Astrocytes Play a Critical Role in the Pathology of EAE

Summary

Principal Investigator: JOHN ROLAND BETHEA
Abstract: Project Summary Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are believed to be initiated by T cell-mediated immune responses to myelin antigens. In recent years, however, a significant body of evidence has been compiled indicating the contribution of various cell populations within the central nervous system (CNS), such as microglia and astrocytes, to the development and progression of the disease. Nevertheless, the role of these cell types is far from being clearly understood. Chronic neuroinflammation and demyelination may also contribute to disease progression and chronic neurological deficits. In all these processes, in MS as well as in many other neurodegenerative diseases, astrocytes have been demonstrated to play an active role. Astrocytes respond to injury by becoming "reactive" or "gliotic", a complex cellular response whose functional significance is still poorly understood. For instance, reactive astrocytes release neurotrophins essential for neuronal survival and repair, and are also responsible for the production of pro-inflammatory molecules (cytokines, chemokines, growth factors, NO etc) growth-inhibitory molecules detrimental to functional recovery. Many of the processes occurring in reactive astrocytes are regulated by NF-kB, a key modulator of inflammation and secondary injury. The studies outlined in this proposal are designed to investigate the role of astroglial NF-kB in the pathophysiology of experimental autoimmune encephalomyelitis (EAE), taking advantage of a transgenic mouse model generated in our laboratory (GFAP-IkBa-dn mice) where NF-kB is functionally inactivated in cells expressing GFAP, such as astrocytes and non-myelinating Schwann cells. Preliminary data indicate that blocking astroglial NF-kB significantly reduces disease severity, improves functional recovery following EAE and reduces neuroinflammation and demyelination. This leads us to hypothesize that reactive astrocytes significantly contribute to disease progression and development of chronic neurological deficits in EAE and MS. This hypothesis will be tested in the four specific aims outlined below. While the results generated in our transgenic mice are very promising, the studies in Aim 1 will compare our GFAP-IkBa-dn mice to two additional mouse lines (described below) to confirm that the results obtained so far in our experimental model are uniquely associated with the astrocyte-specific inhibition of the NF-kB pathway. The first mouse line (73.12xffIKKb) is obtained by breeding a GFAP-Cre line developed in Dr. Sofroniew's laboratory to a floxed (f/f) IKKb line generated in the laboratory of Dr. Michael Karin. The second mouse line (GFAPCreERT2xffIKKb) is obtained by breeding a tamoxifen inducible GFAP-Cre line (CreERT2) developed in Dr. McCarthy's lab to the same floxed (f/f) IKKb line. In Aims 2 and 3 we will use the line(s) that provides the most robust clinical improvement over the corresponding control mice to further investigate the mechanisms at the basis of the protection provided by blocking astroglial NF-kB. Specifically, studies in Aim 2 will determine if there are differences in blood brain permeability and infiltration of leukocytes in the CNS of diseased WT and mutant mice. Studies in Aim 3 will determine the mechanisms through which inhibiting astroglial NF-kB promotes an anti-inflammatory response. Studies in this aim will focus on how inhibiting astroglial NF-kB alters T and B cell responses in the spinal cord. Finally, since demyelination is a hallmark of this disease and could be modulated by neuroinflammation, studies in Aim 4 will investigate the effect of the inhibition of astroglial-NF-kB on oligodendrocyte survival and demyelination. Our experiments will not only give insights into NF-kB signaling mechanisms, but also elucidate astrocyte responses under pathological conditions. Ultimately, our goal is to determine if interfering with these responses could be beneficial as a therapeutic strategy for MS and other neurological disorders.
Funding Period: 2009-05-15 - 2014-04-30
more information: NIH RePORT

Top Publications

  1. ncbi Glial NF-κB inhibition alters neuropeptide expression after sciatic nerve injury in mice
    Yan Ping Zhang
    Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
    Brain Res 1385:38-46. 2011
  2. pmc Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination
    Roberta Brambilla
    The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami 1095 NW 14th Terrace, Miami, FL 33136, USA
    Brain 134:2736-54. 2011
  3. pmc Transgenic inhibition of astroglial NF-κB protects from optic nerve damage and retinal ganglion cell loss in experimental optic neuritis
    Roberta Brambilla
    Department of Neurological Surgery, The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, FL 33136, USA
    J Neuroinflammation 9:213. 2012
  4. pmc IL7Rα contributes to experimental autoimmune encephalomyelitis through altered T cell responses and nonhematopoietic cell lineages
    Jessica J Ashbaugh
    Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
    J Immunol 190:4525-34. 2013
  5. pmc Activation of NF-κB in Schwann cells is dispensable for myelination in vivo
    Paul D Morton
    The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
    J Neurosci 33:9932-6. 2013
  6. ncbi Astrocytes play a key role in EAE pathophysiology by orchestrating in the CNS the inflammatory response of resident and peripheral immune cells and by suppressing remyelination
    Roberta Brambilla
    The Miami Project to Cure Paralysis, Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, Florida The Neuroscience Program, Miller School of Medicine, University of Miami, Miami, Florida
    Glia 62:452-67. 2014

