Psychoneuroimmunology Immune System & Neuroinflammation …

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Psychoneuroimmunology Immune System &

Neuroinflammation Basics:Part 1 in PNI Series

October 2018 MRC2.PSY.D.00036


This presentation is sponsored by Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) and Lundbeck.

Materials were developed in collaboration with Vladimir Maletic, MD, University of South Carolina School of Medicine.

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Provide an understanding of the immune system, including key cell types

Describe mechanisms by which peripheral inflammation is transmitted to the central nervous system

Elucidate the key cell lines and processes underlying neuroinflammation

Outline potential causes and consequences of neuroinflammation

Discuss potential treatment modalities targeting neuroinflammation

Objectives

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Overview

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Basics of the Immune System

What is Inflammation?

Types of Inflammation: Peripheral vs Central Nervous Systems

Inflammatory Response in the Brain

Underlying Mechanisms

Key Cell Lines/Players Involved

Potential Causes of Inflammation

Treatments Targeting Neuroinflammation


Overview of The Immune

System &

Inflammation

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The Immune System



What Is Inflammation?• Local accumulation of fluid, plasma proteins, and white blood cells

due to physical injury, infection, or local immune response1,3

Acute inflammation: early and frequent transient episodes1,3

Chronic inflammation: persistent infection or autoimmune disease1,3

Mediated by cytokines (lymphokines, interleukins, and other proteins made by cells that affect the behavior of other cells)1,2

Function1

Deliver effector molecules and cells to injury site

Prevent spread of infection

Repair tissue damage

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1. Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. The front line of host defense. Available from: http://www.ncbi.nlm.nih.gov/books/NBK27105/.

2. Turner et al. 2014 Biochimica et Biophysica Acta 1843: 2563–2582.3. Okin & Medzhitov 2012 Curr Biol. 22(17):1-16.


Types Of Inflammation Peripheral

Acute response to injury1

Aids in repair and resolution of injury/condition1

Can stimulate behavioral changes in the brain2

CNS/neuroinflammation

Chronic glial activation (microglia and astrocytes)1

Exaggerated expression of proinflammatory mediators in the CNS (e.g., cytokines, reactive oxygen species)1

Cause or consequence of neural dysfunction?1

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CNS=Central Nervous System 1. Bilbo SD et al. J Neuroimmune Pharmacol. 2012;7(1):24-41; 2. Teeling JL, Perry VH. Neuroscience. 2009;158(3):1062-73.


INFLAMMATORY RESPONSE

IN THE BRAIN


Key Players Underlying Neuroinflammation1-8

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1. Bilbo SD et al. J Neuroimmune Pharmacol. 2012;7(1):24-41; 2. Turner et al. 2014 Biochemica et Biophysica Acta 1843:2563-2582. 3. Miller AH & Raison C 2016 NATURE REVIEWS IMMUNOLOGY 16:22-34.; 4. Haroonet al. 2017 Neuropsychopharmacology REVIEWS 42:193–215.; 5. Ferger AI et al. J Neuroinflammation. 2010;7:45; 6. Jones KA & Thomsen C. Mol Cell Neurosci. 2013 Mar;53:52-62; 7. Najjar S et al. J Neuroinflammation. 2013;10:43; 8. Kim HW et al. Neurobiol Dis. 2010;37(3):596-603.

Component Role/Contribution

Glial Cells Microglia; astrocytes; oligodendrocytes

Cytokines Immune/inflammatory molecules

Glutamate Excitotoxicity

Mitochondria/Oxidative Stress Cellular damage

HPA Axis Chronic stress

S100B & Arachidonic Acid Effector molecules in inflammatory pathways


Glial Cells

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Microglia1-5

Primary immune cells in the brain Change phenotype and produce soluble factors in response to cell damage and

pathogens Produce both pro- and anti-inflammatory mediators

Astrocytes2-5

Most abundant glial cell type Express toll-like receptors (TLRs) and inflammatory molecules (eg, cytokines) Modify permeability of blood-brain barrier Proliferate after inflammation to restore brain homeostasis

Oligodendrocytes1-3,5

Produce myelin Can produce neurotrophins that affect microglia expression

1. Bilbo SD et al. J Neuroimmune Pharmacol. 2012;7(1):24-41; 2. Teeling JL, Perry VH. Neuroscience. 2009;158(3):1062-73; 3. Purves D et al (eds). Neuroscience. 5th Edition. Sinauer Associates, 2012.; 4. Maletic & Raison. The New Mind-Body Science of Depression. 1st Edition. W.W. Norton & Company, Inc. 2017; 5. Haroon et al. 2017 Neuropsychopharmacology REVIEWS 42:193–215.



