Microglia preconditioning (priming) in central nervous system pathologies Florence Perrin florence.perrin@umontpellier.fr Montpellier, October 2018 1
Spanish anatomists Glia = glue in Greek Santiago Ramon y Cajal. Nobel prize with Golgi, 1906 Pío del Río Hortega, 1919. La reazione nera = Sylver method. 2
Microglia : definition During development 1 Enter the CNS during early development 2 «Invader» of mesodermal origin with amoeboid morphology 3 Use vessels and white matter tracts as «guidance» to enter the CNS In mature CNS (healthy/pathologies) 1 Transformed into a branched, ramified morphology 2 Evenly dispersed throughout the CNS 3 Occupy a defined territory 4 Undergo morphological modifications in pathological conditions, acquire amoeboid morphology 5 Amoeboid microglia, migrate, proliferate and phagocytose 3
Microglia transformation upon activation «Resting» surveillant or ramified microglia Activated microglia Phagocytic or «amoeboid microglia» Sentinel Pío del Río Hortega 4
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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 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 7 dynamic process
Microglia in pathological conditions Debate: Replenishment of microglia from the blood system in the adult and under pathological conditions? The intrinsic adult microglial population does not originate from blood cells but only from an intrinsic source. The intrinsic pool of microglia replaces the microglia population if depleted. However, in diseases with BBB damages there is an infiltration of monocytes-derived macrophages. 8
Microglia in pathological conditions Beneficial Phagocytosis of cellular debris Supress inflammation (IL-10; TGFb) Neuroprotection : non functional synapses Removal of apototic cells Trauma : scar Pro re-generative molecules Detrimental Inflammation (IL-6, TNFa, IL1b) Neurotoxicity Trauma : scar Anti re-generative molecules 9
Microglia in pathologies Glioma: brain tumors. Strongly infiltrated by intrinsic microglia and peripheral monocytes. Neuro-Inflammatory diseases Multiple sclerosis: Microglia and macrophages are considered as the damaging elements in MS. Early events preceding demyelination and lesion formation. Stroke: neuronal depletion, activation of microglia, and infiltration of blood-borne immune cells (BBB breakdown). 10
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. Alzheimer s disease: 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. Parkinson s disease: Microgliosis. a-synuclein Amyotrophic lateral sclerosis: SOD-1. 11
Control SOD SOD Before symptoms onset After symptoms onset Degenerative processes Gliosis P0 P30 P60 P90 P120 death Decrease Repartition + Decrease Gerber et al., 2012, PloS One. 7(4): e36000. 12
Iba1 CD11b Merge Control, P60 SOD, P60 Activated microglia Control, P90 SOD, P90 Phagocytic «amoeboid microglia» 13
Microglia in trauma The glial scar 14
Microglia psychiatric disorders Autism Spectrum Disorder: expression of immune-related genes is increased in the brain. Changes in density and morphology of microglia compatible with microglial activation. Potential link with alterations of immune response during prenatal and/or early post natal development. Affective Disorders: Schizophrenia: microglial abnormalities. Activated microglia, inflammatory cytokines, stimulate indoleamine 2, 3- dioxygenase activity, deplete CNS tryptophan, ultimately lower levels of serotonin and alterations in glutamate, dopamine, and downstream ROS. 15
Microglia and aging Aged microglia become more responsive to proinflammatory stimuli More responsive to IL-6, TNFa, IL1b Young Old Increased soma Thicker processes Less sensitive to IL-10; TGFb Less motile IL-6, TNFa, IL1b, ROS 16 Pro-inflammatory transcripts
Microglia priming Hypothesis: result from persistent neuroinflammation and/or exposure of microglia to misfolded proteins or neuronal debris (aging or neuropathological diseases). Primed microglia: enhanced response in reaction to peripheral stimuli (peripheral inflammation, injury and stress). LPS-induced pro-inflammatory activity in aged brain is not suppressed by IL-10, TGF-β, or IL-4. Microglia priming is insensitive to anti-inflammatory regulation. Microglia priming: increased neuronal loss and enhanced progression of neurodegenerative diseases. 17
Microglia and lifestyle COMMUNICATION Immune system COMMUNICATION USUAL SUSPECTS 18
Microglia modulation: early-life/prenatal and adulthood Elevated glucocorticoids (GCs) promote activation of microglia. GCs Release of IL1b (cytokine) and prostaglandin PGE2 Hypothalamic-pituitary-adrenal axis (HPA) 19
Neuroinflammation induced by Early life stress primes microglia leading to a potentiated response to subsequent stress. New neuroimmune circuit: microglia activation facilitate the recruitment of inflammatory monocytes to the brain and reinforce stress-related behaviors. GC release decreases motivation to obtain reward. PGE2 mediate elevated anxiety and social avoidance induced by repeated social defeat. Thus, stress induced microglia alterations participate in the regulation of some aspects of cognitive function. Stress : risk factor for depression, anxiety & psychiatric disorders. 20
Neuroinflammation induced by Microglia express receptors for several metabolic factors and hormones: they may participate in metabolic function. High-fat diet / hypercaloric challenge / hypercholesterolemia Reactive microglia (and astrocytes) early- Over nutrition might prime the immune system: life/prenatal and adulthood 21
Neuroinflammation induced by Postmortem brains of alcoholics: increased microglial activation Alcohol-induced activation of microglia: release of proinflammatory factors (TNF-a and ROS) that increase neurotoxicity. + Pro-inflammatory factors 22
Balancing neuroinflammation Minocycline: broad-spectrum tetracycline antibiotic that cross the BBB, anti-inflammatory, anti-apoptotic and neuroprotective in animal models of neurological diseases. Minocycline inhibits neuroinflammation. Ginseng: effect on microglia function. Inhibits inos, modulates increase in TNFa, 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 antiinflammatory cytokines, and reduced levels of pro-inflammatory cytokines. Microglia in response to exercise produce growth factors (BDNF and IGF1) which in turn keeps the neuronal network intact and maintains the generation of new neurons. 24
References Glial physiology and pathophysiology A. Verkhratsky, A. Butt. Wiley-Blackwell Microglia in Physiology and Disease Susanne A. Wolf, H.W.G.M. Boddeke and Helmut Kettenmann. Annu. Rev. Physiol. 2017. 79:619 43 25