Brain, Cytokines, Demyelination, Immunology, Inflammation, Multiple Sclerosis, Myelination, Neurobiology, Regeneration
MA, University of Cambridge, UK
VetMB, University of Cambridge, UK
PhD, University of London, UK
National Multiple Sclerosis Society
Project 2. What are the mechanisms controlling entry of inflammatory cells into the CNS parenchyma?
Inflammatory lesions in conditions such as MS and NMO are characterized by entry of inflammatory cells and soluble factors (such as antibodies) into the CNS parenchyma. These events are associated with breakdown of the blood-brain barrier (BBB), which in healthy adults separates the CNS from the rest of the body. The BBB is an endothelial barrier, but its integrity is controlled by other cell types, notably astrocytes and pericytes.
Importantly, our research has identified reactive astrocytes as key controllers of BBB permeability in inflammatory lesions, acting via plasticity factors such as VEGF-A and ECGF1/TP. Most notably, we have found that genetic or therapeutic blockade of these astrocyte-derived factors limits BBB disruption and inflammatory cell and antibody entry, and reduces neurologic deficit in models of MS. These studies have generated an FDA-approved phase Ib clinical trial testing the impact of VEGF-A blockade on disease exacerbation in NMO patients (ClinicalTrials.gov: NCT01777412). We are currently investigating the molecular mechanisms by which reactive astrocytes regulate BBB permeability, and whether they also directly regulate leukocyte migration in inflammatory CNS lesions.
Project 1. How does the environment of the CNS control inflammatory lesion size and the potential for repair?
Astrocytes are the most numerous cell type in the mammalian CNS, and respond to inflammation or injury with a graded transcriptional program driven by pro- or anti-inflammatory mediators. These changes, called reactive astrogliosis, profoundly impact surrounding neural and non-neural cells. One of the major goals of our work is to understand the functional impact of reactive astrogliosis on other cell types within the CNS, with a translational focus.
Recently, we have found that an astrocyte-derived family of growth factors, which signal via the gp130 receptor and the transcription factor Stat3, are required for normal CNS white matter formation and myelination, and that these factors act in part via transcriptional activators of the Kruppel-like factor (Klf) family. Conditional inactivation of Stat3 or Klf6 in the precursors of myelinating cells, called oligodendrocyte progenitors, results in failure of CNS myelination and complete absence of white matter formation. We are currently investigating whether the Stat3-Klf6 axis is also required for successful repair of myelin and return of function in models of MS.
Laitman BM, John GR. Understanding How Exercise Promotes Cognitive Integrity in the Aging Brain [review]. PLoS Biology 2015 Nov; 13(11): e1002300.
Melamed E, Levy M, Waters PJ, Sato DK, Bennett JL, John GR, Hooper DC, Saiz A, Bar-Or A, Kim HJ, Pandit L, Leite MI, Asgari N, Kissani N, Hintzen R, Marignier R, Jarius S, Marcelletti J, Smith TJ, Yeaman MR, Han MH, Aktas O, Apiwattanakul M, Banwell B, Bichuetti D, Broadley S, Cabre P, Chitnis T, De Seze J, Fujihara K, Greenberg B, Hellwig K, Iorio R, Jarius S, Klawiter E, Kleiter I, Lana-Peixoto M, Nakashima , O'Connor K, Palace J, Paul F, Prayoonwiwat N, Ruprecht K, Stuve O, Tedder T, Tenembaum S, Garrahan JP, Aires B, van Herle K, van Pelt D, Villoslada P, Waubant E, Weinshenker B, Wingerchuk D, Würfel J, Zamvil S. Update on biomarkers in neuromyelitis optica [review]. Neurology® Neuroimmunology & Neuroinflammation 2015 Aug; 2(4): e134.
Kremer S, Renard F, Achard S, Lana-Peixoto MA, Palace J, Asgari N, Klawiter EC, Tenembaum SN, Banwell B, Greenberg BM, Bennett JL, Levy M, Villoslada P, Saiz A, Fujihara K, Chan KH, Schippling S, Paul F, Kim HJ, de Seze J, Wuerfel JT, Cabre P, Marignier R, Tedder T, van Pelt D, Broadley S, Chitnis T, Wingerchuk D, Pandit L, Leite MI, Apiwattanakul M, Kleiter I, Prayoonwiwat N, Han M, Hellwig K, van Herle K, John G, Hooper DC, Nakashima I, Sato D, Yeaman MR, Waubant E, Zamvil S, Stüve O, Aktas O, Smith TJ, Jacob A, O'Connor K. Use of Advanced Magnetic Resonance Imaging Techniques in Neuromyelitis Optica Spectrum Disorder [review]. JAMA Neurology 2015 Jul; 72(7): 815-22.