Microglial Function & Activation

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1. Gomez-Nicola and V. Hugh Perry et al,2015, The Neuroscientist, 21(2):169-184. Image licensed via CC.


Cytokines

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1. Miller AH et al. Biol Psychiatry. 2009;65(9):732-41.


Cytokine Classification

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1. Turner et al. 2014 Biochimica et Biophysica Acta 1843: 2563–2582

First described in 1957, there are 300+ cytokines, chemokines, or growth factors identified to date1

Cytokines can be pro-inflammatory or anti-inflammatory1

Classification Family Members

Adaptive Immunity Common γ chain receptor ligands IL-2, IL-4, IL-7, IL-9, IL-15, IL-21

Common β chain (CD131) receptor ligands IL-3, IL-5, GM-CSF

Shared IL-2β chain (CD122) IL-2, IL-15

Shared receptors IL-13 (IL-13R-IL4R complex)

TSLP (TSLPR-IL-7R complex)

Pro-Inflammatory Signals IL-1 IL-1α, IL-1β, IL-1ra, IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-36Ra, IL-37 and IL-1Hy2

IL-6 IL-6, IL-11, IL-31, CNTF, CT-1, LIF, OPN, OSM

TNFα TNFα, TNFβ

IL-17 IL-17A-F, IL-25 (IL-17E)

Type I-III IFN IFNα, IFNβ, IFNω, IFNκ, Limitin; IFNγ; IFNλ1 (IL-29), IFNλ2 (IL-28A), IFNλ3 (IL-28B)

Anti-Inflammatory Signals IL-10 IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, IL-29

IL-12 IL-12, IL-23, IL-27, IL-35CNTF=ciliary neurotrophic factor; CT-1=cardiotrophin-1;GM-CSF=granulocyte macrophage-colony stimulating factor; IFN=interferon; LIF=leukaemia inhibitory factor; OPN=osteopontin; OSM=oncostatin M; TNFα= tumor necrosis factor α; TSLP=thymic stromal lymphopoietin.


Neuroimmune Network Hypothesis

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1. Nusslock and Miller 2015 Biological Psychiatry, 80(1):23-32.


Cytokines Impact on Glutamate

Glutamate transporters were originally identified in rat brain: GLAST, GLT-1, and EAAC1. Their human homologues are: excitatory amino acid transporter 1 (EAAT1), EAAT2 and EAAT3, respectively1,2.

1. Sheldon and Robinson, 2007, Neurochemistry International 51:333–355 (left image)2. Kim et al, 2011, J. Cell. Physiol. 226: 2484–2493 (right image)

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Glutamate

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Haroon et al. 2017 Neuropsychopharmacology REVIEWS, 42, 193–215


Oxidative phosphorylation (“oxphos”) →ATP synthesis1

Mitochondrial impairment in neurodegeneration1

Inhibitors can induce CNS inflammatory reactions1

MPTP

May trigger microglial activation and neuroinflammation2

Evidence from animal models of neurodegeneration2

Possible accumulation of damaged mitochondria3

Microglial activation may trigger mitochondrial dysfunction3

Mitochondria

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1. Gubellini P et al. Biochim Biophys Acta. 2010;1802(1):151-61; 2. Ferger AI et al. J Neuroinflammation. 2010;7:45; 3. Di Filippo M et al. J Alzheimers Dis. 2010;20 Suppl 2:S369-792. Image: Gubellini P et al. Biochim Biophys Acta. 2010;1802(1):151-61



Oxidative Stress Oxphos can produce reactive oxygen species (ROS) or

reactive nitrogen species (RNS)1

Antioxidants stabilize ROS/RNS2

Oxidative stress occurs when ROS/RNS overtake antioxidants3

Brain is particularly vulnerable to oxidative stress4

High levels of substrates and a lack of antioxidants

Vicious cycle between microglia and oxidative stress leading to inflammation

Damage by oxidative stress observed in major depressive disorder, bipolar disorder, schizophrenia, and obsessive-compulsive disorder4

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1. Berk M et al. Neurosci Biobehav Rev. 2011;35(3):804-17; 2. Bitanihirwe BK, Woo TU. Neurosci Biobehav Rev. 2011;35(3):878-93; 3. Moylan S et al. Neurosci Biobehav Rev. 2014;45:46-62; 4. Najjar S et al. J Neuroinflammation. 2013;10:43

