title: Physical Exercise Attenuates Experimental Autoimmune Encephalomyelitis by Inhibiting Peripheral Immune Response and Blood-Brain Barrier Disruption.
abstract: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) caused by demyelination, immune cell infiltration, and axonal damage. Herein, we sought to investigate the influence of physical exercise on mice experimental autoimmune encephalomyelitis (EAE), a reported MS model. Data show that both strength and endurance training protocols consistently prevented clinical signs of EAE and decreased oxidative stress, an effect which was likely due to improving genomic antioxidant defense-nuclear factor erythroid 2-related factor (Nrf2)/antioxidant response elements (ARE) pathway-in the CNS. In addition, physical exercise inhibited the production of pro-inflammatory cytokines interferon (IFN)-γ, interleukin (IL)-17, and IL-1β in the spinal cord of mice with EAE. Of note, spleen cells obtained from strength training group incubated with MOG35-55showed a significant upregulation of CD25 and IL-10 levels, with a decrease of IL-6, MCP-1, and tumor necrosis factor (TNF)-α production, mainly, during acute and chronic phase of EAE. Moreover, these immunomodulatory effects of exercise were associated with reduced expression of adhesion molecules, especially of platelet and endothelial cell adhesion molecule 1 (PECAM-1). Finally, physical exercise also restored the expression of tight junctions in spinal cord. Together, these results demonstrate that mild/moderate physical exercise, when performed regularly in mice, consistently attenuates the progression and pathological hallmarks of EAE, thereby representing an important non-pharmacological intervention for the improvement of immune-mediated diseases such as MS. Graphical Abstract Schematic diagram illustrating the beneficial effects of physical exercise during experimental model of MS. Physical exercise, especially strength (ST) and endurance (ET) training protocols, inhibits the development and progression of disease, measured by the mean maximal clinical score (1.5 and 1.0, respectively), with inhibition of 30 % and 50 %, respectively, based on the AUC, compared with EAEuntreated group. In addition, ST and ET decreased oxidative stress, possibly, through genomic antioxidant defense, Nrf2-Keap1 signaling pathway, in the CNS. Physical exercise inhibited the production of inflammatory cytokines, such as IFN-γ, IL-17 and IL-1β in the spinal cord after EAE induction, as well as spleen cells obtained from ST group showed a significant upregulation of regulatory T cell markers, such as CD25 and IL-10 levels, and blocked IL-6, MCP-1 and TNF-α production, mainly, during acute and chronic phase of EAE. Finally, these immunomodulatory effects of exercise were associated with inhibition of adhesion molecules and reestablishment of tight junctions expression in spinal cord tissue, thereby limiting BBB permeability and transmigration of autoreactive T cells to the CNS. NO, nitric oxide; GPx, glutathione peroxidase, GSH, glutathione; Nrf2, nuclear factor (erythroid-derived 2)-like 2; CNS, central nervous system; BBB, blood-brain barrier; IFN-g, interferon-gamma; IL-17, interleukin 17; IL-1b, interleukin-1beta.
authors.affiliation: Laboratory of Exercise Biochemistry and Physiology, Postgraduate Program in Health Sciences, Health Sciences Unit, Universidade do Extremo Sul Catarinense, 88806-000, Criciúma, SC, Brazil.
authors.forename: Priscila S
authors.initials: PS
authors.lastname: Souza
authors.affiliation: Laboratory of Autoimmunity and Immunopharmacology, Campus Araranguá, Universidade Federal de Santa Catarina, Rodovia Jorge Lacerda, Km 35,4-Jardim das Avenidas, 88900-000, Araranguá, SC, Brazil.
authors.forename: Elaine D
authors.initials: ED
authors.lastname: Gonçalves
authors.affiliation: Laboratory of Exercise Biochemistry and Physiology, Postgraduate Program in Health Sciences, Health Sciences Unit, Universidade do Extremo Sul Catarinense, 88806-000, Criciúma, SC, Brazil.
