Inflammasomes Flashcards
Outline of what inflammasomes do
Inflammasomes trigger capsases that triggers the release of cytokines
What are inflammasomes?
Wheel-like supramolecular complexes formed in the cytosol
What do inflammasomes do?
Elicit immune responses in response to PAMPs or DAMPs
What are the three parts of an inflammasome?
Upstream sensor
Adaptor molecule
Downstream effector
What are inflammasomes named after?
Their upstream sensors
What are the names of common inflammasomes?
NLRP1
NLRP2
NLRP3
NLRC4
What is an example of an adaptor molecule?
ASC
What does an adaptor molecule do?
Links the upstream sensor to the downstream effector
What is binding of the domains governed by?
Protein-protein interactions between shared binding domains
What is the main goal of an inflammasome?
To increase production of IL-1b and IL-18 which mounts an inflammatory response
What is the net result of inflammasome assembly?
Cleavage of caspases into active forms to increase the production of cytokines
What is the main cytokine produced by inflammasomes?
IL-1b
What do the cytokines accomplish?
Pyroptosis
What is pyroptosis?
Messy cell death
Combination between apoptosis and necrosis
DNA is cleaved and contents of the cell spill out
How can pyroptosis be beneficial?
Pyroptosis of macrophages for example can lead to the spilling of pro-inflammatory cytokines which induce inflammation in damaged area
How can inflammasomes become activated?
Via changes in the environment - membrane potential in response to damage to cell membrane causing leakage of potassium and ATP
Oxidative stress
Protease activity
How are inflammasomes and crystal diseases related?
When macrophages ingest crystals, this activates NLRP3 inflammasomes
Causes IL-1b release
What mutations in the inflammasomes has been linked to autoinflammatory diseases?
CAPS
Mutation to the NLRP3 gene
Leads to excessive IL-1b secretion
How does the CAPS mutation lead to autoinflammation?
Mutations lower the threshold of inflammasome activation in the presence of other soluble factors
What is the role of inflammasome in development of rheumatoid arthiritis?
Not well established
What mutations in the inflammasome have been linked to rheumatoid arthiritis?
Homozygous carriers of RA have shown loss of function of a component of NLRP3 - CARD8
Polymorphisms in NLRP3 and CARD8 have increased susceptibility to develop RA
What proof is there that inflammasomes are related to RA development?
Synovial tissue of RA patients have increased IL-1b concentrations
What is the A20 gene?
RA susceptibility gene
How is the A20 gene related to inflammasomes?
Absence of A20 show increased IL-1b and NLRP3
What is the link between inflammasomes and SLE?
Inhibition of NLRP3, caspase-1 and IL-18 have shown to benefit nephritis in murine models of lupus
How can we use inflammasomes as therapeutic solutions for diseases?
Anti-IL1 therapies have been successful in diabetes type II and juvenile arthritis