Oxygen

Electron lost, creating unstable “reactive” species1


Oxidative Stress (cont’d)

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1. Berk M et al. Neurosci Biobehav Rev. 2011;35(3):804-17; 2. Bitanihirwe BK, Woo TU. Neurosci Biobehav Rev. 2011;35(3):878-93; 3. Moylan S et al. Neurosci Biobehav Rev. 2014;45:46-62; 4. Najjar S et al. J Neuroinflammation. 2013;10:43


Stress & HPA-axisHPA Modification May Underlie Immune System ChangesEarly life stress leading to permanent immune changes1; proinflammatory phenotype:

Higher C-reactive protein levels1

Increased IL-6 levels in response to stress1

Increased NF-κB-dependent transcription1

Increased TLR4 levels1

Bi-directional Relationship between HPA and Immune SystemGlucocorticoid receptor inhibits cytokine production2

Glucocorticoid resistance increased cytokine release2

Chronic cytokine exposure: Increases HPA activation: ACTH, cortisol, and CRH release3

Glucocorticoid resistance chronic cortisol elevation & reduced inflammatory control3

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1. Fagundes CP. Brain Behav Immun. 2013; 27C: 8-12; 2. Jones KA, Thomsen C. Mol Cell Neurosci. 2013 Mar;53:52-62; 3. Haroon E et al. Neuropsychopharmacology. 2012;37(1):137-62. Image: Belmaker RH. CNS Spectr. 2008;13(8):682-7.


Psychosocial stressors activate brain areas evolved to respond to environmental danger

Sympathetic nervous system activation Increased NE

Parasympathetic nervous system signaling withdrawn Decreased ACh

Activation of immune cells that release inflammatory cytokines

Stress, HPA-axis, and Inflammation1

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1. Raison CL et al, 2010 Arch Gen Psychiatry, 67(12), 1211-1224. Figure: Bower and Irwin 2016 Brain, Behavior, and Immunity, 51:1-11.


Contributors to Neuroinflammation: S100B and Arachidonic Acid

Arachidonic Acid• Substrate for prostaglandins: inflammatory

response, fever, and pain sensitivity3

• Levels associated with pro-inflammatory cytokines, excitotoxicity, and apoptosis4

• COX-1/COX-2 inhibition reduce depressive-like behavior in animal model3

S100B• Mediates cell-cell interactions in brain1

• Low levels: inhibit microglial TNF-α release2

• High levels: neuronal apoptosis, inflammation, RNS, microglial TNF-α secretion2

• Serum levels correlate with mood disorders, schizophrenia, and suicidality1,2

1. Steiner J et al. J Neurol Neurosurg Psychiatry. 2006;77(11):1284-7; 2. Najjar S et al. J Neuroinflammation. 2013;10:43; 3. Haroon E et al. Neuropsychopharmacology. 2012;37(1):137-62; 4. Kim HW et al. Neurobiol Dis. 2010;37(3):596-603 Images: (L): Choi SH et al. Trends Pharmacol Sci. 2009;30(4):174-81; (R) Donato R, et al. Biochimica et Biophysica Acta. 2009:1008-1022

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Potential Causes Of

Inflammation


Environmental Social/external environment

o Chronic stress or trauma1

o Harsh family environments/early stress2

o Mitochondrial toxins3

Internal/micro-environmento Infections/peripheral immunity4

o Gut microflora5

o Maternal inflammation6

o Chronic priming of microglia7

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1. Baker DG et al. 2012 Neuropharmacology;62(2):663-73; 2. Fagundes CP et al. 2013 Brain Behav Immun;27(1):8-12; 3. Di Filippo M et al. 2010 J Alzheimers Dis., 20 Suppl 2:S369-79; 4. Bilbo SD et al. J Neuroimmune Pharmacol. 2012;7(1):24-41; 5. Goyal DK, Miyan JA. Front Endocrinol (Lausanne). 2014;5:29; 6. Meyer U et al. Pediatr Res. 2011;69(5 Pt 2):26R-33R; 7. Lue LF et al. Mol Neurobiol. 2010;41(2-3):115-28.


