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A10HA > 16 - ETosis Pathology and Disease > Flashcards

16 - ETosis Pathology and Disease Flashcards

1
Q

Is the extruded DNA solely from a nuclear source?

A

Yousefi et al., 2009
- neutrophils primed with GM-CSF and stimulated by TLR-4 and C5a receptors generated extracellular traps comprising mitochondrial DNA
- mitochondrial DNA ROS-dependent, and occurs independently of cell death

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2
Q

NET formation vs NETosis

A

NET formation:
- mitochondrial DNA
- efficient innate immune response
- supports adaptive tune responses
- rapid resolution of inflammation
NETosis:
- cell rupture and nuclear collapse
- immunopathology
- excessive inflammation
- possible autoimmune responses

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3
Q

What happens in response to pathogens?

A
  • Evidence that neutrophils can detect pathogen size and release traps against larger pathogens, demonstrated by Branzk et al (2014) using fungal cells
  • ‘Decision’ regulated by competition for neutrophil elastase (NE)
    Neutrophils that meet a microbe too large to be phagocytosed do not form phagosomes
  • NE released into cytosol without membrane fusion, and is then free to
    translocate to the nucleus and drive chromatin decondensation
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4
Q

Does size selection operate in vivo? (Branzk et al, 2014)

A
  • Mice infected via intra-tracheal route with wild-type Candida albicans (able to form yeast and hyphae) and with a C. albicans mutant unable to form hyphae (yeast-locked hgc1Δ )
  • Lung tissue showed presence of traps only with wild-type C. albicans
  • NETosis induced by small bacteria, but often species whose virulence creates large aggregates and/or interferes with phagosomal killing (e.g. S. aureus, Pseudomonas aeruginosa, Neisseria gonorrhoea)
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5
Q

Protection during pregnancy?

A
  • Neutrophils collected from patients with intra-amniotic infection (infection of chorion, amnion, amniotic fluid, placenta, or a combination).
    1. Maternal (peripheral blood) samples.
  • Unstimulated
    2. Maternal (peripheral blood) samples.
  • Stimulated with PMA
    3. Amniotic fluid neutrophils.
  • Unstimulated
  • AF neutrophils: assumed to be of foetal origin, but may be mix of maternal/foetal
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6
Q

Pathogen evasion of ETs

A
  1. Inhibition of NET formation, e.g., by induction of IL-10 or production of inhibitory factors
  2. capsule: increases resistance to killing
  3. secretion of endonuclease
  4. conversion of NET-derived products into cytotoxic molecules

e.g., S. aureus adenosine synthase (a 5’,3’-nucleotidase) converts NET-derived nucleotides into dAdo, triggering apoptosis in macrophages

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7
Q

Role of lysins in pathogen evasion

A
  • significant NET induction observed with/without pneumolysin
  • S. pneumoniae, wild type, +ve pneumolysin
  • S. pneumonia, mutant, -ve pneumolysin
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8
Q

What did pneumolysin do to the bacteria?

A

Pneumolysin reduced quantity of bacteria trapped on the NETs

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9
Q

Diseases/pathologies associated with extracellular traps

A

Pre-eclampsia, Cystic fibrosis, Gum disease, Thrombosis, Strokes, Pancreatitis, Antherosclerosis, Arthritis, Autoimmunity, Psoriasis, Cancer

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10
Q

What is human preeclampsia?

A

Severe disorder of late pregnancy, linked to placental abberancies, particularly elevated release of inflammatory syncytiotrophoblast debris

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11
Q

What are the symptoms of pre-eclampsia

A

Symptoms: hypertension, proteinuria, extreme cases lead to liver/kidney failure, or foetal hypoxia

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12
Q

Pre-eclampsia: in vitro and in vivo

A
  • Known that pre-eclampsia associated with elevated foetal cell-free DNA
  • Placenta-derived microparticles (syncytiotrophoblast microparticles: STBM) inducing NET formation in vitro
  • In vivo – NETs in close contact with syncytiotrophoblast layer
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13
Q

Syncytiotrophoblast

A

Epithelial structure of placental villi that invades uterine tissue and determines which substances cross the placenta (e.g., nutrients and oxygen) and which do not (e.g., maternal hormones and certain
toxins)

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14
Q

Tissue sections of placenta from pre-eclampsia

A
  • Normal placenta: NEts present within villi or adjacent to syncytiotrophoblast
  • Pre-eclamptic: NEts diffuse throughout intervillous space
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15
Q

What is cystic fibrosis caused by?

