title: Tissue Transglutaminase contributes to experimental multiple sclerosis pathogenesis and clinical outcome by promoting macrophage migration.
abstract: Multiple sclerosis is a serious neurological disorder, resulting in e.g., sensory, motor and cognitive deficits. A critical pathological aspect of multiple sclerosis (MS) is the influx of immunomodulatory cells into the central nervous system (CNS). Identification of key players that regulate cellular trafficking into the CNS may lead to the development of more selective treatment to halt this process. The multifunctional enzyme tissue Transglutaminase (TG2) can participate in various inflammation-related processes, and is known to be expressed in the CNS. In the present study, we question whether TG2 activity contributes to the pathogenesis of experimental MS, and could be a novel therapeutic target. In human post-mortem material, we showed the appearance of TG2 immunoreactivity in leukocytes in MS lesions, and particular in macrophages in rat chronic-relapsing experimental autoimmune encephalomyelitis (cr-EAE), an experimental MS model. Clinical deficits as observed in mouse EAE were reduced in TG2 knock-out mice compared to littermate wild-type mice, supporting a role of TG2 in EAE pathogenesis. To establish if the enzyme TG2 represents an attractive therapeutic target, cr-EAE rats were treated with TG2 activity inhibitors during ongoing disease. Reduction of TG2 activity in cr-EAE animals dramatically attenuated clinical deficits and demyelination. The mechanism underlying these beneficial effects pointed toward a reduction in macrophage migration into the CNS due to attenuated cytoskeletal flexibility and RhoA GTPase activity. Moreover, iNOS and TNFα levels were selectively reduced in the CNS of cr-EAE rats treated with a TG2 activity inhibitor, whereas other relevant inflammatory mediators were not affected in CNS or spleen by reducing TG2 activity. We conclude that modulating TG2 activity opens new avenues for therapeutic intervention in MS which does not affect peripheral levels of inflammatory mediators.
authors.affiliation: VU University Medical Center, Neuroscience Campus Amsterdam, Dept. Anatomy & Neurosciences, The Netherlands.
authors.forename: Miriam E
authors.initials: ME
authors.lastname: van Strien
authors.affiliation: VU University Medical Center, Neuroscience Campus Amsterdam, Dept. Molecular Cell Biology and Immunology, Amsterdam, The Netherlands.
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
authors.affiliation: VU University Medical Center, Neuroscience Campus Amsterdam, Dept. Anatomy & Neurosciences, The Netherlands.
authors.forename: Navina L
authors.initials: NL
authors.lastname: Chrobok
authors.affiliation: VU University Medical Center, Neuroscience Campus Amsterdam, Dept. Anatomy & Neurosciences, The Netherlands.
authors.forename: John G J M
authors.initials: JGJM
authors.lastname: Bol
authors.affiliation: VU University Medical Center, Neuroscience Campus Amsterdam, Dept. Anatomy & Neurosciences, The Netherlands.
authors.forename: John J P
authors.initials: JJP
authors.lastname: Breve
authors.affiliation: VU University Medical Center, Neuroscience Campus Amsterdam, Dept. Molecular Cell Biology and Immunology, Amsterdam, The Netherlands.
authors.forename: Susanne M P
authors.initials: SMP
authors.lastname: van der Pol
authors.affiliation: VU University Medical Center, Neuroscience Campus Amsterdam, Dept. Molecular Cell Biology and Immunology, Amsterdam, The Netherlands.
authors.forename: Gijs
authors.initials: G
authors.lastname: Kooij
authors.affiliation: Dept. Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jaap D
authors.initials: JD
authors.lastname: van Buul
authors.affiliation: BioA2z Inc, San Francisco, CA, USA.
authors.forename: Marcela
authors.initials: M
authors.lastname: Karpuj
authors.affiliation: Beckman Center for Molecular Medicine, Stanford University, Stanford, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.affiliation: VU University Medical Center, Neuroscience Campus Amsterdam, Dept. Anatomy & Neurosciences, The Netherlands.
authors.forename: Micha M
authors.initials: MM
authors.lastname: Wilhelmus
authors.affiliation: VU University Medical Center, Neuroscience Campus Amsterdam, Dept. Anatomy & Neurosciences, The Netherlands.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sestito
authors.affiliation: VU University Medical Center, Neuroscience Campus Amsterdam, Dept. Anatomy & Neurosciences, The Netherlands.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Drukarch
authors.affiliation: VU University Medical Center, Neuroscience Campus Amsterdam, Dept. Anatomy & Neurosciences, The Netherlands. Electronic address: amw.vandam@vumc.nl.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Van Dam
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000473:pathology; D042783:Endothelial Cells / Q000201:enzymology / Q000473:pathology; D005260:Female; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000201:enzymology* / Q000473:pathology; D009186:Myelin Sheath / Q000201:enzymology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013116:Spinal Cord / Q000201:enzymology / Q000473:pathology; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018836:Inflammation Mediators; D007555:Isoxazoles; C510621:KCC 009; D012333:RNA, Messenger; C000717609:Tgm2 protein, rat; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: Demyelination; Experimental autoimmune encephalomyelitis; Immunohistochemistry; Migration; Multiple sclerosis