The major hallmark of demyelinating diseases such as multiple sclerosis (MS), transverse myelitis, and neuromyelitis optica (NMO) is immune cell infiltration into the central nervous system (CNS; i.e., brain, spinal cord and optic nerve), resulting in myelin destruction. Myelin is the insulation around nerve fibers (i.e., axons) that is important for the conduction of nerve impulses. Demyelination of the neuronal axon not only slows propagation of nerve impulses, but causes axonal injury, resulting in motor and vision impairments, bowel/bladder dysfunction, pain sensation, and cognitive decline. New early-stage myelin cells appear at lesion sites in demyelinating diseases, but fail to reform myelin as they would during normal development. The DeSilva lab focuses on three major areas of research:
1) Blocking immune cell infiltration into the CNS
2) Protecting the CNS during the onslaught of immune cell infiltration
3) Promoting regeneration of myelin in the CNS
The most common form of MS is relapsing–remitting (RRMS), whereby exacerbations of symptoms are followed by a period of remission. A relapse is defined as a clinical event involving the onset of neurological symptoms caused by inflammation in the CNS. NMO has a similar relapsing-remitting disease progression; however, lesions are selective to the optic nerve and spinal cord and are relatively absent in the brain, unlike MS. Transverse myelitis is an acute inflammatory event selective to the spinal cord and in many cases patients are paralyzed within several hours or days. Some patients recover partially, but many patients with severe attacks have major disabilities. In some cases, transverse myelitis may present as a first relapse to develop later into MS or NMO.
Protecting the CNS
Disease-modifying therapies for MS are effective at reducing relapses, but do not eliminate them and have not been proven to slow disease progression. Therefore, therapeutic strategies to protect the CNS have clinical relevance. Using pharmacological and genetic approaches, the DeSilva lab has shown that excessive glutamate release from the system Xc- transporter expressed in microglia and macrophages causes excitotoxic damage to myelin in models of autoimmune neuroinflammation. To better understand the mechanisms driving glutamate release and its potential human clinical applications, the DeSilva lab is selectively and inducibly deleting the system Xc- transporter and its target proteins in cells of the peripheral and CNS in models of autoimmune neuroinflammation.
Blocking Immune Cell Infiltration into the CNS
While it appears that excitotoxic mechanisms play an important role in autoimmune demyelination, recent data from the DeSilva laboratory also provide evidence that glutamate contributes to immune cell infiltration into the CNS. The DeSilva lab has shown that pharmacological blockade or genetic deletion of system Xc- attenuated T cell infiltration into the CNS. Infiltration of primed T cells into the CNS is thought to initiate pathogenesis of demyelinating diseases. Furthermore, immune cells express many glutamate receptors and transporters necessary for glutamate regulation, corroborating evidence that glutamate contributes to immune cell trafficking into the CNS. The goal of this project is to understand the role of glutamate in immune cell migration and blood-brain barrier permeability in autoimmune demyelination.
Activity-Dependent Myelination and Regeneration in the CNS
The cells that form myelin are called oligodendrocytes, which are generated from oligodendrocyte progenitor cells (OPCs). Under normal conditions, OPCs mature into myelinating oligodendrocytes that ensheath nerve fibers, allowing for proper signal conduction. In pathological conditions, such as in demyelinating diseases, OPCs fail to form myelin as they normally would during development. Research in the DeSilva lab focuses on signaling factors between nerve fibers and early stage myelin-producing cells that are necessary to initiate myelination, with a special focus on the neurotransmitter glutamate. Glutamate is the primary excitatory neurotransmitter of the CNS. The DeSilva lab has shown that activity-dependent glutamate release from neurons is a necessary factor to promote myelination during development. This process may be perturbed in autoimmune neuroinflammation, where the DeSilva lab has shown that excessive glutamate release occurs through the system Xc- transporter triggering a glutamate imbalance. This work suggests that glutamate signaling must be properly activated in demyelinating diseases in order for new early stage myelin-producing cells to initiate remyelination.
Scarlett Evonuk Ph.D.
Archana Marathi MBBS, M.S.
Ashley Nemes Ph.D.
