Innate Immunity: Toll Like Receptors Flashcards
What is PRR?
Pathogen recognition receptors
What are PAMPs?
Pathogen-associated molecular patterns
Give an example of PRR?
Toll Like Receptor 4
TLR4
Give an example of PAMP?
LPS from gram-negative bacteria
What is DAMPs?
Danger-associated molecular patterns
From host cells
Example of DAMPs?
Amyloid Beta
Amyloid plaques formed in Alzheimer’s disease affect the brain.
Pathogen recognition receptors recognize…
PAMPS
Induce immune response
What does the recognition of PAMPS initiate?
Chemokines/ cytokines to recruit cells
Phagocytosis of pathogens
Lysis of pathogens by antimicrobial peptides
What are 3 individual immune responses of interferons and cytokines?
- Signal neighboring cells to put up barriers
- Signal infected cells to die
- Recruitment of white blood cells (neutrophil +monocytes) to stimulate long-lasting immunity
Describe TLR4?
Expressed surface of phagocyte
Inactive- not bound to ligand
Bind to ligand- brings 2 changes together which allows activation of downstream signaling cascade
Results- transcription of inflammatory mediators/TRIF pathway
How many pathways does the binding of TLR4 and LPS induce?
2
1. MyD88 dependent pathway -> Nf-kB
2. TRIF dependent pathway -> IRFs
Explain TLR4 intracellular signaling cascade leading to NF-Kb?
LPS binds to TLR4
Adaptor molecule -MyD88
NF-Kb
What is NK-Kb?
Transcription factor
Gene expression of wide range of inflammatory genes
What inflammatory genes are expressed by the transcription factor NF-Kb?
Cytokines - TNF, IL-1, IL-6
Chemokines (CCL2, CXCL8)
Endothelial adhesion molecules (E-selectin)
Costimulatory molecules (CD80, CD86) - adaptive immune response
What is the significance of endothelial adhesion molecules (E-selectin)?
Cells that line the blood vessel walls
Allow recruitment of neutrophil and monocyte to site of infection.
Explain TLR4 intracellular signaling cascade leading to IRFs.
TLR4 + LPS
TRIF
IRFs
-> expression of type I interferon (IFN a/b) genes -> secretion of type I interferon
What are chemokines?
Chemical signals
Attract immune cells toward the site of infection
Change adhesion cells (line blood vessel wall)
What are interferons important for?
Driving an antiviral response.
What is the structure of TLR?
Extracellular circle of repeated leucine (amino acid)
Without ligand- not active
Interacts with ligand - active
Conformational change intracellular TIR domain
What is TIR domain?
Intracellular domain
Transmembrane Interleukin Receptor (TIR)
Explain the TLR4 downstream cascade in detail.
Binding of LPS induces conformation change in TIR
Allows binding of universal adaptor molecule MyD88
Promotes association of IRAK 1&4 Kinases
Creating docking site for TRAF6
TRAF-6-IRAK1 dimer complex dissociates
Complexes with TAK1 (+ other proteins) causing kinase activation
-> Activates NFkappaB + Map kinase pathways -> increased transcription of inflammatory genes
How to activate NFkappa B?
Inactive- NFKappa B with IKappB (bound to it) (IKB)
TRAF6 - Results in activation, phosphorylation of IKB
Degraded in proteosome
Degradation of IKB -> NFKappaB free to move inside the nucleus
Binds to promoter and activates gene transcription of all inflammatory genes
How to activate NFkappa B?
Inactive- NFKappa B with IKappB (bound to it) (IKB)
TRAF6 - Results in activation, phosphorylation of IKB
Degraded in proteosome
Degradation of IKB -> NFKappaB free to move inside the nucleus
Binds to promoter and activates gene transcription of all inflamatory
TLR activation in macrophages results in…
- Oxidative burst
-> production of oxygen radicals
->produced in lysosomes (phagolysosome)
-> directly kill bacteria (phagocytosis) - Inflammatory cytokine/ chemokine release
TLR activation in dendritic cells results in…
- Inflammatory cytokines
- Antigen presentation on surface -> related to adaptive immune system (T cells -> memory response)
How many types of TLR exist?
Up to 10
