HTHSCI 1DT3 Study Guide - Quiz Guide: Homeobox, Fate Mapping, Mitogen
23 Jun 2018
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Describe the role of microglia:
i) in the healthy brain
i) how they adapt and change with infection
iii) what role they play in degenerative disease. Refer to specific examples in your answer
Introduction
Microglia are resident mononuclear phagocytes that form part of the immune defence in the
central nervous system.
Several types of CNS macrophages:
Ramified microglia – immune surveillance in brain parenchyma
Perivascular macrophage
Meningeal macrophage
Choroid plexus macrophage
‘Ramified’ Microglia are ‘normal, resting state’ microglia, with many long processes.
Dynamic changes to microglial processes de novo. Can quickly change into activated
microglia (reactive state) when necessary.
Distributed throughout the CNS, important immunological role in the CNS including:
Primary defence (in injury / infection)
Removal of cell debris
Trophic support
Neuroprotection.
Constant monitoring of extracellular environment, and direct contact with neurons,
astrocytes, blood vessels.
Idea that they arise from outside the CNS during development (and migrate into CNS) –
myeloid origin?
Ransohoff, Cardona (2010) – PU1 important gene for myeloid cell differentiation (including
macrophages). KO PU1 resulted in no microglia being detected in CNS of null mice
(suggest they are myeloid origin).
Believed that expansion of microglia occurs in-situ in brain parenchyma following migration.
Healthy Brain – can be defined as undisrupted BBB?
Vallieres (2003) irradiation of host rat to kill bone marrow, and then transplantation of GFP-
labelled bone marrow cells from donor (transgenic) rat – showed GFP+ve perivascular cells,
but no ramified microglia in host. Mildner (2007) further showed only presence of GFP+ve
microglia in spinal cord.
Believed that in non-disrupted BBB (i.e. ‘healthy brain’), bone marrow progenitors infiltrate
CNS and form perivascular macrophages (around blood vessels) only.
Microglia maintained through endogenous proliferation within brain?
Neurones provide ‘calming’ signals to maintain quiescent state of microglia, and reduce
antigen presentation processes:
CD200 receptor on neurone / CD200R on microglia
Electrical activity in neurons inhibits microglia activation
Fractalkine produced by neurones bind CX3CR1 on microglia (stop activation)
Adaptations to Infection (With/without BBB disruption)
Change from highly ramified morphology to short processes with enlarged soma.
New microglia derived from significant endogenous proliferation of existing microglia.
Mildner (2010) – circulating monocytes preferentially recruited to lesioned brain. Only
differentiated into microglia if brain was irradiated (and blocked existing microglia from
dividing).
May occur with neuronal dysfunction or injury, leading to disinhibition of microglial
quiescence.
Microglia sense infection/inflammatory stimuli by:
Pattern Recognition Receptors (TLR, CR3)
Fc receptors – upregulated with activation
Complement Receptors
Chemokine Receptors
Cytokine Receptors
Activated microglia – multiple functions:
Cell proliferation, migration
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Cell proliferation, migration
Secretion of pro-inflammatory mediators (e.g. TNFa, IFNg, IL-1)
Secretion of anti-inflammatory and neurotrophic factors (TGFß, IL-4)
Cytotoxic factors (NO, ROS, Glutamate)
Prostanoids (PGD2, PGE2)
Antigen presentation capability increased
Upregulated MHC Class II Receptors
Increased T-Cell antigen presentation
Stimulation of CD4 Th Cells to produce cytokines
Phagocytosis
Upergulation of immune cell surface receptors
Rat Facial Axotomy Model – Shows neuroprotective role of microglia
Axotomy of facial MN in periphery – causes immediate microglia response in facial
nucleus.
Microglia activated by fractalkine signalling, and massive ATP release from
distressed neurones. Possibly massive release of fractalkine above normal ‘baseline
levels’ induces proliferation of microglia, or fractalkine in combination with massive
ATP release?