Do J, Kim D, Kim S, Valentin-Torres A, Dvorina N, Jang E, Nagarajavel V, DeSilva TM, Li X, Ting AH, Vignali DAA, Stohlman SA, Baldwin WM 3rd, Min B. (2018) Treg-specific IL-27Rα deletion uncovers a key role for IL-27 in Treg function to control autoimmunity. Proc Natl Acad Sci U S A. 114(38):10190-10195. PMID: 28874534; PMCID: PMC5617261
Evonuk KS, Moseley CE, Doyle RE, Weaver CT, DeSilva TM. (2017) Determining Immune System Suppression versus CNS Protection for Pharmacological Interventions in Autoimmune Demyelination. J Vis Exp (115). PMID: 27685467; PMCID: PMC5092010
Evonuk KS, Prabhu SD, Young ME, DeSilva TM. (2016) Myocardial ischemia/reperfusion impairs neurogenesis and hippocampal-dependent learning and memory. Brain Behav Immun pii: S0889-1591(16)30410-X. PMID: 27600185
Cala CM, Moseley CE, Steele C, Dowdy SM, Cutter GR, Ness JM, DeSilva TM. (2016) T cell cytokine signatures: Biomarkers in pediatric multiple sclerosis. J Neuroimmunol 297:1-8. PMID: 27397070; PMCID: PMC4940981
Watson JA, Bhattacharyya BJ, Vaden JH, Wilson JA, Icyuz M, Howard AD, Phillips E, DeSilva TM, Siegal GP, Bean AJ, King GD, Phillips SE, Miller RJ, Wilson SM. (2015) Motor and Sensory Deficits in the teetering Mice Result from Mutation of the ESCRT Component HGS. PLoS Genet 11(6):e1005290. PMID: 26115514; PMCID: PMC4482608
Evonuk KS, Baker BJ, Doyle RE, Moseley CE, Sestero CM, Johnston BP, De Sarno P, Tang A, Gembitsky I, Hewett SJ, Weaver CT, Raman C, DeSilva TM. (2015) Inhibition of System Xc(-) Transporter Attenuates Autoimmune Inflammatory Demyelination. J Immunol 195(2):450-63. PMID: 26071560; PMCID: PMC4490999
Haynes RL, DeSilva TM, Li J. (2012) Mechanisms of perinatal brain injury. Neurol Res Int 2012:157858. PMID: 22848819; PMCID: PMC3403495
DeSilva TM, Borenstein NS, Volpe JJ, Kinney HC, Rosenberg PA. (2012) Expression of EAAT2 in neurons and protoplasmic astrocytes during human cortical development. J Comp Neurol 520(17):3912-32. PMID: 22522966; PMCID: PMC3781602
Moehle MS, Webber PJ, Tse T, Sukar N, Standaert DG, DeSilva TM, Cowell RM, West AB. (2012) LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci 32(5):1602-11. PMID: 22302802; PMCID: PMC3532034
DeSilva TM, Kabakov AY, Goldhoff PE, Volpe JJ, Rosenberg PA. (2009) Regulation of glutamate transport in developing rat oligodendrocytes. J Neurosci 29(24):7898-908. PMID: 19535601; PMCID: PMC2926807
Gerstner B, Lee J, DeSilva TM, Jensen FE, Volpe JJ, Rosenberg PA. (2009) 17beta-estradiol protects against hypoxic/ischemic white matter damage in the neonatal rat brain. J Neurosci Res 87(9):2078-86. PMID: 19224575; PMCID: PMC2770176
DeSilva TM, Billiards SS, Borenstein NS, Trachtenberg FL, Volpe JJ, Kinney HC, Rosenberg PA. (2008) Glutamate transporter EAAT2 expression is up-regulated in reactive astrocytes in human periventricular leukomalacia. J Comp Neurol 508(2):238-48. PMID: 18314905; PMCID: PMC2911955
Bassan M, Liu H, Madsen KL, Armsen W, Zhou J, DeSilva T, Chen W, Paradise A, Brasch MA, Staudinger J, Gether U, Irwin N, Rosenberg PA. Interaction between the glutamate transporter GLT1b and the synaptic PDZ domain protein PICK1. Eur J Neurosci 27(1):66-82. PMID: 18184314; PMCID: PMC4341970
Gerstner B, DeSilva TM, Genz K, Armstrong A, Brehmer F, Neve RL, Felderhoff-Mueser U, Volpe JJ, Rosenberg PA. (2008) Hyperoxia causes maturation-dependent cell death in the developing white matter. J Neurosci 28(5):1236-45. PMID: 18234901; PMCID: PMC4305399
DeSilva TM, Kinney HC, Borenstein NS, Trachtenberg FL, Irwin N, Volpe JJ, Rosenberg PA. (2007) The glutamate transporter EAAT2 is transiently expressed in developing human cerebral white matter. J Comp Neurol 501(6):879-90. PMID: 17311320