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- 1. Glia Journal Club Review Paper: An Inflammation-centric view of neurological disease: beyond the neuron Authors: Stephen D. Skaper, Laura Facci, Morena Zusso, & Pietro Giusti Journal: Frontiers in Cellular Neuroscience Published: March 21, 2018 Andrew Roman May 12th, 2021
- 2. Introduction • Inflammation—the body’s response to tissue damage • Chronic Inflammation
- 3. Neuroinflammation • Acute and chronic • Central to PNS pathogenesis • Connections to immune system
- 4. Homotypic and heterotypic cell-cell interactions • Inflammation process – Microglia – Astrocytes • Mast cells and glia – Microglia – Astrocytes – Oligodendrocytes
- 5. Glia
- 6. Microglia • Various roles – Immunosurveillance – Phagocytosis – Antigens presented to T-cells – Cytokine/chemokine production – Regulatory
- 7. Complement receptor 3/C3 • Signaling pathway regulates phagocytosis • Retinal ganglion cells • Synaptic pruning – Activated in early AD – Synaptic loss Neuron, Volume: 74, Issue: 4, Pages: 691-705, First published: 24 May 2012, DOI: 10.1016/j.neuron.2012.03.026
- 8. CD11c+ microglia • Required for myelination and neurogenesis • Neonatal subset EMBO J, Volume: 36, Issue: 22, Pages: 3292-3308, First published: 28 September 2017, DOI: (10.15252/embj.201696056)
- 9. Activation states • M1 – Classic • M2 – Alternative polarization • Intermediate activation status – MS lesions • Dynamic range of phenotypes
- 10. Autoimmune encephalomyelitis (EAE) • Mouse model for MS – Inhibition of microglial secretions reduces severity – Transplanted polarized M2 microglia eases recovery Glia, Volume: 62, Issue: 5, Pages: 804-817, First published: 14 February 2014, DOI: (10.1002/glia.22643)
- 11. Two sides of microglia • Physiological – Homeostasis – Synaptic maturation • Pathological – Chronic inflammation Front. Cell. Neurosci., Volume: 12, Article: 72, Pages 1-26, First published: 21 March 2018, DOI: (https://doi.org/10.3389/fncel.2018.00072)
- 12. Astrocytes • Maintain blood brain barrier • Endothelial cells surrounded by astrocytic end feet • Regulate growth of axonal extensions • Myelination • Intracellular communication building
- 13. Injury and astrocytes • Increases reactivity • Growth factors
- 14. Microglial-astrocytic interaction • Autocrine/paracine mechanisms – Beneficial – Detrimental Front. Cell. Neurosci., Volume: 12, Article: 72, Pages 1-26, First published: 21 March 2018, DOI: (https://doi.org/10.3389/fncel.2018.00072)
- 15. Oligodendrocytes • Produce CNS myelin • Develop from migratory oligodendrocyte precursor cells (OPC) • Nourish axons
- 16. Monocarboxylate transporter 1 (MCT1) • releases lactate • mitochondrial ATP Curr. Opin. Neurobiol., Volume: 23, Issue: 6, Pages 1065-1072, First published: 4 October 2013, DOI: https://doi- org.ezproxy.lib.uh.edu/10.1016/j.conb.2013.09.008
- 17. OL lineage surface markers • Cells mature in response to factors • Cells express receptor-ligand pairs • Support long-term integrity of axons
- 18. Neuroinflammation is Amplified by Mast Cell—Glia and Glia—Glia Crosstalk
- 19. Complement system • Contributes to cross-talk • C5a and CD88 activity • CNS inflammation
- 20. C5a-C5a receptor pathway • brain inflammation injury – intracerebral hemorrhage • C5aR is crucial for microglia activity Mol. Neurobiol., Volume: 23, Issue: 8, Pages 6187-6197, First published: 5 October 2016, DOI: 10.1007/s12035-016-0141-7
- 21. C3 and Alzheimer’s Disease • Central complement factor • Interacts with microglial C3a receptor • β-amyloid pathology J. Neurosci., Volume: 36, Issue: 2, Pages 577-589, First published: 13 January 2016, DOI: https://doi.org/10.1523/JNEUROSCI.2117-15.2016
- 22. Astroglial NF-κB • Neuronal β-amyloid overproduction • Extracellular C3 • Alzheimer’s disease Neuron, Volume: 85, Issue: 1, Pages: 101-115, First published: 18 December 2014, DOI: https://doi.org/10.1016/j.neuron.2014.11.018