Chapouly C, Tadesse Argaw A, Horng S, Castro K, Zhang J, Asp L, Loo H, Laitman BM, Mariani JN, Straus Farber R, Zaslavsky E, Nudelman G, Raine CS, John GR. Astrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions. Brain : a Journal of Neurology 2015 Jun; 138(Pt 6): 1548-67.
Kim HJ, Paul F, Lana-Peixoto MA, Tenembaum S, Asgari N, Palace J, Klawiter EC, Sato DK, de Seze J, Wuerfel J, Banwell BL, Villoslada P, Saiz A, Fujihara K, Kim SH. MRI characteristics of neuromyelitis optica spectrum disorder: an international update [review]. Neurology 2015 Mar; 84(11): 1165-73.
Smith ES, Jonason A, Reilly C, Veeraraghavan J, Fisher T, Doherty M, Klimatcheva E, Mallow C, Cornelius C, Leonard JE, Marchi N, Janigro D, Argaw AT, Pham T, Seils J, Bussler H, Torno S, Kirk R, Howell A, Evans EE, Paris M, Bowers WJ, John G, Zauderer M. SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease. Neurobiology of Disease 2015 Jan; 73: 254-68.
Dutta DJ, Zameer A, Mariani JN, Zhang J, Asp L, Huynh J, Mahase S, Laitman BM, Argaw AT, Mitiku N, Urbanski M, Melendez-Vasquez CV, Casaccia P, Hayot F, Bottinger EP, Brown CW, John GR. Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination. Development (Cambridge, England) 2014 Jun; 141(12): 2414-28.
Rusielewicz T, Nam J, Damanakis E, John GR, Raine CS, Melendez-Vasquez CV. Accelerated repair of demyelinated CNS lesions in the absence of non-muscle myosin IIB. Glia 2014 Apr; 62(4): 580-91.
Brück W, Pförtner R, Pham T, Zhang J, Hayardeny L, Piryatinsky V, Hanisch UK, Regen T, van Rossum D, Brakelmann L, Hagemeier K, Kuhlmann T, Stadelmann C, John GR, Kramann N, Wegner C. Reduced astrocytic NF-κB activation by laquinimod protects from cuprizone-induced demyelination. Acta Neuropathologica 2012 Sep; 124(3): 411-24.
Argaw AT, Asp L, Zhang J, Navrazhina K, Pham T, Mariani JN, Mahase S, Dutta DJ, Seto J, Kramer EG, Ferrara N, Sofroniew MV, John GR. Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. The Journal of Clinical Investigation 2012 Jul; 122(7): 2837-2845.
John GR, Chen LF, Rivieccio MA, Melendez-Vasquez CV, Hartley A, Brosnan CF. Interleukin-1beta induces a reactive astroglial phenotype via deactivation of the Rho GTPase-Rock axis. J Neurosci 2004 Mar 17; 24(11): 2837-2845.
John GR. Investigation of astrocyte - oligodendrocyte interactions in human cultures. In: Astrocytes. Humana Press; 2012. pp401-14.
Zhang J, Kramer EG, Asp L, Dutta DJ, Navrazhina K, Pham T, Mariani JN, Argaw AT, Melendez-Vasquez CV, John GR. Promoting myelin repair and return of function in multiple sclerosis [review]. FEBS Letters 2011 Dec; 585(23): 3813-20.
Gaupp S, Arezzo J, Dutta DJ, John GR, Raine CS. On the occurrence of hypomyelination in a transgenic mouse model: a consequence of the myelin basic protein promoter?. Journal of Neuropathology and Experimental Neurology 2011 Dec; 70(12): 1138-50.
John GR, Simpson JE, Woodroofe MN, Lee SC, Brosnan CF. Extracellular nucleotides differentially regulate interleukin-1beta signaling in primary human astrocytes: implications for inflammatory gene expression. J Neurosci 2001 Jun 15; 21(12): 4134-4142.
John GR, Shankar SL, Shafit-Zagardo B, Massimi A, Lee SC, Raine CS, Brosnan CF. Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat Med 2002 Oct; 8(10): 1115-1121.
