Neuroinflammation

Question 1

What are glia cells and what is their function?

Answer 1

Glial cells = the innate immune-system in the brain
Maintains homeostasis in the central nervous system but can overreact in a way that can worsen neuronal damage
Two main types: microglia and astrocytes

Question 2

What are the roles of microglia?

Answer 2

Perform the role of the macrophage in the central nervous system:
• maintenance of homeostasis
• surveillance (detection of pathogenic disturbances)
• effector cell (remove pathogen by itself and by attracting and activating other cell-types)
• resolution of inflammation and restoration of tissue (healing)
• growth factor production
• phagocytic and antigen-presenting

Question 3

What are the two types of activation for resting microglia?

Answer 3

1. M1 = inflammatory reaction
2. M2 = anti-inflammatory reaction
   BUT the M1/M2 polarization paradigm is becoming less and less accepted and used

Question 4

What are the roles of astrocytes?

Answer 4

Supportive functions on neurons in ”resting conditions”:
• peri-synaptic astrocytes: neurotransmitter clearance
• ionic balance
• part of blood-brain barrier (BBB)
• neurotrophin (induce the survival, development and function of neurons) production

Question 5

How do gila cells evolve with age (4 things)?

Answer 5

• increase of reactivity
• decrease of phagocytosis
• decrease of neuronal support
• decrease of lysosomal function

Question 6

What is glial priming?

Answer 6

During the first infection: because of an aberrant neural activity and increased levels of pathogenic factors this leads to increased expression of pro-inflammatory genes
=> primed!
At a second infection there will be an exaggerated response

Question 7

What happens when there is a loss of homeostasis resulting in neuronal dysfunction and glial activation?

Answer 7

• impaired glutamate clearance (excitotoxicity)
• increased glutamate signaling
• activation of neurons (neuroinflammation)
• detrimental purine signaling from injured neurons

Question 8

What happens to an inflamed neuron?

Answer 8

Over expression of NF-kB protein complex induces gene activation which leads to decreased functionality and survivability of the neuron

Question 9

Generally speaking, what is important to maintain homeostasis in the brain?

Answer 9

Communication among neurons, microglia and astrocytes

Question 10

How can microglia respond to inflamed neuron?

Answer 10

• M2 activation and secretion of anti-inflammatory cytokines
• M1 inhibition by CD200 receptor binding with neuron

Question 11

How do specialized pro-resolving mediators (SPMs) act (secreted from apoptotic neutrophils after ”finishing their work” to stimulate their removal by phagocytosis, together with removal of other cellular and molecular debris, while down-regulating inflammation and stimulate regeneration)?

Answer 11

SPMs induce resolution in immune cells:
• downregulate inflammation
• inhibit neutrophil infiltration by reducing vessel permeability
• increased phagocytosis

Protective effects on:
• neurons in vitro
• immune-cells
• cardiomyocytes

Question 12

Why is neuroinflammation in Alzheimer’s disease considered a vicious circle?

Answer 12

• Inflammatory regulatory element (NF-kB) on the APP gene
• Inflammation promotes amyloidogenic processing of APP
• Aß can induce inflammation
• Dead neurons activate glia
• Neuronal kinases activated by inflammation can phosphorylate tau
+ decrease of specialized pro-resolving mediators (SPMs)