- 23. Works cited • Lian, H., Yang, L., Cole, A., Sun, L., Chiang, A. C.-A., Fowler, S. W., Shim, D. J., Rodriguez-Rivera, J., Taglialatela, G., Jankowsky, J. L., Lu, H.-C., & Zheng, H. (2015). NFKB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer's Disease. Neuron, 85(1), 101-115. https://doi.org/10.1016/j.neuron.2014.11.018 • Lian, H., Litvinchuk, A., Chiang, A. C.-A., Aithmitti, N., Jankowsky, J. L., & Zheng, H. (2016). Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease. J. Neurosci., 36(2), 577-589. https://doi.org/10.1523/JNEUROSCI.2117-15.2016 • Saab, A. S., Tzvetanova, I. D., Navem K.-A. (2013). The role of myelin and oligodendrocytes in axonal energy metabolism. Curr. Opin. Neurobiol., 23(6), 1065-1072. https://doi-org.ezproxy.lib.uh.edu/10.1016/j.conb.2013.09.008 • Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., Ransohoff, R. M., Greenberg, M. E., Barres, B. A., & Stevens, B. (2012). Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron, 74(4), 691-705. 10.1016/j.neuron.2012.03.026 • Skaper, S.D., Facci, L., Zusso, M., & Giusti, P. (2018). An inflammation-centric view of neurological disease: beyond the neuron. Front. Cell. Neurosci., 12(17), 1-26. https://doi.org/10.3389/fncel.2018.00072 • Wlodarczyk, A., Holtman, I. R., Krueger, M., Yogev, N., Bruttger, J., Khorooshi, R., Benmamar-Badel, A., Boer-Bergsma, J. J., Martin, N. A., Karram, K., Kramer, I., Boddeke, E. W., Waisman, A., Eggen. B. J., & Owens, T. (2017). A novel microglial subset plays a key role in myelinogenesis in developing brain. EMBO J., 36, 3292-3308. https://doi.org/10.15252/embj.201696056 • Yuan, B., Fu, F., Huang, S., Lin, C., Yang, G., Ma, K., Shi, H., & Yang, Z. (2016). C5a/C5aR Pathway Plays a Vital Role in Brain Inflammatory Injury via Initiating Fgl-2 in Intracerebral Hemorrhage. Mol. Neurobiol., 54(8), 6187-6197. 10.1007/s12035-016-0141-7 • Zhang, X.-M., Lund, H., Mia, S., Parsa, R., & Harris, R. A. (2014). Adoptive transfer of cytokine‐induced immunomodulatory adult microglia attenuates experimental autoimmune encephalomyelitis in DBA/1 mice. Glia, 62(5), 804-817. https://doi.org/10.1002/glia.22643 This presentation has been designed using resources from PoweredTemplate.com
Editor's Notes
- Various causes ie. infection Source is located and repaired Duration may vary Acute vs. chronic Tissue damage Regulatory mechanisms Immune system Medical burden
- Stimulation of glia Ordering of immune elements Chronic pain Autism Mood disorders Pro-inflammatory mediators Infection Stress
- Tissue-resident Blood-borne Immune-system derived
- Organizes complex multicellular interactions Cell death Neurogenesis Maturation Synaptic pruning
- (A) Immunohistochemistry for the alpha subunit of CR3 (CD11b) reveals that microglia express high levels of CR3/CD11b (left column) in the P5 dLGN (top panels) versus older ages (P20, bottom panels). Total microglia are visualized with GFP (CX3CR1+/EGFP, right column). Insets are magnified regions (red asterisks). Scale bar = 100 μm. (B) Immunohistochemistry in the developing dLGN for C3 (red). A single plane confocal image reveals that C3 levels are increased in the P5 dLGN versus older ages (P9, P60). Scale bar = 10 μm. (C and E) Representative surface rendered microglia (green) from P5 dLGN of WT (left) or KO (right) littermates in which RGC inputs were labeled with CTB-594 (red, contralateral) and CTB-647 (blue, ipsilateral). Insets are enlarged regions demonstrating reduced RGC input engulfment (red and blue) in CR3 (C) and C3 (E) KO mice. Grid line increments = 5 μm. (D and F) P5 CR3 KO (D) and C3 KO (F) mice (black bars) engulf significantly fewer RGC inputs as compared to WT littermates (white bars). All data are normalized to WT control values. (D) ∗p < 0.04 by Student's t test, n = 3 mice/genotype. (E) ∗p < 0.01 Student's t test, n = 4 mice/genotype. All error bars represent SEM. See also Figure S5.