Zhang J, Zhang Y, Dutta DJ, Argaw AT, Bonnamain V, Seto J, Braun DA, Zameer A, Hayot F, Lòpez CB, Raine CS, John GR. Proapoptotic and antiapoptotic actions of Stat1 versus Stat3 underlie neuroprotective and immunoregulatory functions of IL-11. Journal of Immunology (Baltimore, Md. : 1950) 2011 Aug; 187(3): 1129-41.
Zhang J, Kramer EG, Mahase S, Dutta DJ, Bonnamain V, Argaw AT, John GR. Targeting oligodendrocyte protection and remyelination in multiple sclerosis [review]. The Mount Sinai Journal of Medicine, New York 2011; 78(2): 244-57.
Zhang Y, Jalili F, Ouamara N, Zameer A, Cosentino G, Mayne M, Hayardeny L, Antel JP, Bar-Or A, John GR. Glatiramer acetate-reactive T lymphocytes regulate oligodendrocyte progenitor cell number in vitro: role of IGF-2. Journal of Neuroimmunology 2010 Oct; 227(1-2): 71-9.
Liu JS H, John GR, Sikora A, Hua LL, Lee SC, Brosnan CF. Modulation of interleukin-1beta and tumor necrosis factor alpha signaling by P2 purinergic receptors in human fetal astrocytes. J Neurosci 2000 Jul 15; 20(14): 5292-5299.
Zhang Y, Zhang J, Navrazhina K, Argaw AT, Zameer A, Gurfein BT, Brosnan CF, John GR. TGFbeta1 induces Jagged1 expression in astrocytes via ALK5 and Smad3 and regulates the balance between oligodendrocyte progenitor proliferation and differentiation. Glia 2010 Jun; 58(8): 964-74.
Zhang Y, Argaw AT, Gurfein BT, Zameer A, Snyder BJ, Ge C, Lu QR, Rowitch DH, Raine CS, Brosnan CF, John GR. Notch1 signaling plays a role in regulating precursor differentiation during CNS remyelination. Proceedings of the National Academy of Sciences of the United States of America 2009 Nov; 106(45): 19162-7.
Gurfein BT, Zhang Y, López CB, Argaw AT, Zameer A, Moran TM, John GR. IL-11 regulates autoimmune demyelination. Journal of Immunology (Baltimore, Md. : 1950) 2009 Oct; 183(7): 4229-40.
Duffy HS, John GR, Lee SC, Brosnan CF, Spray DC. Reciprocal regulation of the junctional proteins claudin-1 and connexin43 by interleukin-1beta in primary human fetal astrocytes. J Neurosci 2000 Dec 1; 20(23): RC114.
Argaw AT, Gurfein BT, Zhang Y, Zameer A, John GR. VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown. Proceedings of the National Academy of Sciences of the United States of America 2009 Feb; 106(6): 1977-82.
Brosnan CF, John GR. Revisiting Notch in remyelination of multiple sclerosis lesions [review]. The Journal of Clinical Investigation 2009 Jan; 119(1): 10-13.
Zhang Y, Taveggia C, Melendez-Vasquez C, Einheber S, Raine CS, Salzer JL, Brosnan CF, John GR. Interleukin-11 potentiates oligodendrocyte survival and maturation, and myelin formation. The Journal of Neuroscience : the official journal of the Society for Neuroscience 2006 Nov; 26(47): 12174-85.
Argaw AT, Zhang Y, Snyder BJ, Zhao ML, Kopp N, Lee SC, Raine CS, Brosnan CF, John GR. IL-1beta regulates blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program. Journal of Immunology (Baltimore, Md. : 1950) 2006 Oct; 177(8): 5574-84.
John GR, Scemes E, Suadicani SO, Liu JS, Charles PC, Lee SC, Spray DC, Brosnan CF. IL-1beta differentially regulates calcium wave propagation between primary human fetal astrocytes via pathways involving P2 receptors and gap junction channels. Proc Natl Acad Sci U S A 1999 Sep 28; 96(20): 11613-11618.
Omari KM, John G, Lango R, Raine CS. Role for CXCR2 and CXCL1 on glia in multiple sclerosis. Glia 2006 Jan; 53(1): 24-31.
Omari KM, John GR, Sealfon SC, Raine CS. CXC chemokine receptors on human oligodendrocytes: implications for multiple sclerosis. Brain : a journal of neurology 2005 May; 128(Pt 5): 1003-15.
Rivieccio MA, John GR, Song X, Suh HS, Zhao Y, Lee SC, Brosnan CF. The cytokine IL-1beta activates IFN response factor 3 in human fetal astrocytes in culture. Journal of Immunology (Baltimore, Md. : 1950) 2005 Mar; 174(6): 3719-26.
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