title: Myeloid cell transmigration across the CNS vasculature triggers IL-1β-driven neuroinflammation during autoimmune encephalomyelitis in mice.
abstract: Growing evidence supports a role for IL-1 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), but how it impacts neuroinflammation is poorly understood. We show that susceptibility to EAE requires activation of IL-1R1 on radiation-resistant cells via IL-1β secreted by bone marrow-derived cells. Neutrophils and monocyte-derived macrophages (MDMs) are the main source of IL-1β and produce this cytokine as a result of their transmigration across the inflamed blood-spinal cord barrier. IL-1R1 expression in the spinal cord is found in endothelial cells (ECs) of the pial venous plexus. Accordingly, leukocyte infiltration at EAE onset is restricted to IL-1R1(+) subpial and subarachnoid vessels. In response to IL-1β, primary cultures of central nervous system ECs produce GM-CSF, G-CSF, IL-6, Cxcl1, and Cxcl2. Initiation of EAE or subdural injection of IL-1β induces a similar cytokine/chemokine signature in spinal cord vessels. Furthermore, the transfer of Gr1(+) cells on the spinal cord is sufficient to induce illness in EAE-resistant IL-1β knockout (KO) mice. Notably, transfer of Gr1(+) cells isolated from C57BL/6 mice induce massive recruitment of recipient myeloid cells compared with cells from IL-1β KO donors, and this recruitment translates into more severe paralysis. These findings suggest that an IL-1β-dependent paracrine loop between infiltrated neutrophils/MDMs and ECs drives neuroinflammation.
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec, QC G1V 4G2, Canada.
authors.forename: Sébastien A
authors.initials: SA
authors.lastname: Lévesque
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec, QC G1V 4G2, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Paré
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec, QC G1V 4G2, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: Mailhot
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec, QC G1V 4G2, Canada.
authors.forename: Victor
authors.initials: V
authors.lastname: Bellver-Landete
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Département de Neurosciences, Faculté de Médecine, Université de Montréal, Montréal, QC H2X 0A9, Canada.
authors.forename: Hania
authors.initials: H
authors.lastname: Kébir
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Département de Neurosciences, Faculté de Médecine, Université de Montréal, Montréal, QC H2X 0A9, Canada.
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Lécuyer
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Département de Neurosciences, Faculté de Médecine, Université de Montréal, Montréal, QC H2X 0A9, Canada Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Jorge Ivan
authors.initials: JI
authors.lastname: Alvarez
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Département de Neurosciences, Faculté de Médecine, Université de Montréal, Montréal, QC H2X 0A9, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prat
authors.affiliation: Department of Neurological Surgery, The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: de Rivero Vaccari
authors.affiliation: Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Keane
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec, QC G1V 4G2, Canada steve.lacroix@crchul.ulaval.ca.
authors.forename: Steve
authors.initials: S
authors.lastname: Lacroix
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D019899:Paracrine Communication / Q000235:genetics / Q000276:immunology*; D013116:Spinal Cord / Q000276:immunology* / Q000473:pathology; D057705:Transendothelial and Transepithelial Migration / Q000235:genetics / Q000276:immunology*
chemical_list: C587672:IL1B protein, mouse; D053583:Interleukin-1beta