Days after axotomy:
Activated microglia surround axotomised perikarya
Do not display phagocytosis, but release neuroprotective/regenerative factors
e.g. TGFß
Deafferentation – protects axotomised neurons from afferent excitatory
impulses
Weeks after axotomy – microglial activation subsides following successful
regeneration (i.e. successful whisker movement). Microglia die by apoptosis.
However, severe insult causes drastic neurotoxic effects of microglia:
Microglia activity surpass host tolerance mechanisms
Excess acute, or sustained chronic activation is detrimental to neurons
Seen in degenerative diseases (below).
Activated microglia activity can be measured by PK11195 to show detrimental
effects – but limitation is that not all activated microglia are bad?
Degenerative Disease
Alzheimer’s Disease – Neurodegenerative tauopathy, degeneration of neurons (associated
with accumulation of hyperphosphorylated tau in PHF/NFT, and Aß plaques).
Neurotoxic – Accumulation of microglia in senile plaques, animal models of AD
Induces chronic neuroinflammatory changes – increased microglial activation
throughout disease progression.
Neuroprotective role – Simard (2006) showed microglia can phagocytose Aß
plaques and restrict plaque formation.
El Khoury (2007) early microglial accumulation in AD delays disease progression.
But could progressive positive feedback and activation of microglia be both
detrimental and neuroprotective? (Despite neuroprotective nature of phagocytosing
Aß plaques, they produce more neurotoxic elements e.g. ROS, TNFa, IFN, IL that
cause neuroinflammation and neurodegeneration)
MS
MS is a chronic, inflammatory demyelinating degenerative disorder of myelination in
the central nervous system.
MS characterised by stages of inflammation, demyelination, axonal loss and
neurodegeneration.
Microglial role identified in throughout all phases of the disease.
Inflammation occurs through:
Free radical release by peripheral immune cells/activated microglia (OH-,
OON-, NO),
Glutamate release by microglia causes excitotoxicity,
Cytokine release by immune cells and microglia (TNF, IL1ß, IFN-g)
Initial lesions also demonstrate apoptotic oligodendrocytes and activated microglia,
even before inflammatory responses?
Activated T-Cells infiltrate into brain parenchyma, release inflammatory cytokines
that activate microglia.
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that activate microglia.
Activated microglia release cytokines and NO mediating initial attack.
Microglia engulf myelin, present to CD4+ and cause further activation of T-
Cell/microglia.
Myelin activated microglia also release proinflammatory cytokines (IL1, IL6, TNF)
that directly damage oligodendrocytes, myelin sheath and axons.
Parkinson’s
Alcoholic Brain Damage
Evidence shows alcohol can activate microglia by TLR4 stimulation
TLR4 associated with increased ROS production and neuroinflammation
TLR4 KO mice showed a marked reduced microglial response
Conclusion
Importance of microglia
Neuroprotective, but can have neurotoxic activity if above tolerance threshold
Important in understanding the role, to mediate appropriate modulatory therapy that
can improve neurodegenerative disorder progression?
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Document Summary
Describe the role of microglia: in the healthy brain, how they adapt and change with infection, what role they play in degenerative disease. Introduction o o o o o o o o o. Microglia are resident mononuclear phagocytes that form part of the immune defence in the central nervous system. Ramified microglia immune surveillance in brain parenchyma. Ramified" microglia are normal, resting state" microglia, with many long processes. Can quickly change into activated microglia (reactive state) when necessary. Distributed throughout the cns, important immunological role in the cns including: Constant monitoring of extracellular environment, and direct contact with neurons, astrocytes, blood vessels. Ransohoff, cardona (2010) pu1 important gene for myeloid cell differentiation (including macrophages). Ko pu1 resulted in no microglia being detected in cns of null mice (suggest they are myeloid origin). Believed that expansion of microglia occurs in-situ in brain parenchyma following migration. Healthy brain can be defined as undisrupted bbb? o o o o.
