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PT4024 > NLRP3 inflammasome > Flashcards

NLRP3 inflammasome Flashcards

1
Q

what is the NLRP3 inflammasome?

A

the NLRP3 inflammasome is a signalling scaffold that coordinates the activation of inflammatory mediators in particular in response to endogenous DAMPs released due to reduction in physical activity, increased consumption of processed foods, aging

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2
Q

name and describe the three types of Pathogen Recognition receptors?

A
  1. Molecules present in the serum, like C-reactive protein, complement.
  2. Receptors present on cell surface and on endosome - Toll-like Receptors (TLRs)
  3. Intracytoplasmic recognition molecules like NOD-Like receptor (NLR) and RIG-like receptor (RLR)
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3
Q

Name the three components of an inflammasome?

A

a sensor molecule
Adaptor apoptosis-associated speck-like protein containing a CARD (ASC)
effector protease caspase 1

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4
Q

what does activation of the sensor molecule result in?

A

ASC self-association into a helical fibrillary assembly leading to the formation of a pyroptosome.

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5
Q

NLRP3 inflammasome acts as molecular scaffold for the activation of _ via proximity induced autocatalytic activation

A

NLRP3 inflammasome acts as molecular scaffold for the activation of procaspase 1 via proximity induced autocatalytic activation

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6
Q

what does active caspase 1 trigger the release of?

A

caspase 1 triggers the release of IL-1B and IL-18 (proinflammatory cytokines)

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7
Q

name the three important domains in the NLRP3 sensor molecule

A

NACHT Domain - has ATPase activity, needed for ATP binding for NLRP3 activation.
Leucine Rich Repeat (LRR) domain - for detection of stimuli, thought to induce autoinhibition by folding back onto NACHT domain.

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8
Q

describe NLRP3 inflammasome assembly and function upon stimulation

A
  1. NLRP3 oligomerizes via NACHT domains
  2. NEK7 (kinase) interacts with NLRP3 and oligomerizes NLRP3 into a complex critical for ASC recruitment
  3. Oligomerized NLRP3 recruits ASC resulting in helical filament formation.
  4. Assembled ASC recruits procaspase 1 through interactions with CARD
  5. Proximity-induced caspase 1 undergoes self cleavage and activation is induced.
  6. caspase 1 cleaves IL-1B and IL-18, these are secreted.
  7. Gasdermin D (GSDMD) is also cleaved by caspase 1 which inserts into the membrane, forms pores and induces pyroptosis
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9
Q

the quantity of which NLRP3 inflammasome component is the rate-limiting step of its activation?

A

the quantity of NLRP3 in the cell at rest

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10
Q

what is priming

A

the first signal which primes the cell by initiating the transcription of the NLRP3 gene, increasing its expression

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11
Q

what receptors need to be engaged for the inflammasome to be primed?

A

pathogen recognition receptors

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12
Q

what does activation of PRRs lead to

A

Nuclear factor kappa B (NFKB) activation and NLRP3 gene transcription

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13
Q

what effect does priming with LPS have on macrophage metabolism?

A

priming with LPS shifts macrophage metabolism from oxidative phosphorylation to glycolysis

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14
Q

what is the second function of priming?

A

the induction of post-translational modifications of NLRP3 which stabilises the NLRP3

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15
Q

Phosphorylation of _ position of LRR domain inhibits NLRP3 activation

A

Y861

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16
Q

Phosphorylation of _ in NACHT domain by PKA inhibits, while protein kinase D (activates)

A

phosphorylation of S295 in NACHT domain by PKA inhibits while PKD activates

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17
Q

what enzyme do bile acids induce and how does this affect NLRP3 inflammasome

A

bile acids induce PKA which suppresses NLRP3 activation

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18
Q

dephosphorylation at _ inhibits NLRP3 activation by preventing NLRP3 oligomerization and interaction with ASC

A

dephosphorylation at S198 inhibits NLRP3 activation by preventing NLRP3 oligomerisation with ASC

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19
Q

Name some examples of DAMPs

A

ATP, cholesterol crystals, urate crystals, alpha-synuclein

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20
Q

Name some examples of PAMPs

A

LPS, peptidoglycan, Bacterial RNA-DNA hybrid, ssRNA, dsRNA, beta-glucans

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21
Q

Name some examples of PAMPs

A

LPS, peptidoglycan, Bacterial RNA-DNA hybrid, ssRNA, dsRNA, beta-glucans

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22
Q

what are the unifying factors of NLRP3 activators?

A

all induce cellular stress, which is sensed by NLRP3

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23
Q

what are the most commonly accepted activating stimuli for NLRP3

A

K+ Influx through ion channels
cathepsin release following destabilisation of lysosomal membranes
mitochondrial dysfunction (mitochondrial ROS/DNA or cardiolipin)
metabolic changes

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24
Q

what are ionophores?

A

bacterial pathogenesis factors - efflux of K+ as a method of sensing presence of bacteria

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25
Q

what is the P2X purinoreceptor

A

high levels of extracellular ATP (due to dying cells in the vicinity of inflammasome-containing cells) result in ion influx via opening of ligand gated ion channel of P2X purinoreceptor - efflux of K+ in addition to Ca2+

26
Q

what bacterial pore-forming toxin activates NLRP3 via K+ influx?

