Toll-like receptors Flashcards
What are toll like receptors?
- a class of proteins that play a key role in the innate immune system
- come from our germline
- single, membrane-spanning, non-catalytic receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes
- Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses
Does TLR signaling turn on inflammation?
yes
How do innate cells respond to an infection?
- phagocytosis
- antimicrobials
- cytokines and chemokines
- antigen presentation
What are pathogen associated molecular patterns (PAMPs)?
- components of the microbe
- recognized by PRRs
What are pattern recognition receptors (PRRs)?
- recognize microbial PAMPs
- include TLRs
- distinguish self from non-self
- can be secreted, on cell surface or intracellular
What are the functions of PRRs?
- activation of pro-inflamatory signaling
- opsonization
- coagulation
- apoptosis
- complement activation
- phagocytosis
What do toll like receptors recognize?
multiple structurally unrelated PAMPs
What is the TLR domain structure?
Extracellular - leucine-rich repeats (LRR)
Intracellular - Toll/interleukin-1 receptor domain
What TLR recognizes triacyl lipopeptide and what adapters are activated?
- TLR1 and TLR2
- TIRAP and MyD88 -> inflammatory cytokines
What TLR recognizes diacyl lipopeptide and what adapters are activated?
- TLR2 and TLR6
- TIRAP and MyD88 -> inflammatory cytokines
What TLR recognizes dsRNA and what adapters are activated?
- TLR3
- Trif -> inflammatory cytokines and Type I IFN
What TLR recognizes LPS and what adapters are activated?
- TLR4
- TRAM and Trif -> inflammatory cytokines and Type I IFN
- TIRAP and MyD88 -> inflammatory cytokines
What TLR recognizes ssRNA and what adapters are activated?
- TLR7 and TLR8
- MyD88 -> inflammatory cytokines and Type I IFN
What TLR recognizes Flagellin and what adapters are activated?
- TLR5
- MyD88 -> inflammatory cytokines
What is the bacterial component on gram-negative bacteria that stimulates innate immunity?
lipopolysaccharide (LPS)
What is the bacterial component on gram-positive bacteria that stimulates innate immunity?
- lipoteichoic acid
- peptidoglycan
What are innate genes induced by TLR signaling?
- inflammatory cytokines
- chemokines
- antimicrobials
What are adaptive genes induced by TLR signaling?
- MHC
- co-stimulatory molecules
What happens when a TLR binds to a ligand?
- dimerization of extracellular LRR domains
- signaling by intracellular TIR domains
Where are TLRs that recognize bacteria or fungi?
cell surface
Where are TLRs that recognize DNA or RNA?
endosome
Which TLR moves from the surface to the endosome?
TLR4
Why are TLR3, 7, 8, 9 in the endosome?
intracellular localization facilitates recognizing viral DNA and ssRNA and prevents recognition of self - prevents autoimmune disease
What makes sure TLRs are delivered to the right place?
Unc93b1
Can mutations in genes that regulate TLR3 transport/localization affect human disease as well as mutations in TLR3?
yes, mutations in Unc93b cause the same disease as mutations in TLR3
What transcription factors do TLR signaling activates?
- NFκB
- AP-1
- IRF
What are the two adaptor proteins of TLR signaling?
- Trif
- MyD88
- build up signaling pathways
What are the two TLR4 signaling pathways?
cell surface - Myd88 dependent
endosome - TRIF dependent -> delayed
Describe the TLR4 signaling Myd88-dependent pathway.
- LPS stimulates TLR4-MD2 dimerization
- recruits Myd88
- Myd88 recruits kinases (IRAK-4, IRAK-1, IRAK-2)
- ligase Taf6 recruited -> activates MAPKKK TAK1
- TAK1 activates IKK complex, which phosphorylates IκB
- IκB is ubiquinated and degraded -> releases NFκB
- NFκB translocates into the nucleus
What are negative regulators for TLR4?
Many places where they can turn the pathway off
What happens when IRAK-4 is mutated?
- recurrent bacterial infections (because TLR4 pathway)
- no further infections after 8 yrs
What are three TLR pathways that can be used as targets for treatment?
Agonists - enhancing immunity to infectious disease
- enhancing vaccine efficacy
Antagonists - treating inflammatory diseases