A

Caused by mutations in cystic fibrosis transmembrane conductance regulator (CFTR) gene

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16
Q

What does cystic fibrosis code for?

A

Codes for an anion channel, resulting in altered transcellular chloride and bicarbonate transport

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17
Q

Characteristics of cystic fibrosis

A
  • Disproportionate neutrophil abundance
  • NETs abundant at sites of infection
  • Thick mucus facilitates microbial lung colonization
  • Persistent, neutrophil-rich inflammation
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18
Q

Cystic fibrosis disease research progression

A
  • > 85% CF patients suffer premature mortality through respiratory complications
  • Progress slow due to lack of animal models, currently pigs and ferrets being used as both species develop similar lung conditions
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19
Q

Normal lung vs CF lung

A

NORMAL:
- degranulation
- bacterial killing by phagocytosis
- phagocytosis of apoptotic neutrophils
- resolution of inflammation

CF LUNG:
- NET formation in response to bacteria
- frustrated inflammation
- possible lung damage from neutrophil contents

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20
Q

What does NE do?

A

Degrades lung structural proteins, reduces ciliary motility

21
Q

Where are NETs present in CF?

A

NETs present in CF sputum - palliative treatment includes inhalation of recombinant DNase-1

22
Q

Neutrophils in cystic fibrosis

A
  • CF lung shows higher proportion of neutrophil survival
  • Unclear whether this arises from primary neutrophil defect or a response to chronic inflammation
23
Q

CF and apoptosis

A
  • CF neutrophils show decreased apoptosis
  • Delayed apoptosis related to a loss of cystic fibrosis transmembrane conductance regulator (CFTR) function
  • Demonstrated by CFTR null neutrophils from CFTR-/- piglets (CF piglets)
24
Q

What is prolonged cystic fibrosis neutrophil lifespan due to?

A
  • Prolonged CF neutrophil lifespan is not caused by inflammation
  • CF neutrophils show normal baseline apoptotic signalling of both Mcl-1
    (antiapoptotic) and BAX (proapoptotic) proteins, implicated in inflammation-induced neutrophil survival
25
Q

NET production: CF neutrophils vs healthy

A

CF neutrophils form more NETs than healthy controls when aged in culture conditions

26
Q

Inflammatory responses in cystic fibrosis

A
  • NETs stimulate an inflammatory response from macrophages, which is exaggerated in CF
  • Demonstrated by co-culture of net-producing neutrophils and monocyte-derived macrophages (MDM), which showed increased production of cytokines IL-8 and TNF
27
Q

NETs and gum disease

A
  • NETs involved in periodontitis, caused by Porphyromonus
  • Neutrophils recruited into gingival crevices
  • Chronic periodontitis/hyper-coagulation associated with atherothrombosis
  • Has been associated with abdominal aneuryism
28
Q

NETs and cancer

A
  • Evidence exists that circulating tumour cells trapped by NETs in vitro
  • Murine model demonstrated microvascular NET deposition and trapping of lung carcinoma cells
  • Trapping associated with increased formation of micrometastases at 48 hours and gross metastatic disease
  • Effects were abrogated by DNAse or neutrophil elastase inhibitor
29
Q

NETs & cancer associated thrombosis

A
  • high level of association between cancer and thrombosis
  • evidence that tumour cell vesicles (exosomes) stimulate NETs
30
Q

NETs and heparin-induced thrombocytopenia (HIT)

A
  • HIT: caused by pathogenic Ab (HIT Abs) specific for complexes of heparin and cytokine
  • CXCL4 (aka PF4 - platelet factor 4)
  • CXCL4 released in high concentrations at sites of platelet activation
  • Binds to surface glycosaminoglycans (GAGs) on platelets, monocytes, endothelial cells, and neutrophils
31
Q

NETs and COVID-19

A

“Patients with COVID-19: in the dark NETs of neutrophils” Ackerman et al.
- Neutrophilia directly correlates with disease severity in COVID-19
- Increased serum levels of NET degradation products (neutrophil-derived
- MPO-DNA, citrullinated histone H3) closely parallel lung distress and predict COVID-19 severity
- NETs abundant in circulation, and in lung and kidney tissues of COVID-19 patients