A

streptolysin O

27
Q

what is alum?

A

first discovered adjuvant and most commonly used in vaccines againstt HepB, tetanus, and HPV; induces K+ efflux

28
Q

what causes lysosomal disruption

A

phagocytosis of crystals (cholesterol, uric acid) or protein aggregates (amyloid-beta)

29
Q

what precedes lysosomal swelling and damage?

A

lysosomal acidification

30
Q

what are the cysteine proteases key to lysosomal disruption?

A

cathepsins

31
Q

what are mitochondrial-related ligands for NLRP3?

A

mitochondrial ROS, oxidised mtDNA, phospholipid cardiolipin

32
Q

what is hexokinase 2 function and what does its displacement cause?

A

hexokinase 2 enhances glucose metabolism, displacement of this enzyme from mitochondria trigger increase in mitochondrial Ca2+ causing depolarization and mitochondrial cell death

33
Q

what metabolic change products can activate the inflamasome

A

free fatty acids, palminate,

34
Q

what effect do SCFAs have on NLRP3 Inflammasome activity?

A

they are anti-inflammatory, inhibit priming and activation of NLRP3 inflammmasome by palminate

35
Q

what is the name of the ketone body that inhibits NLRP3 activation

A

beta-hydroxybutyrate

36
Q

what downstream product of NLRP3 activation is inhibited by BHB in murine models of CAPS and in urate crystal model of inflammation?

A

caspase 1 and IL-1B release

37
Q

what is the mechanism behind BHB regulation of NLRP3 inflammasome

A

inhibition of the K+ efflux

38
Q

what is CAPS?

A

Cryopyrin-associated periodic syndromes, group of systemic auto-inflammaotry disorders caused by mutations in the NLRP3 gene. gain of function mutations (spontaneous inflammasome formation in absence of ligand)

39
Q

what interleukin has been found to be elevated in crohn’s disease? what subset of T helper cells does this promote?

A

IL-18, which promotes Th1 response (pathogenic)

40
Q

what do NLRP3 null mice have?

A

increased insulin sensitivity and pancreatic beta cells

41
Q

what are cholesterol crystals associated with?

A

NLRP3-mediated atherosclerosis

42
Q

what are monosodium urate crystals associated with

A

gout flares

43
Q

what are calcium oxalate crystals associated with?

A

kidney dysfunction

44
Q

how do protein aggregates activate the NLRP3 inflammasome?

A

they aggregate and are too large for lysosomal degradation, causing them to accumulate until lysosomal rupture, which subsequently activates NLRP3 inflammasome

45
Q

name drug that blocks IL-1 receptor, its indications, limitation, and administration

A

anakinra, modified IL-1RA, effective for CAPS, RA, short plasma half-life, daily injections required

46
Q

name the drug that inhibits both IL-1B and IL-1a

A

rilonacept, a solubel decoy receptor

47
Q

name the IL-1B neutralising antibody, half life, approved use, administration, BBB penetrative?

A

canakinumab, 26 hour half-life, IV admin, poor BBB penetration

48
Q

direct inhibition of NLRP3 inflammasome activation via?

A

MCC950

49
Q

What kind of drug is MCC950

A

A diarylsulfonylurea small molecule compound

50
Q

what has MCC950 inhibited in human monocytes?

A

ATP-triggered, NLRP3-mediated IL-1B release

51
Q

what preclinical immunopathological models did MCC950 demonstrate therapeutic efficacy against?

A

CAPS, Experimental Autoimmune Encephalitis, Alzheimer disease, atherosclerosis, TBI, cardiac arrhythmias, diabetes, Mi

52
Q

what is the main issue with MCC950 safety profile?

A

hepatotoxicity due to high (1200mg) dose daily

53
Q

what is glyburide typically used for and what are its off-target effect?

A

a T2D drug, potently inhibits NLRP3 activation but requires high doses and MOA is not known, use limited in non-diabetics due to risk of hypoglycaemia

54
Q

what is Dapansutrile (OLT1177)

A

Orally active beta-sulfonyl nitrile molecule that inhibits NLRP3 inflammasome activation

55
Q

what interaction does OLT1177 inhibit?

A

the interaction between ASC and NLRP3

56
Q

what did OLT1177 demonstrate in CAPS patients?

A

reduced IL-1B release in monocytes

57
Q

what did the phase 1 OLT1177 trial exhibit

A

1000mg admin to healthy patients for 8 days showed no biochemical or hematological changes or any adverse effects

58
Q

what did the open-label, proof-of-concept phase 2a trial in adults with monoarticular monosodium urate crystal gout flares show?

A

2000mg for 8 days showed good safety profile, efficacy in reduction of target joint pain

59
Q

name the brain penetrant direct inhibitor

A

inzomelid

60
Q

NLRP3 activation inhibitor for CVD and arthritis?

A

somalix

61
Q

IFM-2427

A

a systemic peripheral NLRP3 antagonist in phase 1 clinical trials for treatment of inflammatory conditions like gout, atherosclerosis and non-alcoholic steatohepatitis

62
Q

DVF890

A

Gut-directed, CNS-penetrant NLRP3 antagonist

PT4024 (6 decks)

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