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Florence Perrin
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Microglia in central nervous system pathologies - Microglia preconditioning
(priming)
Montpellier, October 20th 2020
Spanish anatomistsGlia = glue in Greek
Santiago Ramon y Cajal.Nobel prize with Golgi, 1906
Pío del Río Hortega, 1919.La reazione nera = Sylver
method.
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« Resting » surveillantor
ramified microglia
Activated microglia Phagocytic or« amoeboidmicroglia »
Microglia transformation upon activation (stress). First responders in
the CNS
Pío del Río Hortega
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Sentinel
The life of a microglia
1 – Enter the CNS during early development2 – « Invader » of mesodermal origin, amoeboid morphology3 – Use vessels and white matter tracts as « guidance » toenter the CNS
Development
In mature CNS (healthy/pathologies)
1 – Transformed into a branched, ramified morphology2 – Evenly dispersed throughout the CNS3 – Occupy a defined territory4 – Undergo morphological modifications in pathologicalconditions, acquire amoeboid morphology5 – Amoeboid microglia, migrate, proliferate and phagocytose
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Microglia: immune-competent cells of the CNS
1 – Constantly screen the environment
2 – Professional phagocytes of the brain
3 – Orchestrate the immune response
4 – Interact with infiltrating immune cells
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From the macrophage field, 2 types of activation states :- M1 state as the pro-inflammatory state- M2 state related to repair
Classification is questioned: microglial activation is a highly dynamic process
Debate: Replenishment of microglia from the blood systemin the adult and under pathological conditions ?
Microglia in pathological (stress) conditions
Intrinsic adult microglial population does not originate fromblood cells but only from an intrinsic source.
Intrinsic pool of microglia replaces the microglia populationif depleted.
However, in diseases with BBB damages there is aninfiltration of monocytes-derived macrophages.
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Detrimental
Inflammation (IL-6, TNFa, IL1b)Neurotoxicity
Trauma : scarAnti re-generativemolecules
Beneficial
Phagocytosis of cellular debrisSupress inflammation (IL-10; TGFb)Neuroprotection : non functionalsynapsesRemoval of apototic cells
Trauma : scarPro re-generative molecules
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Microglia in pathological (stress) conditions
Microglia in pathologies
brain tumors. Strongly infiltrated by intrinsicmicroglia and peripheral monocytes.
Microglia and macrophages areconsidered as the damaging elements in MS. Early eventspreceding demyelination and lesion formation.
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Glioma:
Neuro-Inflammatory diseases
Multiple sclerosis:
neuronal depletion, activation of microglia, andinfiltration of blood-born immune cells (BBB breakdown).Stroke:
Microglia in pathologies
Neurodegenerative diseases: misfolded proteins, debris,aggregates.Microglia express dedicated pattern recognition receptors(PRRs) that detect damage-associated molecular patterns(DAMPs) released by damaged cells. Stimulation of PRRs.Release of neuroinflammatory factors.
Microglia suround A-b plaques.Fibrillary forms of Aβ release of pro-inflammatory cytokines(IL-1β, IL-6, TNF-α, TGF-β, ROS…). Environment around Ab
express microglia chemoattractant.
Amyotrophic lateral sclerosis: SOD-1.
Microgliosis. a-synuclein
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Alzheimer’s disease:
Parkinson’s disease:
P30 P60 P90 P120P0 death
Before symptoms onset After symptoms onset
Degenerative processes
Gliosis
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Repartition
Decrease
Decrease
Control SOD SOD
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Gerber et al., 2012, PloS One. 7(4): e36000.
Control, P60
Control, P90
SOD, P60
SOD, P90
Iba1 CD11b Merge
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Activated microglia
Phagocytic« amoeboidmicroglia »
Microglia in trauma
The glial scar14
Microglia psychiatric disorders
expression of immune-relatedgenes increased in the brain. Changes in density andmorphology of microglia compatible with microglial activation.