Detail Information

Publications6

  1. ncbi Glial NF-κB inhibition alters neuropeptide expression after sciatic nerve injury in mice
    Yan Ping Zhang
    Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
    Brain Res 1385:38-46. 2011
    ..Our results showed that glial NF-κB inhibition reduces galanin and CGRP expression, which are neuropeptides that correlate with pain behavior and inflammation after peripheral nerve injury...
  2. pmc Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination
    Roberta Brambilla
    The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami 1095 NW 14th Terrace, Miami, FL 33136, USA
    Brain 134:2736-54. 2011
    ....
  3. pmc Transgenic inhibition of astroglial NF-κB protects from optic nerve damage and retinal ganglion cell loss in experimental optic neuritis
    Roberta Brambilla
    Department of Neurological Surgery, The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, FL 33136, USA
    J Neuroinflammation 9:213. 2012
    ..However, to date, there is no conclusive evidence to support such a causal role for infiltrating peripheral immune cells in the etiopathology of optic neuritis...
  4. pmc IL7Rα contributes to experimental autoimmune encephalomyelitis through altered T cell responses and nonhematopoietic cell lineages
    Jessica J Ashbaugh
    Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
    J Immunol 190:4525-34. 2013
    ..Taken together, these data indicate that multiple cell types use IL7Rα signaling in the development of EAE, and inhibition of this pathway should be considered as a new therapeutic avenue for MS...
  5. pmc Activation of NF-κB in Schwann cells is dispensable for myelination in vivo
    Paul D Morton
    The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
    J Neurosci 33:9932-6. 2013
    ..Using a mouse model, we show that nuclear factor κB activation in Schwann cells is not required for myelination in vivo...
  6. ncbi Astrocytes play a key role in EAE pathophysiology by orchestrating in the CNS the inflammatory response of resident and peripheral immune cells and by suppressing remyelination
    Roberta Brambilla
    The Miami Project to Cure Paralysis, Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, Florida The Neuroscience Program, Miller School of Medicine, University of Miami, Miami, Florida
    Glia 62:452-67. 2014
    ....

Research Grants30

  1. CNS &Peripheral Viral Reservoirs/SIV Model of HIV HAART
    Janice E Clements; Fiscal Year: 2013
    ..We will also test eradication strategies designed to eliminate these reservoirs. ..
  2. Chemokines and Viral-Induced Neurologic Disease
    Thomas E Lane; Fiscal Year: 2013
    ..It is our long-term goal to develop novel interventional treatments for limiting the severity of disease symptoms in MS patients as well as other human demyelinating diseases. ..
  3. Neuroprotection and Myelin Repair Mechanisms in Multiple Sclerosis
    Inderjit Singh; Fiscal Year: 2013
    ....
  4. CYTOKINES IN GLIAL CELLS AND EAE BRAIN
    Inderjit Singh; Fiscal Year: 2013
    ..These studies will identify therapeutic targets for induction of myelin repair in MS and these findings should be applicable to other related neurodegenerative diseases. ..
  5. Nogo Receptors as Therapeutic Targets in a Model of Multiple Sclerosis
    BENJAMIN MATTHEW SEGAL; Fiscal Year: 2013
    ..If successful, NgR antagonists will represent the first class of agents used to treat MS that have both anti-inflammatory and neuroprotective/ neurorestorative properties. ..
  6. INITIATION OF HUMAN LABOR: PREVENTION OF PREMATURITY
    Carole R Mendelson; Fiscal Year: 2013
    ..We propose that these interrelated projects, carried out by a highly interactive research team, will achieve the long-range goals of this Program and contribute to a reduction in the incidence of preterm birth. ..
  7. Elucidating the mechanisms that mediate the effects of lipoic acid in MS
    Sonemany Salinthone; Fiscal Year: 2013
    ..Mechanistic understanding of the cAMP-mediated action of LA will provide guidance in issues relating to drug delivery, dosage requirement, and potentially even in the diagnosis or treatment of different forms or stages of MS. ..
  8. Neurotrophin mimetic therapeutics for HIV-associated neural dysfunction
    Rick B Meeker; Fiscal Year: 2013
    ..The proposed studies will move these compounds closer to therapeutic use by establishing dose-response guidelines and providing detailed information on the underlying molecular and cellular pathways responsible for protection. ..
  9. Molecular and Cellular Mechanisms of IL-17 Signaling
    Xiaoxia Li; Fiscal Year: 2013
    ....
  10. XT-101: A Potent IL-10 Based Therapy for Treating Multiple Sclerosis.
    Raymond A Chavez; Fiscal Year: 2013
    ..Because the method of action of XT-101 is markedly different from all existing or imminent MS treatments, it has the potential to be an extremely useful addition and complement to current medical practice. ..
  11. Increased Therapeutic Potential of Migrating Neural Stem Cells &ASC101 Treatment
    LEONARD P MILLER; Fiscal Year: 2013
    ..EAE is a widely accepted and utilized animal model of MS. If successful, this project will provide the basis for further testing ASC-101 technology in additional animal models of MS using NSCs. ..
  12. The Role of Astroglial-NF--kB in SCI
    JOHN ROLAND BETHEA; Fiscal Year: 2013
    ..Specific Aim 3: Determine what effect inhibiting astroglial- NF?B has on oligogenesis and remyelination following SCI. Specific Aim 4: Investigate the role of CXCL12 and CXCR4 in oligogenesis and remyelination following SCI. ..
  13. CNS injury caused by HIV-1 and alcohol: Protective effects of CB2 activation
    Yuri Persidsky; Fiscal Year: 2013
    ..abstract_text> ..
  14. Mast cell actions in chronic progressive versus relapsing remitting EAE
    JULIANNE K HATFIELD; Fiscal Year: 2013
    ..Aim 2: To examine PMN/MC/Tcell interactions and activation of resident and infiltrating cells in the meninges during EAE. ..