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Anatomy of an Inflammasome
“Adaptor” protein Nod-Like Receptor (NLR) NLRP3 NLRC4 AIM2 Caspase 1 Enzyme capable of cleaving pro-forms of cytokines (IL-1b, IL-18) NLRP3 Casp1 NLRC4 Casp1 Often times we use the name NLRP3 interchangeably with inflammasome by accident. However, the NLRs are actually components of the inflammasome. AIM2 Casp1 Inflammasomes? What do they signal through? Other intracellular receptors? (Hint: nucleic acid detection) 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. Inflammasome Components NLR (NLRP3, NLRC4, AIM2) Adaptor protein Caspase 1
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Steps that lead to upregulation of NLRs
+ 1. TLRs detect pathogen TLR5 TLR4 TLR2 PM MyD88 MyD88 MyD88 3. Increased NLR proteins and Pro-IL1b in cytoplasm TLR signaling cascade leads to gene upregulation Motile bacteria? DNA virus? RNA virus? Membrane damage? (to be discussed more extensively later on) Outcome of inflammasome activation? Outcome of other nucleic acid sensing pathway activation? NLRP3 2. Upregulate gene expression of NLRs (NLRP3, NLRC4, and Aim2) pro-IL1β Nucleus NLRC4 NLRs Note: Pro-IL-18 is NOT upregulated in this manner. It is constitutively (always) expressed. AIM2 Transcription pro-IL-1β
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Remember, broadly there are two types of stimuli that can activate the inflammasomes.
PAMP stimuli Damage Associated Molecular Patterns (DAMPs) – Non-PAMP Stimuli PM b. Pore formation PM a. Pore-forming toxins c. Crystals Asbestos Silica + PM 4. Presence of NLRs in cytoplasm awaiting either PAMP or DAMP stimulus NLRC4 Motile bacteria? DNA virus? RNA virus? Membrane damage? (to be discussed more extensively later on) Outcome of inflammasome activation? Outcome of other nucleic acid sensing pathway activation? NLRP3 AIM2 Detects and is activated by BOTH PAMP and DAMP stimuli Detect and activated by PAMP stimuli ONLY
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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 NLRP3 NLRC4 DNA AIM2 Other Inflammasome Components Float around the cytoplasm until recruited by NLRs during inflammasome assembly. Motile bacteria? DNA virus? RNA virus? Membrane damage? (to be discussed more extensively later on) Outcome of inflammasome activation? Outcome of other nucleic acid sensing pathway activation? Casp1 Casp1 Casp1 Casp1
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Detection, Inflammasome assembly, and activation of Caspase 1
Representative of a DAMP PM PAMP/DAMPs Flagellin NLRP3 Casp1 NLRC4 Casp1 DNA Casp1 AIM2 Motile bacteria? DNA virus? RNA virus? Membrane damage? (to be discussed more extensively later on) Outcome of inflammasome activation? Outcome of other nucleic acid sensing pathway activation? 6. Inflammasome assembly and activation “activation” means all of the components are assembled and Caspase 1 is active and able to cleave other proteins.
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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 Active forms These cytokines send inflammatory signals to other cells Mediate inflammation and fever Flagellin NLRC4 Casp1 DNA Casp1 AIM2 Motile bacteria? DNA virus? RNA virus? Membrane damage? (to be discussed more extensively later on) Outcome of inflammasome activation? Outcome of other nucleic acid sensing pathway activation? pro-IL1β pro-IL18 IL1β IL18 Proteolysis PYROPTOSIS
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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 Flagellin NLRC4 Casp1 DNA Casp1 AIM2 Motile bacteria? DNA virus? RNA virus? Membrane damage? (to be discussed more extensively later on) Outcome of inflammasome activation? Outcome of other nucleic acid sensing pathway activation? Inflammatory cell death Elimination of pathogen niche Antigen exposure Cytokine release pro-IL1β pro-IL18 IL1β IL18 Proteolysis PYROPTOSIS
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