Lecture 5: Microglia, Ependymal, and Endothelial Cells

Why has the brain been considered an immunologically privilged site?

the BBB normally restricts the access of immune cells from the systemic blood

The CNS has its own immune system in place that are activated during cerebral inflammation, injury, and disease. What is this referring to?

microglia cells

What are microlgia?

phagocytes which remove pathogens, debris left by dead cells, or degenerating cells

True or False: Microglia cells are estimated to be 5-20% of total cells in the healthy brain.

true

What are the important microglia functions during development?

• phagocytose degenerating cells that had undergone programed cell death during development

• secrete cytokines and growth factors important for fiber tract development, gliogenesis, and angiogenesis

True or False: Microglia actively contributes to the initiation and progression of CNS disorders including Alzheimer’s disease, ALS, and brain tumors.

true

What presents antigens to T lymphocytes during CNS injury?

microglia cells (MGs)

What are the 2 states of microglia?

• homeostatic MGs

• activated MGs

True or False: MGs react to severe CNS injury, neuronal death, and inflammation by changing their morphology with rapid clonal expansion.

true

What are the core properties of MGs?

• surveillance of homeostatic MGs

  • act as sentinels constantly surveilling the brain environment and adapting their functions to specific triggers (local environment)

• phagocytosis

  • phagocytose pathogens and damaged cells that may threaten the brain homeostasis and function

• secret soluble factors

  • secrete pro-inflammatory and anti-inflammatory factors controlling the inflammatory response in the brain

• neuroinflammation

  • initiate and amplify inflammatory responses

  • recruiting and activate immune cells (T & B cells)

What are the multi-faceted functions of MGs?

• neurogenesis

• myelination

• inflammation

• vasculogenesis

• BBB permeability

• tissue repair

• neuronal function

• synapse remodeling

Describe the role MGs play in neurogenesis.

MGs regulate neuronal proliferation, migration, and survival by secreting growth factors (IGF-1)

Describe the role MGs play in myelination.

MGs help oligodendrocytes maintain and repair the myelin, thereby affecting neuronal excitability

Describe the role MGs play in inflammation.

MGs activate T-cells to become pro-inflammatory and release inflammatory factors that will initiate or regulate the immune response

Describe the role MGs play in vasculogenesis.

MGs secrete growth factors and cytokines that promote vasculogenesis

Describe the role MGs play in BBB permeability.

MGs promote the infiltration of peripheral immune cells into the brain parenchyma

Describe the role MGs play in synapse remodeling.

MGs modify the synapse by partial phagocytosis, prune defective synapses, and insert between pre- and post-synaptic membranes

Describe the role MGs play in neuronal function.

MGs recruit astrocytes and assist them in controlling neurotransmitter levels

Describe the role MGs play in tissue repair.

after removing threats, MGs support tissue repair and wound healing in CNS injuries

True or False: MGs secrete TNF-alpha and IL-1B that increase the expression of leukocyte adhesion molecules on vascular endothelial cells, promoting the BBB permeability/leakage.

true

What do MGs originate from?

yolk sac precursors

After MGs originate from the yolk sac, what happens?

MGs undergo differentiation to be in many different states depending on the spatiotemporal context

True or False: Under normal, healthy conditions, MGs maintain a homeostatic state expressing unique markers (Tmem119, P2RY12) that set them apart from monocyte-derived macrophages. Throughout adulthood, MGs undergo turnover every 4 years.

true

What do microglia states depend on?

• intrinsic determinants: species, ontogeny, sex, or genetic background

• the specific context they inhabit: age, spatial location, and environmental factors including nutrition, microbiota, pathogens, and drugs

Intrinsic determinants and the context affect microglia at multiple levels such as epigenomic, transcriptomic, proteomic, metabolomics, structural, and phenomic, which ultimately determines what?

the different microglia functional and morphological states

What do MGs do in response to brain injury? What does this result in?

MGs undergo activation and down-regulate gene markers for the homeostatic state; it becomes challenging to distinguish MGs from monocyte-derived macrophages and other brain-resident macrophages (meningeal, perivascular, and choroid plexus macrophages)

What are ependymal cells?

multi-ciliated glial cells that form an epithelium lining the inner surfaces of the cerebral ventricles and the central canal of the spinal cord

True or False: Ependymal cells are located at the interface between CSF and brain parenchyma is critical in forming the brain-CSF barrier of the choroid.

true

Ependymal cells have apical ciliary clusters that beat in a coordinated manner to do what?

whirl CSF and regulate its unidirectional flow

How do ependymal cells maintain CSF composition?

by facilitating the transport and exchange of ions, metabolites, growth factors, and waste at the CSF-brain interace

What is hydrocephalus?

a medical condition where CSF builds up in ventricles and often occurs after infection and brain injury

What are some abnormalities in ependymal cells?

• reduced ciliary beating

• increased intracellular space due to changes in tight junctions

• cilia thickening or loss

• detachment of ependymal cells

What do endothelial cells do?

• form cerebral vasculature

• maintain intracerebral milieu

List the cerebral vasculature from outermost to innermost.

1. dura mater

2. subdural space

3. arachnoid membrane

4. subarachnoid space

5. pia mater

6. artery

7. brain

What is stroke?

progressive occlusion of a large arterial trunk

What is vascular dementia?

lesions of small cerebral arterioles by microinfarcts

What is perivascular or vasogenic edema?

accumulation of fluids from the blood

Describe the structures of the cerebral capillary.

• cerebral capillary wall is composed of an endothelial cell, which surrounds the capillary lumen

• a thin basement membrane (basal lamina) surrounds 2 main structural components of the capillaries (pericytes and endothelial cells)

• endfeet of perivascular astrocytes are opposed against this basement membrane

• inter-endothelial tight junctions (Zonula occludens)

• Zonula occludens is unique to brain endothelial cells because it mediates restricted solute transfer via a series of active genes

True or False: Inter-endothelial space in systemic circulation mediates passive solute transfer such as diffusion.

true

What are the regions that lack BBB?

• area postrema

• periventricular organs (hypothalamus, pineal body)

Why are the regions lacking BBB so special?

peptides and other physiological signals in the blood have direct access to neurons of the brain areas with vital autonomic control of the body (cardiovascular function, feeding, and metabolism)