Lecture 6: Inflammation and infection in stroke

Question 1

What is the most common stroke type?

Answer 1

acute ischaemic stroke

Question 2

Most of ischaemic stroke affects which artery?

Answer 2

the middle cerebral artery

Question 3

What are cytokines?

Answer 3

polypeptides associated with inflammation, immune activation, cell differentiation and death

Question 4

Give 5 cell types that produce cytokines

Answer 4

macrophages, activated microglia, endothelial cells, fibroblasts, monocytes, lymphocytes, platelets

Question 5

Describe the intravascular initiation of the inflammatory cascade immediately after vessel occlusion

Answer 5

shear stress on vascular endothelium and platelets
P-selectin (as well as other adhesion molecules) produced within minutes to slow down and attract leukocytes to endothelium
- activation of coagulation cascade enhances inflammation
- breakdown of BBB increases passage of mediators and cells from circulation into brain tissue
- activation of complement
leukocyte cluster formation and clogging exacerbates the ischaemic injury

Question 6

Why might you expect to see more breakdown of the BBB in an older stroke patient?

Answer 6

They likely have some small vessel disease which in itself causes inflammation and subtle BBB breakdown

Question 7

True or false: inflammation is initiated within the brain tissue (parenchyma) itself? why/why not?

Answer 7

True because injured or dying neurons that are not being supplied with sufficient nutrients and energy become injured or die = release DAMPs

Question 8

How does inflammation in the brain parenchyma during a stroke lead to peripheral immune response?

Answer 8

Damaged and dying neurons release DAMPs and cytokines
- these activate microglia which also release cytokines such as IL-1beta and TNF-alpha
- these DAMPs and cytokines gain access to systemic circulation via disrupted BBB or CSF drainage
- induce primary and secondary lymphoid organ immune response resulting in systemic inflammatory response

Question 9

True or false: systemic infection can make the occurrence of a stroke more likely?

Answer 9

True

Question 10

Why might an infection be more likely to occur after a stroke?

Answer 10

Early activation of the immune system is followed by a state of system immunosuppression

patients may be experiencing physical effects (such as immobility, ineffective swallowing mechanism to move pathogens into stomach etc)

breakdown of BBB means pathogens may be more able to enter the brain tissue

Question 11

Give an example of a CNS antigen that may become exposed to the systemic immune system (that otherwise would remain within the brain) due to disruption of the BBB and CSF-brain barrier?

Answer 11

neuron-specific enolase

Question 12

what are the innate immune cells involved in stroke?

Answer 12

Microglia, monocyte-derived macrophages and dendritic cells, neutrophils
mast cells, innate lymphocytes

Question 13

How does neutrophil location change in stroke?

Answer 13

early stroke = intravascular adhesion of neutrophils

later = parenchymal accumulation

Question 14

True or false: microglia and monocyte-derived macrophages have a largely damaging function in ischaemic brain injury?

Answer 14

False, they seem to have largely protective functions

Question 15

Which innate immune cell is activated early and contributes to brain oedema and BBB breakdown?

Answer 15

Mast cells

Question 16

How may high-sensitivity CRP assays be used as a biomarker of cardiovascular damage?

Answer 16

low level increases in CRP may be indicative of low grade chronic inflammation in cardiovascular damage and may be able to predict ischaemic stroke in some populations

Question 17

How can IL-6 be used to identify individuals with increased vascular risk?

Answer 17

IL-6 is a pro-inflammatory cytokine that has been associated with increased vascular risk however IL-6 is also paradoxically linked to anti-inflammatory molecules through complex auto-inhibitory feedback mechanisms

Question 18

How does the relative levels of serum hsCRP to IL-6 relate to risk of ischaemic stroke?

Answer 18

a decrease in levels of hsCRP to IL-6 have shown a decrease in ischaemic stroke risk and may reflect improved immune system homeostasis and reduced underlying inflammatory state.

Question 19

How does inflammation play a key role in destabilisation of vulnerable carotid atherosclerotic plaques?

Answer 19

inflammation plays a key role in destabilisation of vulnerable plaques resulting in plaque rupturing and thrombus formation at that site, which can cause a distal thromboembolism in brain artery and a stroke

Question 20

What do FDG-PET scans tell us?

Answer 20

Flurodeoxyglucose ligand used to target areas of increased metabolic activity
- tumour or patch of inflammation
- can show where there is plaque inflammation in carotid artery

Question 21

The balance between IL-1 and what is important in determining response to infection and inflammation?

Answer 21

IL -1ra (Interkeukin-1 receptor antagonist)

Question 22

What is the effect of IL-1ra on the lesion volume in experimental stroke?

Answer 22

decreases size of the lesion

Question 23

Describe the relationship between inflammation, age and stroke susceptibility

Answer 23

The burden of inflammation increases with age due to chronic low grade inflammation until a threshold is reached at an older age that makes you susceptible to a stroke event. However, transient episodes of high-grade inflammation such as an infection can cause a sharp increase in burden of inflammation that put an individual over the stroke threshold at an earlier age.

Question 24

estimated that 10% of deaths within 30 days of admission with a stroke are due to what?

Answer 24

pneumonia

Question 25

What factors have been consistently shown to increase risk of post-stroke infection?

Answer 25

• older age
• more severe stroke
• total anterior circulation infarction (severe stroke in anterior carotid circulation)
• dysphagia (due to neurological impairment of swallowing mechanism)

–> immunodepression state after acute stroke so immune system not responding in way it should be and patient is more vulnerable to infection

Question 26

What are some features of post-stroke immunodepression?

Answer 26

• dysregulation of normally well balanced brain-immune interactions after acute ischaemic stroke
• impaired cell-mediated immunity
• reduced peripheral blood lymphocyte counts
• impaired T-cell activity

Question 27

What was observed after introduction of LPS (mimic infection) to stroke patients blood samples?

Answer 27

reduced cytokine production and when compared to those who had survived, there was most pronounced state of immunodepression in the patients who did not survive

Question 28

Why is vaccination in those already at increased risk of stroke?

Answer 28

to prevent an acute pre-stroke infection that may trigger a stroke event

Question 29

What are the inflammatory mediators of ischaemic stroke due to COVID-19 infection?

Answer 29

• cytokines (first released by respiratory epithelium, more released by T cells - amplification can lead to cytokine storm)
• NLRP3 inflammasomes (may induce plaque instability)
• inflammation-induced plaque vulnerability (predominance of T-cells, macrophages and neutrophils populating atheromatous plaque leading to rupture, elevation of proteolytic biomarkers such as MMPs)
• Oxidised LDLs (oxLDLs)
  (marker of oxidative stress, disruption of receptor mediated uptake of oxLDL)
• Neutrophil extracellular traps (NETs)
  (marker of inflammation related thrombosis)

Question 30

What are the effects of COVID-19 infection on coagulation and stroke risk?

Answer 30

Coagulation dysfunction:
- D-dimer (increased level is biomarker of impaired fibrinolysis leading to massive fibrin formation and thrombosis)
- reduction in natural anti-coagulant systems