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Topic 2 Inflammation algorithm

  • Learn 3.2, 10.2
  • Review key point in Topic 1:
    • Innate immune system have two ports to detect different types of pathogens
    • TLRs (Toll-like receptors) --> detect things outside membrane --> release pro-inflammatory cytokines like TNF, IL-6
    • RLRs (RIG-I-like receptors) --> detect internal virus --> release Type I interferons, in antiviral state

  • inflammasome Logic

    • in a word: the NLRP3 inflammasome requires a Two-factor authentication to fire, two-signals are reuqired
      • Signal 1: priming (permission)
        • Trigger: PAMPs hit TLRs
        • Process: NF-kB activation
        • Result: Transcription of the raw materials ==NLRP3== and ==Pro-IL-1$\beta$== produced
      • Signal 2: activation (Execution)
        • Trigger: cellular homeostasis breach
          • Main reason: Potassium efflux
          • others: ATP binding P2X7 channels, pore-forming toxins
        • Process:
            1. K+ drops
            1. NLRP3 oligomerizes
            1. Recruits ASC (adaptor)
            1. Recruits Pro-Caspase-1
        • Result: form active ==Caspase-1== enzyme
    • Event: pyroptosis
      • Cytokine processing: ==Caspase-1== cleaves ==Pro-IL-1$\beta$ and Pro-IL-18== into active forms
      • Cell lysis: Caspase-1 cleaves GSDMD
        • The N-terminal of GSDMD punches pores in the cell membrane
        • Outcome: release of cytokines + cell death

  • Non-Canonical inflammasome

    • Sensor changes: Caspase-11 in mice; Caspase-4/5 in human
    • Trigger changes: They detect intracellular LPS, bypassing TLR4
    • Outcome: still, cleave GSDMD and cause pyroptosis, and then activate NLRP3

  • Regulation system

    • Inhibitor: Bile Acids
    • Pathway: TGR5 receptor --> cAMP --> PKA --> inhibit NLRP3
    • Process: PKA phosphorylates NLRP3, preventing it from assembling. This creates a "ubiquitination brake" .

Take home logic for exam:

  1. Dependencies: You can see if self.primed == False: return. This is the Two-Signal Model.

  2. Regulation: You can see if self.pka_active: return. This is the Bile Acid Checkpoint.

  3. Pathology: You can see ORF3a forcing the assemble function directly. This is COVID-19 or other kind of virus that can trigger signal 2