Neuroinflammation Flashcards
Which cells are the resident immune cells of the brain?
Microglia
What does it mean for the brain to be immune privileged?
Microglia are the first line of defence
The BBB significantly limits the entry of immune cells (T cells) in to the brain under normal conditions
What are microglia and astrocytes activated by?
Damaged cells (DAMPS)
Macromolecules (PAMPS)
What can prolonged activation of astrocytes and microglia lead to?
The production of damaging molecules that contribute to the pathogenesis of several neurological disorder
Name some diseases in which prolonged activation of microglia and astrocytes is implicated in
Alzheimers and Parkinsons
Name the three components of the immune system in the brain
- Microglia
- T cells, B Cells and macrophages can infiltrate the CNS from periphery
- Astrocytes, while not immune cells, play an auxiliary role in immune response
Under normal conditions how many T and B cells are in the brain?
Very few are present as the brain is immune privileged
Which cells have innate immune receptors also found in T cells, macrophages etc ?
Microglia, Astrocytes, Neurons, and Endothelial cells
Give an example of a PAMP in the CNS
Microbial/viral proteins
Give an example of DAMPS in the CNS
Misfolded and aggregated proteins - beta amyloid- in Alzheimers and alpha-synuclein in Parkinsons
Extracellular nucleic acid (RNA/DNA) - dead neurons are engulfed away (like in the SN in Parkinson’s)
Give examples of when neuroinflammation is okay
Short term activation is fine
- Recruitment of T and B cells to remove infection
- Clearance of dead neurons during developmental pruning
When is neuroinflammation bad?
Prolonged neuroinflammation has been implicated in development and progression of neurological disorders such as Alzheimer’s and Parkinson’s.
Describe the activation of microglia
Binding of PAMPS and DAMPS activate microglia –> Change morphology and become mobile.
Depending on activation signals, become M1 or M2-like
What are Astrocytes activated by?
DAMPS, PAMPS, cytokines and chemokines
What do neurotrophic factors do?
They send a message to the neurons to keep living
Pro-survival signals
Which brain cells act as APCs?
Microglia
Compare M1 and M2 microglia
M1s:
↓ neurotrophic factors
↑ pro-inflammatory cytokines
Make free radicals and they lead to: •Chronic brain inflammation •Damage to neurons •Neuronal dysfunction
M2:
↑ phagocytosis
↑ neurotrophic factors
Antigen presentation
can be switched off easily
Make anti-inflammatory cytokine and they lead to: •Clearance of debris •Resolution of inflammation •Limited or no damage to neurons
Activation of microglia can produce signalling molecules that affect which other cells of the CNS?
Astrocytes, neurones, BBB
Which signalling molecules are released by activated microglia?
Cytokines, Chemokines, NO and ROS
What do cytokines do in neuroinflammation?
Activate further microglia and astrocytes
Induce apoptosis and necrosis of neurons, astrocytes, microglia
Name some cytokines involved in neuroinflammation
IL-1β, IL-6, IFN-g, TNF-a (Can activate apoptosis)
What is the role of chemokine in the brain?
Promote BBB permeability (letting T cells in eg.)
Cause dysfunction and apoptosis/necrosis of astrocytes, microglia and neurons
What effect do NO and ROS have in the brain?
Damage DNA, proteins, lipids
Induce apoptosis/necrosis of astrocytes, microglia and neurons
How does an unreactive astrocyte compare in morphology to a reactive one?
The astrocyte leaflet is thicker
What are the 2 types of reactive astrocytes?
Hypertrophic ansd scar-forming
Compare the functions of hypertrophic anf scar forming astrocytes
Hypertrophic: Affect function of neighbouring cells via cytokines, chemokines, NO, neurotrophic factors
Are similar to microglia
Scar-forming:
Permanent rearrangement of brain architecture
Are activated in case of serious brain trauma
Compare hypertrophic vs scar-forming astrocytes in their behaviour
Hypertrophic don’t proliferate, scar-forming do
Hypertrophic don’t migrate, scar-forming do
Hypertrophic have individual territory, scar forming don’t
Hypertrophic are reversible if stimuli is removed, scar-forming are permanent
Hypertrophic interact with neurons, oligodendrocytes, BBB and scar-forming interact with non-neuronal inflammatory cells
Give examples of the actions of hypertrophic and scar-forming astrocytes
Hypertrophic: reactive astrocytes at BBB change shape and release chemokines increasing permeability of BBB to T cells
Scar-forming: form physical border around inflamed or damaged tissue thus segregating area from neighbouring functional neuronal circuits
What are the two steps for T/B cells and macrophages to enter the BBB?
Crossing the endothelial cell lining and breaching the glial limitans
Describe the process of T cells crossing the endothelial cell lining
T cells breach endothelial lining and remain in perivascular space where they have access to antigen presenting cells
T cells undergoing immunosurveillance can drain away via CSF
If they present to antigen, T cells undergo transendothelial migration
What is trans endothelial migration?
Entry of T cells and other immune cells strictly regulated by the BBB
Give examples of some molecules involved in trans endothelial migration
Endothelial cells (Selectins, ICAM-1)
T cells (Integrins)
Describe the steps of trans endothelial migration?
- Capture/Rolling: T cell integrin binds to VCAM-1 on the endothelium, T cell PSGL-1 binds to P-selectin on the endothelium
- Chemokines can bind to T cells to activate them
- Arrest: ICAM-1 Binds to T cell integrins
- Crawling: ICAM-2 binds
- Diapedesis - paracellular or transcellular (there is debate as to which is correct)
Describe the process of breaching the glial limitans
Presentation of antigens and/or expression of pro-inflammatory molecules such as chemokines and cytokines allows entry of T cells into the CNS
Cross glial limitans because cytokines make astrocyte feet and pericytes relax and allow the BBB to open
What is the glial limitans?
It is a wall of protein
Describe MS demographics
~ 1/1000 in UK
Affects women more than men
What is MS?
Autoimmune diseases
Immune cells attack myelinated neurons
What are the pathological hallmarks of MS?
Inflammation,
Demyelination, Remyelination, Neurodegeneration and Glial scar formation
-Usually inflammation happens and then stops and repeats (heals)
What happens every time the BBB opens?
It gets damaged a bit
What are focal plaques?
Places in MS where demyelination occurs
How does demyelination have an affect in MS?
Demyelinating disease disrupts conduction of action potentials along neurons.
What causes MS?
Unknown
Describe the role of inflammatory cells in MS
T cells and microglia: At active lesions initial response is from T cells and activated microglia.
Myelin damage correlates with T cell and activated microglia number
T/B cells and macrophages: Once myelin gets destroyed, secondary recruitment of T cells, B cells and macrophages leads to profound damage to BBB
What effect does MS have on myelination?
Loss of oligodendrocyte processes and oligodendrocyte apoptosis
Myelin highly susceptible to damage from cytokines and reactive oxygen species
Why does relapsing and remitting MS turn into progressive?
Due to increasing damage to the BBB
Which diseases are reactiveastrocytes and microglia found in?
Alzheimer’s and Parkinson’s disease
Is neuroinflammation a cause or consequence of disease?
Might be because of varients in microglia
Or could be reacting to the already existing dead neurons
Why does beta-amyloid activate microglia?
It mimics bacterial cell walls
What is the most likely role of neuroinflammation in disease progression?
Prolonged activation and release of mediators such as cytokines and ROS/NO
