Download - Catalyst

Anatomy of an Inflammasome
Nod-Like Receptor (NLR)
• NLRP3
• NLRC4
• AIM2
NLRP3
“Adaptor” protein
Casp1
NLRC4
Casp1
AIM2
Casp1
Caspase 1
Enzyme capable of cleaving
pro-forms of cytokines (IL-1b,
IL-18)
Inflammasomes
When NLR portion recognizes PAMP (or a DAMP in the case of
NLRP3) the inflammasome oligomerizes with an adapator protein
and capsapse 1. Once Caspase-1 become apart of the
inflammasome it is activated and capable of cleaving cytokines and
inducing cell death.
Often times we use the name NLRP3
interchangeably
with
inflammasome
by
accident.
However, the NLRs are actually
components of the inflammasome.
Inflammasome Components
1. NLR (NLRP3, NLRC4, AIM2)
2. Adaptor protein
3. Caspase 1
Steps that lead to upregulation of NLRs
1. TLRs detect pathogen
TLR2
TLR4
TLR5
MyD88
MyD88
MyD88
PM
TLR signaling cascade leads to
gene upregulation
2. Upregulate gene expression of NLRs (NLRP3, NLRC4, and Aim2)
Nucleus
3. Increased NLR proteins and Pro-IL1b
in cytoplasm
NLRP3
pro-IL1β
Transcription
NLRC4
NLRs
AIM2
pro-IL-1β
Note: Pro-IL-18 is NOT
upregulated in this manner.
It is constitutively (always)
expressed.
Remember, broadly there are two types of stimuli that can activate the inflammasomes.
PAMP stimuli
Damage Associated Molecular Patterns (DAMPs) – Non-PAMP Stimuli
PM
PM
a. Pore-forming toxins
b. Pore formation
c. Crystals
•
Asbestos
•
Silica
PM
4. Presence of NLRs in cytoplasm awaiting either PAMP or DAMP stimulus
NLRC4
NLRP3
AIM2
Detects and is activated by BOTH PAMP and DAMP stimuli
Detect and activated by PAMP
stimuli ONLY
Detection, Inflammasome assembly, and activation of Caspase 1
Representative of a DAMP
PM
5. NLRS detect activating Stimuli (PAMPs and/or DAMPs)
PAMP/DAMPs
Flagellin
NLRC4
DNA
AIM2
NLRP3
Other Inflammasome Components
Float around the cytoplasm until recruited by NLRs
during inflammasome assembly.
Casp1
Casp1
Casp1
Casp1
Detection, Inflammasome assembly, and activation of Caspase 1
Representative of a DAMP
PM
PAMP/DAMPs
Flagellin
DNA
NLRC4
Casp1
AIM2
Casp1
NLRP3
Casp1
6. Inflammasome assembly and activation
“activation” means all of the components are assembled and
Caspase 1 is active and able to cleave other proteins.
Detection, Inflammasome assembly, and activation of Caspase 1
Representative of a DAMP
PM
7. Activated Caspase 1 can now cleave Pro-IL1b and IL-18 into active forms.
PAMP/DAMPs
NLRP3
Casp1
NLRC4
Casp1
AIM2
Casp1
Flagellin
DNA
Active forms
• These cytokines send inflammatory
signals to other cells
• Mediate inflammation and fever
Proteolysis
pro-IL1β
pro-IL18
IL1β IL18
PYROPTOSIS
Detection, Inflammasome assembly, and activation of Caspase 1
Representative of a DAMP
PM
7. Activated Caspase 1 can now cleave Pro-IL1b and IL-18 into active forms.
PAMP/DAMPs
NLRP3
Casp1
NLRC4
Casp1
AIM2
Casp1
Flagellin
DNA
Proteolysis
pro-IL1β
pro-IL18
IL1β IL18
PYROPTOSIS
Inflammatory cell death
• Elimination of pathogen niche
• Antigen exposure
• Cytokine release