authors.forename: Giulia S
authors.initials: GS
authors.lastname: Pedroso
authors.affiliation: Laboratory of Exercise Biochemistry and Physiology, Postgraduate Program in Health Sciences, Health Sciences Unit, Universidade do Extremo Sul Catarinense, 88806-000, Criciúma, SC, Brazil.
authors.forename: Hemelin R
authors.initials: HR
authors.lastname: Farias
authors.affiliation: Laboratory of Autoimmunity and Immunopharmacology, Campus Araranguá, Universidade Federal de Santa Catarina, Rodovia Jorge Lacerda, Km 35,4-Jardim das Avenidas, 88900-000, Araranguá, SC, Brazil.|Neurobiology Laboratory of Pain and Inflammation, Department of Physiological Sciences, Center of Biological Sciences, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil.
authors.forename: Stella C
authors.initials: SC
authors.lastname: Junqueira
authors.affiliation: Center of Innovation and Preclinical Studies, Av. Luiz Boiteux Piazza 1302, Cachoeira do Bom Jesus, 88056-000, Florianópolis, SC, Brazil.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Marcon
authors.affiliation: Laboratory of Exercise Biochemistry and Physiology, Postgraduate Program in Health Sciences, Health Sciences Unit, Universidade do Extremo Sul Catarinense, 88806-000, Criciúma, SC, Brazil.
authors.forename: Talita
authors.initials: T
authors.lastname: Tuon
authors.affiliation: Laboratory of Autoimmunity and Immunopharmacology, Campus Araranguá, Universidade Federal de Santa Catarina, Rodovia Jorge Lacerda, Km 35,4-Jardim das Avenidas, 88900-000, Araranguá, SC, Brazil.
authors.forename: Maíra
authors.initials: M
authors.lastname: Cola
authors.affiliation: Laboratory of Exercise Biochemistry and Physiology, Postgraduate Program in Health Sciences, Health Sciences Unit, Universidade do Extremo Sul Catarinense, 88806-000, Criciúma, SC, Brazil.
authors.forename: Paulo C L
authors.initials: PCL
authors.lastname: Silveira
authors.affiliation: Neurobiology Laboratory of Pain and Inflammation, Department of Physiological Sciences, Center of Biological Sciences, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil.
authors.forename: Adair R
authors.initials: AR
authors.lastname: Santos
authors.affiliation: Center of Innovation and Preclinical Studies, Av. Luiz Boiteux Piazza 1302, Cachoeira do Bom Jesus, 88056-000, Florianópolis, SC, Brazil.
authors.forename: João B
authors.initials: JB
authors.lastname: Calixto
authors.affiliation: Laboratory of Exercise Biochemistry and Physiology, Postgraduate Program in Health Sciences, Health Sciences Unit, Universidade do Extremo Sul Catarinense, 88806-000, Criciúma, SC, Brazil.
authors.forename: Cláudio T
authors.initials: CT
authors.lastname: Souza
authors.affiliation: Laboratory of Exercise Biochemistry and Physiology, Postgraduate Program in Health Sciences, Health Sciences Unit, Universidade do Extremo Sul Catarinense, 88806-000, Criciúma, SC, Brazil.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: de Pinho
authors.affiliation: Laboratory of Autoimmunity and Immunopharmacology, Campus Araranguá, Universidade Federal de Santa Catarina, Rodovia Jorge Lacerda, Km 35,4-Jardim das Avenidas, 88900-000, Araranguá, SC, Brazil. rafaelcdutra@gmail.com.
authors.forename: Rafael C
authors.initials: RC
authors.lastname: Dutra
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D005260:Female; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D008221:Lymphoid Tissue / Q000276:immunology; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D010539:Permeability; D010805:Physical Conditioning, Animal; D010807:Physical Endurance; D012720:Severity of Illness Index; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D062725:Tight Junction Proteins / Q000378:metabolism
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D018836:Inflammation Mediators; D062725:Tight Junction Proteins
keywords: Experimental autoimmune encephalomyelitis; Inflammatory mediators; Multiple sclerosis; Physical exercise