- deletion of Igf1 from CD11c+ microglia leads to reduction of brain weight and significant impairment in primary myelination expression of CD11c is a marker for ‘primed’ microglia that are not fully activated but rather are in a pre-activation state (Holtman et al., 2015; Norden and Godbout, 2013). The appearance of CD11c + microglia has also been reported during postnatal development and normal aging (Bulloch et al., 2008; Kaunzner et al., 2012).
- or pro-inflammatory or neuroprotective M1 through M2
- EAE mice treated with M2 microglia have reduced inflammatory responses and less demyelination in the CNS at day 30 postimmunization (day 15 after adoptive microglia transfer) as assessed by immunohistochemistry. Schematic figure illustrated that CNS tissues from EAE mice were divided into 10 segments and stained with hematoxylin–eosin, luxol fast blue, and antibodies against Iba1 and GFAP, with inflammatory cell infiltration being assessed blindly in a semiquantitative fashion, from − (no infiltration) to +++ (severe infiltration). The infiltration scores indicated that transfer of M2 microglia led to diminished spinal cord destruction. Representative slices from lumbar spinal cord showed reduced degree of inflammation and demyelination in mice treated with M2 microglia. Fluorescent DiI‐labeled microglia (red) were detected in the olfactory bulb 24 and 72 h after delivery. DiI‐labeled cells were designated as microglia by staining with Iba1 (green) and DAPI (blue). DiI‐positive cells were detected in the brain‐draining deep cervical lymph nodes (LN) 72 h after delivery. **P < 0.01; ***P < 0.001. Data represent two independent experiments. Adoptive transfer of cytokine‐induced immunomodulatory adult microglia attenuates experimental autoimmune encephalomyelitis in DBA/1 mice
- Surveillance Functional & structural changes Length of exposure to activators Systemic inflammation Diabetes Obesity
- a highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from non-selectively crossing into the extracellular fluid of the central nervous system where neurons reside Ca2+ signaling Uptake/release
- Changes morphology GFAP expression+++ Proliferation Pro-inflammatory molecules
- Microglial phagocytosis debris clearance Anti-inflammatory cytokine production Trophic cell survival agents Unresolved pro-inflammatory molecules Pathological environment in brain BBB compromise Immune cell infiltration Gliosis Cell death
- Glial metabolic support for myelinated axons. Oligodendrocytes (green) myelinate and physically insulate long axons (brown), but properly assembled myelin does not deprive the axonal compartment from rapid access to metabolites. Capillaries and astrocytes (blue) provide a constant source of glucose, which enters oligodendrocytes and undergoes glycolysis. Lactate (or pyruvate) diffuses through glial cytoplasmic (‘myelinic’) channels, and reaches the periaxonal space (yellow) via monocarboxylate transporters (MCT1). Here, axonal uptake of glycolysis products (via MCT2) supports mitochondrial energy metabolism, and thereby, long-term functional integrity of myelinated axons. Note that glial metabolites will pass to myelinated axons through a series of myelinic channels (blue), which include the paranodal loops and the inner and outer lip of myelin. Astrocytes are gap junction-coupled (Cx47/Cx30) to oligodendrocytes and myelin. This panglial pipeline provides a physical connection between capillaries and axons, and allows distribution of ions and metabolites. Similarly in grey matter, astrocytic processes enwrap synapses, and provide metabolic support. During short periods of acute glucose shortage, astrocytes can hydrolyze glycogen, and sustain the supply of glucose and lactate to the oligodendroglial/axonal and synaptic compartments.
