) dsRNA FlagellinUnmethylated
CpG DNA
TLR2TLR1 TLR5TLR3 TLR9TLR6TLR2
Lipoteichoic acids (G+)RVS F protein
LPS (G-)
TLR4CD14 MD-2
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The horseshoe structure of TLR3
TLR3 structure showing attached sugars (spheres) and internal structures (wires, arrows, and helixes)
GNU Free Documentation License
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MyD88 TRIF
TLR3TLR7
TLR2
PKA TAK1 PKR
p38 JNK
MKKs lkBp50
p65
MyD88
LPS
TLR4
MyD88
MD2LBP
dsRNA
TBK1IKKe
MDA-5RIG-1
IPS1
TLR9JAK2
mTOR
PI3K
CD14
TLR types
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TLR signalingInduces potent innate immune responses that signal through adaptor molecules:• Myeloid differentiation factor 88 (MyD88)• Toll/interleukin (IL)-1 receptor (TIR) domain
containing adaptor protein (TIRAP)• TIR domain containing adaptor inducing interferon
(IFN) (TRIF)• TRIF-related adaptor molecule (TRAM) to activate
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TLR signaling
TAB2
TLR4
MD2
LBP
TRAF6TRIF TBK1
IRAK1
IRAK4RIP
PI3K
Akt ERK1/2
MEK1/2
p38
MKK3/6
MAP3Ks
JNK
MKK4/7
AP-1
TAK1TRAP TRAM
IRF3
IRF3
IKKs
IkB
NFkB
NFkB
MyD88
IKKe
CD14
Nucleus
Cytoplasm
Plasma membrane
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TLR related transcription factors• Nuclear factor (NFkB) • Activator protein 1 (AP-1)• Interferon regulatory factors (IRFs) to induce antibacterial and antiviral responses
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Toll-like receptor inhibitors
MyD88 TRIF
TLR3TLR7
TLR2
PKA
SP600125SB203580
U0126
PD98059
H-89
Celastrol
Bay11-7082
2-Aminopurine
PepinhTRIFPepinhMYD
TAK1 PKR
p38 JNK
MKKs lkBp50
p65
MyD88
Polymixin B
CLI095
LPS
TLR4
MyD88
MD2LBP
dsRNA
BX795TBK1IKKe
MDA-5RIG-1
IPS1
TLR9
Chloroquine
JAK2
Wortmannin
Rapamycin
LY294002
AG490
mTOR
PI3K
CD14
OxPAPC
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Inflammatory cytokines • Interleukin-1 (IL-1) • Tumor necrosis factor-alpha (TNF-alpha)• Interleukin-12 (IL-12)• Chemokines such as interleukin-8 (IL-8), MCP-1, and
RANTES
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Opsonins• Acute phase proteins like mannose-binding lectin
(MBL), C-reactive protein (CRP)• C3b C4b complement factors• Surfactant proteins in the alveoli SP-A and SP-D • The antibody molecule IgG can function as an
opsonin
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Secreted PRRs• Complement receptors• Collectins • Pentraxin proteins such as serum amyloid and C-reactive
protein • Lipid transferases • Peptidoglycan recognition proteins (PGRs)• LRR, XA21D• One very important collectin is mannan-binding lectin
(MBL), a major PRR of the innate immune system that binds to a wide range of bacteria, viruses, fungi and protozoa. MBL predominantly recognizes certain sugar groups on the surface of microorganisms but also binds phospholipids, nucleic acids and non-glycosylated proteins.
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Complement receptors
CR1
CR2
CR3
CR4
CR2
CR3
CR4CRIg
SIGNR1
C3aR
C5aR
C1qR
CD46
CD55
CD59
C3aR
C5aR
C1qRP
Antigen recognitionand uptake
Pathogen recognitionand/or clearance
Modulation of TH1/TH2commitment
Antigen recognitionand uptake
Cytokine modulationand APC maturation
CR1 Inhibits cell proliferationExpressed on <15%
UnknownExpressed on <5%
Cytokine modulationExpressed on activation
T-cell traffickingUpregulated by activation
Cytokine modulation
CD46
CD55
CD59
Activation/proliferation, cytokine modulation andlineage commitment
APC T cell
TÁMOP-4.1.2-08/1/A-2009-0011Overview of complement receptor (CR) and Toll-like receptor signaling
TLRCR3 C5aR
C3b
gC1qR
C1q
CD46
iC3b
C5
Bacteria Viruses
Erk1/2 PI3KTLR4-induced IL-12 inhibited
by posttranscriptional mechanism
Nucleus
IL-12p35IL-12/IL-23p40IL-23p19IL-27p28
IRF-1,IRF-8
C5a