Which immune cells first arrive at an infection site during inflammation & why?
Neutrophils -> attracted to site of infection by Interleukins (CXCL8/IL-8)
Macrophages -> recruited by Neutrophils (follow chemokine gradient, more at site & less the farther you go)
What is the usual outcome of a localized inflammatory response & what if fails?
Rapid localization and destruction of the pathogen
-> if failure to localize pathogen: widespread reaction or septic shock
What is a septic shock & how induced & symptoms?
life-threatening condition resulting from a widespread inflammatory response
bacterial Endotoxin (f.e. LPS) or Superantigens cause excessive release of pro-inflammatory cytokines (TNF-α, IL-1 & IL-6)
Uncontrollable fever (death in up to 30%)
Why can septic shock be more dangerous than the initial infection?
pro-infalmmatory cytokines (f.e. TNF-a) important but here uncontrolled & systemic inflammatory response -> severe damage to host tissues and organs
What are the 2 types of inflammation?
Pathogen inducd inflammation & sterile inflammation (host-derived molecules f.e. cytosolic content)
What is efferocytosis?
sensing, recognition, and removal of cellular corpses by phagocytosis
cell releases DAMPS (Damage Associated Molecular Patterns) “eat me” signal -> sensed by PRRs (Pathogen Recognition Receptors)
What is the difference between Apoptosis, Necroptosis & Pyroptosis?
Apoptosis
Programmed cell death
Cell shrinks, DNA fragments, membrane stays intact -> Non-inflammatory (IL-10 & TGF-b)
Necroptosis
Regulated necrosis (programmed)
Cell swells & bursts -> Inflammatory (IL-12, IL-6, IL-1)
Pyroptosis
Triggered by infection (especially intracellular bacteria)
Caspase-1 activation → Gasdermin pores → cell lysis
Inflammatory (IL-12, IL-6, IL-1)
How does the “eat me” signal get presented on cell?
Flippase enzyme reason why “eat me” signal normally not presented (actively sends it to inner leaflet of plasma membrane)
-> inactivated during apoptosis
“eat me signal” -> Phosphatidylserine (PS)
-> normally on inner leaflet of plasma membrane -> apoptosis -> exposed on outer leaflet by scramblase
What cell death pathways cause inflammation & what don't & role of Caspase?
Apoptosis (Caspase 3, 6, 7 dependent) -> no inflammation
Pyroptosis (Caspase 1, 11 dep.) -> inflammation
Necroptosis, MPT-RN, Parthanatos, Ferroptosis, NETosis (Caspase indep.) -> inflam.
What types of PRRs & where?
Toll-like receptor (TLR)
Plasma membrane: 1&2, 2&6, 4, 5
Endosomal membr.: 3, 7, 8, 9
Cytoplasmic: NRL & RLR
What is an inflammasome & aim & how formed & components?
inflammasome: multi-protein complex inside immune cells (detects DAMPs & PAMPs)
induced by NLRs due to inf. or damage -> aim: inflamm & cell death (via gasdermin D & pyroptosis)
Components: sensor pr. + ASC + Caspase -> activated & engine formed when ATP comes in
What is the difference between canonical & non-canonical inflammasome pathway?
Canonical: Caspase 1
Non-canonical: Caspase 4, 5 (mice 11)
What happens in a sterile inflammation?
inflammation not bc of pathogen
inflammasome formation
C-reactive protein high in inflammation -> not high in isterile inflammation
What are examples of inflammasome associated disease & how formed?
Inflammasome disease occur when hypo- or hypoactive
Gout (uric acid crystals)
Alzheimer’s disease (amyloid-beta plaques)
Familial Mediterranean Fever (CAPS)
Macrophage activation syndrome (MAS)
Diseases related to dysfuntional sensing of nucleic acid ligand?
f.e. Interferon I (IFN-a) dysregulation -> SAVI (STING associated (overactive) Vasculopathy in infancy)
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