GeneticsPolymorphisms Proinflammatory cytokine genes in AD2 and MDD3

Redox impairment and S100B genes in schizophrenia4,5

Proinflammatory cytokine genes linked to antidepressant resistance3

Linked to disease severity in MDD and bipolar disorder3

Epigenetics Increased methylation from oxidation4

Reduced methylation of immune related genes in PTSD6

Early DNA methylation changes linked to adult immune dysregulation7

Antioxidant genes down regulated in bipolar disorder8

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1. Eikelenboom P et al. Neural Transm. 2004;111:281-294; 2. Bufalino C et al. Brain Behav Immun. 2013;31:31-47; 3. Najjar S et al. J Neuroinflammation. 2013;10:43; 4. Bitanihirwe BK, Woo TU. NeurosciBiobehav Rev. 2011;35(3):878-93; 5. Baker DG et al. Neuropharmacology. 2012 Feb;62(2):663-73; 8. Fagundes CP et al. Brain Behav Immun. 2013 Jan;27(1):8-12; 7. Rege S, Hodgkinson SJ. Aust N Z J Psychiatry. 2013;47(12):1136-51.


Genetics1

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1. Borrelli E et al. Neuron. 2008;60(6):961-74.


Potential Anti-Inflammatory Treatment Approaches


Pharmacologic Anti-Inflammatory Treatments

Cytokines and Related Pathways Focused set of targets in CNS (IL-1β, IL-6, TNF-α and IFN-α)1

Inhibitors of cytokines and downstream effectors under investigation1

Peripheral administration of IL-1β or TNF-α-neutralizing antibodies effective in animal depression models1

Positive effects of anti-cytokine antibodies and biologics on mood2,3

May not efficiently enter brain3

Mitochondria/Oxidative Stress Some mood stabilizers enhance homeostasis of mitochondrial cell membranes4

Coenzyme Q10 and N-acetyl cysteine enhance free radical scavenging4

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1. Jones KA, Thomsen C. Mol Cell Neurosci. 2013 Mar;53:52-62; 2. Wager-Smith K, Markou A. Neurosci Biobehav Rev. 2011;35(3):742-64; 3. Haroon E et al. Neuropsychopharmacology. 2012;37(1):137-62; 4. Berk M et al. Neurosci Biobehav Rev. 2011;35(3):804-17.


Pharmacologic Anti-Inflammatory Treatments

Steroids Neurosteroids have a beneficial role in psychiatric disorders1

Prednisone may help treatment-resistant depression2

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) COX-2 inhibitor

Reduced depression scores3

Ameliorates symptoms of MDD, bipolar disorder, schizophrenia, and OCD1

Aspirin Neuroprotective effects and antidepressant enhancement3

May reduce core symptoms of schizophrenia3

Further reduced oxidative stress when added to an SSRI3

May attenuate antidepressant effects of SSRIs but not other antidepressants1

Antibiotics Evidence for antidepressant effects of certain antibiotics2

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1. Najjar S et al. J Neuroinflammation. 2013;10:43; 2. Wager-Smith K, Markou A. Neurosci Biobehav Rev. 2011;35(3):742-64; 3. Berk M et al. Neurosci Biobehav Rev. 2011;35(3):804-17.


Non-pharmacologic Anti-Inflammatory Interventions1-11

Caloric Restriction/Intermittent Fasting Cognitive Behavioral Therapy Enhanced Nutrition Exercise Increased Socialization Meditation/Mindfulness Probiotics/Prebiotics/

Synbiotics Sleep

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1. Gonzalez et al. 2012 Oral Dis. January; 18(1): 16–312. Lopresti 2017 Australian & New Zealand Journal of Psychiatry, 51(6) 565–582.3. Casas et al. 2014 Endocrine, Metabolic & Immune Disorders - Drug Targets;14:245-254. Woods et al. 2012 Aging and Disease Volume 3, Number 1:131-140.5. Kennedy et al. 2017 Journal of Alzheimer’s Disease 55:1–18

6. Lacey et al. 2014 Psychoneuroendocrinology 50, 85—94.7. Yang et al. 2014 Soc Sci Med.; 107: 124–135.8. Kok et al. 2013 Psychological Science 24(7) 1123–1132.9. Rosenkranz et al. 2016 Psychoneuroendocrinology; 68: 117–12510. Plaza-Diaz et al. 2017 Nutrients 9, 55.11. Irwin et al. 2016 Biol Psychiatry;1; 80(1): 40–52.


The human immune system is a highly evolved and complex structure

Inflammation underlies many diseases and disorders of modern society, impacting both the peripheral and central nervous systems

Multiple components of inflammation have been elucidated, yet we have a lot to learn

Multiple intracellular and environmental sources may contribute to neuroinflammation

A growing body of evidence suggests neuroinflammation contributes to pathology of psychiatric disorders

Various pharmacologic and non-pharmacologic strategies target and reduce inflammation, with more on the horizon

Summary

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Thank You

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Psychoneuroimmunology Immune System & Neuroinflammation …