- proliferation migration differentiation survival neurotransmitters hormones prostaglandins nuclear receptors
- Complement system receptors NF-κB Brain-derived neurotrophic factor (BDNF) ATP
- microglia astrocytes
- C5aR enhanced microglia infiltration of the perihematomal region. After 3 days post ICH modeling, mice (n = 10 per group) were deeply anesthetized in a transcardial manner. The brains were removed and postfixed. The perihematomal region of cerebral tissue was collected, and microglia were analyzed with anti-Iba-1 antibody (×400 magnification, A–D). Experiments performed in triplicate showed consistent results. Data are presented as the mean ± standard error of mean (SEM) of three independent experiments. *P < 0.05
- Astrocytic C3 upregulation in APP transgenic mice. A, C, Representative double immunostaining for C3 and astrocytic marker GFAP in the hippocampus of APP/TTA transgenic mice at 8 months of age (A) and APP/PS1 transgenic (Tg) animals at 18 months (C). Littermate TTA and WT mice were used as controls for bigenic APP/TTA and Tg mice, respectively. B, D, Quantification of C3 fluorescence intensity in GFAP+ cells in APP/TTA (B) or Tg (D) hippocampal regions. N = 126 (TTA), 145 (APP/TTA), 87 (WT), 88 (Tg) cells collected randomly from sections of three animals per genotype. E, Representative double immunostaining for C3 and microglial marker Iba1 in the hippocampus of Tg animals. F, qPCR measurement of C3 mRNA levels in WT primary astroglial and microglial cultures treated with 100 nm Aβ42 or reverse peptide (rAβ42). Three internal controls (GAPDH, PGK1, and ACTB) were used. N = 3 cultures per condition. Scale bars: 50 μm. *p ≤ 0.05; ***p ≤ 0.001 (B, D, Student's t test; F, two-way ANOVA followed by Bonferroni's post hoc analysis)
- C3 targets astroglial NFKB which damages healthy neurons an effect corrected by blocking the C3aR (A) Double immunostaining of wild-type or IκBα KO astroglia (WTA or KOA) cocultured neurons with anti-synaptophysin (Syn) and anti-MAP2 (MAP2) antibodies. Scale bar, 10 μm. (B) Same as (A) except that anti-VGluT1 (VGluT1) antibody was used instead of Syn. The images underneath each panel are enlarged views of the bracketed areas. Scale bar, 10 μm. (C) Quantification of the number of Syn+MAP2+, VGluT1+MAP2+, or VGAT+MAP2+ synaptic puncta per 10 μm of dendrite in WTA and KOA cocultured neurons. nWTA Syn = 31, nKOA Syn = 28, nWTA VGluT1 = 57, nKOA VGluT1 = 52, nWTA VGAT = 45, and nKOA VGAT = 52 (Student’s t test). (D) Quantification of total MAP2-positive dendritic lengths in WTA and KOA cocultured neurons. nWTA = 38 and nKOA = 42 (Student’s t test). (E) Representative dendritic structure. Scale bar, 20 μm. (F) Quantification of dendritic complexity of WTA and KOA cocultured neurons by Sholl analysis. nWTA = 39 and nKOA = 44 (two-way ANOVA). (G) Double-staining of Syn and MAP2 of WT neurons treated with vehicle (PBS) or 5 μg/ml C3. Scale bar, 10 μm. (H) Quantified synaptic density of neurons treated with PBS or C3 at 1, 2, or 5 μg/ml. nPBS = 36, n1 μg/ml = 33, n2 μg/ml = 37, and n5 μg/ml = 29 (one-way ANOVA followed by Bonferroni post hoc analysis). (I) Representative dendritic structures of WT neurons treated with PBS or 5 μg/ml C3. Scale bar, 20 μm. (J) Dendritic complexity quantification of WT neurons treated with PBS or C3 at 1, 2, and 5 μg/ml. nPBS = 116, n1 μg/ml = 66, n2 μg/ml = 53, and n5 μg/ml = 68 (two-way ANOVA followed by Bonferroni post-hoc analysis). ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001. See also Figure S2.