Potential link: alterations of immune response during pre-natal and/or early post natal development.
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Schizophrenia: microglial abnormalities. Activated microglia,inflammatory cytokines, stimulate indoleamine 2, 3-dioxygenase activity, deplete CNS tryptophan, ultimatelylower levels of serotonin and alterations in glutamate,dopamine, and downstream ROS.
Autism Spectrum Disorder:
Affective Disorders:
Microglia and aging Aged microglia become more responsive to pro-inflammatory stimuli
Young
OldIncreased somaThicker processesLess motile
Less sensitive to IL-10; TGFb
More responsive toIL-6, TNFa,
IL1b
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IL-6, TNFa,
IL1b, ROSPro-inflammatory transcripts
Microglia priming Hypothesis: result from persistent neuroinflammationand/or exposure of microglia to misfolded proteins orneuronal debris (aging or neuropathological diseases).
Primed microglia: enhanced response in reaction toperipheral stimuli (peripheral inflammation, injury andstress).
Microglia priming: increased neuronal loss and enhancedprogression of neurodegenerative diseases.
LPS-induced pro-inflammatory activity in aged brain is notsuppressed by IL-10, TGF-β, or IL-4. Microglia priming isinsensitive to anti-inflammatory regulation.
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Microglia and lifestyle
USUAL SUSPECTS
COMMUNICATION
COMMUNICATION
Immune system
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Microglia modulation: early-life/prenatal and adulthood
Release of IL1b (cytokine) andprostaglandin PGE2
Hypothalamic-pituitary-adrenalaxis (HPA)
GCs
Elevated glucocorticoids (GCs) promote activation ofmicroglia.
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Early life stress primes microglia leading to a potentiatedresponse to subsequent stress.
GC release decreases motivation to obtain reward.PGE2 mediate elevated anxiety and social avoidance inducedby repeated social defeat.
Microglia activation facilitates recruitment of inflammatorymonocytes to the brain and reinforce stress-relatedbehaviors.
Thus, stress induced microglia alterations participate inthe regulation of some aspects of cognitive function.Stress : risk factor for depression, anxiety & psychiatricdisorders.
Neuroinflammation induced by
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Neuroinflammation induced by
Microglia express receptors for several metabolic factorsand hormones: they may participate in metabolic function.
High-fat diet / hypercaloric challenge / hypercholesterolemia
Reactive microglia (and astrocytes)
Over nutrition might prime the immune system: early-life/prenatal and adulthood
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Neuroinflammation induced by
Postmortem brains of alcoholics: increased microglialactivationAlcohol-induced activation of microglia: release of pro-inflammatory factors (TNF-a and ROS) that increaseneurotoxicity.
+Pro-inflammatory
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Balancing neuroinflammationMinocycline: broad-spectrumtetracycline antibiotic that cross theBBB, anti-inflammatory, anti-apoptoticand neuroprotective in animal models ofneurological diseases. Minocyclineinhibits neuroinflammation.
Ginseng: effect on microglia function.Inhibits iNOS, modulates increase inTNFa, Il-1b and IL-6 following LPS.Protective effects via phospho-p38,iNOS and COX-2
Honey (polyphenols), grapes (resveratrol), curcumin, fish oil (polyunsaturated fatty acid). 23
Balancing Neuroinflammation
Dietary restriction: attenuates age-related microglia and astrocytes activation
Exercise: Elevated expression of anti-inflammatory cytokines, and reduced levels ofpro-inflammatory cytokines.
Microglia in response to exercise producegrowth factors (BDNF and IGF1) which in turnkeeps the neuronal network intact and maintainsthe generation of new neurons
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References
Glial physiology and pathophysiologyA. Verkhratsky, A. Butt. Wiley-Blackwell
Microglia in Physiology and DiseaseSusanne A. Wolf, H.W.G.M. Boddeke and Helmut Kettenmann. Annu. Rev. Physiol. 2017. 79:619–43
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