Intro to Neuroinflammation

Question 1

List the groups of inflammatory mediators.

Answer 1

• Cytokines (cyto=cell, kinos = movement) → interleukins, interferons, TNFs, TGFs
• Chemokines → CCs, CXCs, CXXXCx
• Eicosanoids (signaling molecules made by oxidation of fatty acids) → prostaglandins, leukotrienes
• Amines → histamine, ATP
• Growth factors/hormones → NGF, VEGF, Leptin
• Enzymes → MMPs
• Free radicals → nitric oxide, H2O2

Question 2

What is the function of inflammation and what are is 5 cardinal features.

Answer 2

•	First response of the immune system to infection or injury
•	Is protective – removes injurious stimuli and is involved in healing
•	First defined by Cornelius Celsus
•	5 cardinal features:
−	Rubor → redness
−	Color → heat
−	Tumor → swelling
−	Dolor → pain
−	Functio laesa → loss of function

Question 3

Why was the brain thought to be an immune privileged site, with no inflammation?

Answer 3

Does inflammation occur in the nervous system?
• Had you asked this 20 years ago, people would have said no
• The brain was considered an immune-privileged site, and people didn’t believe immune cells could penetrate

Why?
• There are no B or T cells
• People think there is no lymph (although recent research suggests there may be)
• Thought that the BBB rendered the brain impermeable
− Paul Ehrlich → when staining in animals, noticed that the brain was never stained
− Edwin Goldmann → injected dye into the brain CSF, the brain stained by the rest of the body did not

The BBB:
• Endothelial cells in the blood vessels that line the brain are different than those lining blood vessels in the periphery
− Astrocyte end-feet and pericytes surround the vessel almost completey
− Tight junctions and cadherin-mediated adherans junctions exist between the endothelial cells. These don’t exist in the periphery
− Transport proteins are lowly expressed in the brain endothelial cells

Question 4

What evidence suggests that the brain is not immune privileged, and inflammation does occur?

Answer 4

• The CNS is capable of dynamic immune and inflammatory responses to a variety of insults
• Immune cells can be found in the brain during disease, eg) neutrophils after stroke
• The brain contains resident immune cells (microglia) that response in a similar way that macrophages do
• Brain cells (microglia) can respond to infection/injury and release inflammatory mediators

Question 5

What are the inflammatory cells within the CNS?

Answer 5

Microglia:
• Main immune cells of the brain (derived from the myeloid macrophage lineage)
• Express PRRs
• Rapidly activated in response to CNS infections/injury
• Act as ACPs (express MHC) and phagocytose
• Produce large amounts of inflammatory mediators

Astrocytes
•	Express some PRRs
•	Express cytokine and chemokine rceptors
•	Express various inflammatory mediators
•	Involved in the glial scar formation

Neurons
• Express some cytokine and chemokine receptors
• Express some inflammatory mediators
• Involved in neuro-immune interactions

Oligodendrocytes
• Express cytokine and chemokine receptors
• Express some inflammatory mediators
• Key player in the pathogenesis of MS, because they make myelin

Endothelial cells
• Key sensors of peripheral and central infection (PRRs, cytokine receptors)
• Key plays in neutrophil extravasation
• Key produces of chemokines

Question 6

What is the glial scar

Answer 6

• Gliosis is a reactive cellular process that occurs after injury to the CNS
• The glial scar is the bodies mechanism to protect and begin the healing process in the nervous system
• Has both beneficial and detrimental effects
− Many neuro-developmental inhibitor molecules are secreted by cells within the scar that prevent complete recovery of the CNS.
− On the other hand, absence of the scar has been associated with impairments in the repair of the BBB.

Question 7

What are the general features of neuroinflammation?

Answer 7

• Glial cell activation
− Microglia, astrocytes (resident)
− Macrophages can get in during injury
• Synthesis of inflammatory mediators
− Cytokines, free radicals, prostaglandins, complement, chemokines
− Neurones are very sensitive to these
• Oedema
− Swelling – bad in the brain, because it is encased in the skull.
− Often what kills people after stroke etc, rather than the injury itself.
• Expression of adhesion molecules
− A way for immune cells to get in from the periphery
− Selectins, ICAMs etc…
• Invasion of immune cells not normall found in the brain
− Eg) In MS, see T cells in the spinal cord
• Disruption of the BBB