NLRP3 Inflammasome

Question 1

Inflammsomes are intracellular supramolecular complexes comprising of:

Answer 1

1. Sensor molecule
2. Adaptor apoptosis-associated speck-like protein containing a CARD (ASC)
3. Effector protease caspase 1

Question 2

NLRP3 is a tripartite protein containing:

Answer 2

1. Amino-terminal PYRIN domain
2. Nucleotide binding NACHT domain
3. Carboxy-terminal leucine-rich repeat (LRR) domain

Question 3

What steps does NLRP3 undergo for post-translational modifications?

Answer 3

Phosphorylation and ubiquitylation

Question 4

Name the most commonly accepted stimuli for NLRP3:

Answer 4

1. Potassium efflux through ion channels
2. Cathepsin release following destabilization of lysosomal membranes
3. Mitochondrial dysfunction (mitochondrial ROS, mitochondrial DNA or cardiolipin)
4. Metabolic changes

Question 5

Which SCFAs inhibit NLRP3 priming and activation by palmitate?

Answer 5

Butyrate and propionate

Question 6

Name 3 proteins (biologics) that inhibit the IL-1 signalling pathway

Answer 6

1. Anakinra (modified IL-1RA, effective in treating NLRP3 driven diseases)
2. Rilonacept - soluble decoy receptor that binds both IL-1Beta and IL-1alpha
3. Canakinumab - IL-1Beta neutralizing antibody

Question 7

Which biologics that inhibit the the IL-1 signalling pathway have poor BBB penetration?

Answer 7

Anakinra and Canakinumab

Question 8

Name some drugs that directly inhibit NLRP3 activation?

Answer 8

MCC950 and Glyburide and OLT1177

Question 9

Whats MCC950 MOA (one sentence)

Answer 9

MCC950 binds to NLRP3 and blocks its ability to hydrolyze ATP.

Question 10

Whats Glyburide MOA (one sentence).

Answer 10

Inhibits NLRP3 activation

Question 11

Saturated fatty acid, Palmitate …….. ROS and consequently …… NRLP3 inflammasome activation

Answer 11

increases, increases

Question 12

SCFA’s butyrate and propionate ….. NLRP3 priming and activation by palmitate

Answer 12

inhibit