title: Involvement of calcitonin gene-related peptide and receptor component protein in experimental autoimmune encephalomyelitis.
abstract: Calcitonin Gene-Related Peptide (CGRP) inhibits microglia inflammatory activation in vitro. We here analyzed the involvement of CGRP and Receptor Component Protein (RCP) in experimental autoimmune encephalomyelitis (EAE). Alpha-CGRP deficiency increased EAE scores which followed the scale alpha-CGRP null>heterozygote>wild type. In wild type mice, CGRP delivery into the cerebrospinal fluid (CSF) 1) reduced chronic EAE (C-EAE) signs, 2) inhibited microglia activation (revealed by quantitative shape analysis), and 3) did not alter GFAP expression, cell density, lymphocyte infiltration, and peripheral lymphocyte production of IFN-gamma, TNF-alpha, IL-17, IL-2, and IL-4. RCP (probe for receptor involvement) was expressed in white matter microglia, astrocytes, oligodendrocytes, and vascular-endothelial cells: in EAE, also in infiltrating lymphocytes. In relapsing-remitting EAE (R-EAE) RCP increased during relapse, without correlation with lymphocyte density. RCP nuclear localization (stimulated by CGRP in vitro) was I) increased in microglia and decreased in astrocytes (R-EAE), and II) increased in microglia by CGRP CSF delivery (C-EAE). Calcitonin like receptor was rarely localized in nuclei of control and relapse mice. CGRP increased in motoneurons. In conclusion, CGRP can inhibit microglia activation in vivo in EAE. CGRP and its receptor may represent novel protective factors in EAE, apparently acting through the differential cell-specific intracellular translocation of RCP.
authors.affiliation: Neuroscience Institute, C.N.R., Via Vanvitelli 32, 20129 Milano, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sardi
authors.affiliation: Neuroscience Institute, C.N.R., Via Vanvitelli 32, 20129 Milano, Italy; Dept. of Medical Biotechnol. Translational Medicine, University of Milano, Via Vanvitelli 32, 20129 Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Zambusi
authors.affiliation: Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Finardi
authors.affiliation: Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ruffini
authors.affiliation: Dept. of Biochem. Mol. Biol., University of Miami, Miami, FL 33101, USA.
authors.forename: Adviye A
authors.initials: AA
authors.lastname: Tolun
authors.affiliation: Dept. of Neurobiol. Anatomy, University of Rochester, 601 Elmwood Avenue, Box 603, Rochester, NY 14642, USA.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Dickerson
authors.affiliation: Neuroscience Institute, C.N.R., Via Vanvitelli 32, 20129 Milano, Italy; Dept. of Medical Biotechnol. Translational Medicine, University of Milano, Via Vanvitelli 32, 20129 Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Righi
authors.affiliation: Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Zacchetti
authors.affiliation: Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy; Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milano, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Grohovaz
authors.affiliation: Dept. of Pharmacol. Biomol. Sci., University of Milano, Via Trentacoste 2, 20133 Milano, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Provini
authors.affiliation: Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Furlan
authors.affiliation: Neuroscience Institute, C.N.R., Via Vanvitelli 32, 20129 Milano, Italy; Dept. of Medical Biotechnol. Translational Medicine, University of Milano, Via Vanvitelli 32, 20129 Milano, Italy. Electronic address: stefano.morara@in.cnr.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Morara
mesh_terms: D053607:Adrenomedullin / Q000378:metabolism; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005620:Freund's Adjuvant / Q000276:immunology / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism*
chemical_list: C491563:Crcp protein, mouse; D016207:Cytokines; D004791:Enzyme Inhibitors; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D018015:Receptors, Calcitonin Gene-Related Peptide; C445081:myelin oligodendrocyte glycoprotein (35-55); D053607:Adrenomedullin; D005620:Freund's Adjuvant; D015740:Calcitonin Gene-Related Peptide
keywords: CSF delivery; Microglia; Neuroinflammation; Neuropeptides; Nuclear localization; Quantitative image analysis
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