32
Q

Possible therapeutic interventions of COVID-19

A

Possible therapeutic interventions:
- Heparin (neutralizes histones)
- Cytokine inhibitors
- DNAses
- Pro-inflammatory inhibitors

33
Q

Cell death comparison

A
  • NECROSIS: uncontrolled, passive, affects large areas of cells
  • APOPTOSIS: controlled, energy dependent, occurs in single cells, clusters
  • ET-OSIS: controlled, ROS dependent, primarily occurs in phagocytes but not exclusively
34
Q

What are other forms of cell death (not apoptosis etc.)

A

Autophagy/autophagic cell death, pyroptosis, necroptosis

35
Q

Stages of autophagic cell death

A
  1. phagophore - isolation membrane
  2. cytosolic proteins and organelles
  3. vacuoles appear in cell, no nuclear condensation
  4. autophagosome
  5. (+ acid hydrolyses in lysosome) autolysosome
36
Q

Features of autophagy

A
  • May be activated by starvation, cellular damage
  • Removes protein complexes, damaged organelles or intracellular pathogens
  • Can occur when apoptosis is blocked
  • Can cause cell death – sporadic clearance of cell remains by phagocytes
37
Q

Pyroptosis

A
  • Novel, pro-inflammatory form of cell death induced by Salmonella and Shigella
  • Uniquely dependent on caspase-1 (not involved in apoptotic cell death)
38
Q

Role of caspase-1 in pyroptosis

A
  • Caspase-1: processes pro-forms of inflammatory cytokines IL-1 and IL-18
  • Caspase-1 activation in macrophages infected with Salmonella or Shigella results in processing of these cytokines and death of the host
    cell
  • Observed caspase-1 activation/dependence during cell death in immune, CNS, and cardiovascular systems indicates significant role of pyroptosis in various biological system
39
Q

Comparison of apoptosis and pyroptosis characteristics

A
  • cell lysis (P)
  • cell swelling (P)
  • pore formation (P)
    -membrane bedding (A)
  • nuclear condensation (A/P)
  • DNA fragmentation (TUNEL positive) (A/P)
  • caspase-1 activation (P)
  • caspase 3 activation (A)
  • caspase 7 activation (P)
  • MOMP/ cytochrome C release (A)
  • ICAD cleavage (A)
  • PARP cleavage (A)
  • glycolysis enzyme inactivation (A/P)
  • inflammation (P)
40
Q

What kind of cell death is HIV associated with?

A

Pyroptosis

41
Q

Necroptosis

A
  • Mediated via death receptor family proteins, e.g. Tumour Necrosis Factor (TNF), as well as several other PRRs
  • Caspase-independent
  • occurs independently of caspases, dependent on kinases, such as receptor- interacting protein kinase (RIP-1)
42
Q

When does necroptosis occur?

A

Occurs when caspase-8 activation is absent

43
Q

What is necroptosis dependent on?

A

Dependent on interaction between kinases:
- Receptor-interacting protein kinase (RIP) -1—-> RIP-3 —-> Mixed-Lineage Kinase domain-Like (MLKL)

44
Q

What is necroptosis beneficial for?

A

Beneficial as ‘back-up’ e.g. viral inhibition of apoptosis

45
Q

What is released in necroptosis (compare to apoptosis?

A

In NECROPTOSIS there is massive DAMP release and it is a strong inducer of inflammation
In APOPTOSIS there is limited DAMP release and weak inducer of inflammation

DAMP:
Damage-Associated Molecular Pattern e.g. cytokines (IL-1), alarmins,
nucleic acid, histones, heat-shock proteins

46
Q

What are NETs beneficial in and detrimental to?

A

Neutrophil extracellular trap beneficial in anti-microbial defence, detrimental in certain disease conditions, e.g. pre-eclampsia, cystic fibrosis, gum disease, cancer, thrombosis and COVID-19

47
Q

What do neutrophils in CF show?

A

Neutrophils in cystic fibrosis show decreased apoptosis, increased survival, increased NET production and stimulate the inflammatory response of Mφs

48
Q

What does evidence suggest about NETs and cancer?

A

Evidence suggests extracellular traps may facilitate cancer development through metastases

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