title: IL-1α Gene Deletion Protects Oligodendrocytes after Spinal Cord Injury through Upregulation of the Survival Factor Tox3.
abstract: Spinal cord injury (SCI) causes the release of danger signals by stressed and dying cells, a process that leads to neuroinflammation. Evidence suggests that inflammation plays a role in both the damage and repair of injured neural tissue. We show that microglia at sites of SCI rapidly express the alarmin interleukin (IL)-1α, and that infiltrating neutrophils and macrophages subsequently produce IL-1β. Infiltration of these cells is dramatically reduced in both IL-1α(-/-) and IL-1β(-/-) mice, but only IL-1α(-/-) mice showed rapid (at day 1) and persistent improvements in locomotion associated with reduced lesion volume. Similarly, intrathecal administration of the IL-1 receptor antagonist anakinra restored locomotor function post-SCI. Transcriptome analysis of SCI tissue at day 1 identified the survival factor Tox3 as being differentially regulated exclusively in IL-1α(-/-) mice compared with IL-1β(-/-) and wild-type mice. Accordingly, IL-1α(-/-) mice have markedly increased Tox3 levels in their oligodendrocytes, beginning at postnatal day 10 (P10) and persisting through adulthood. At P10, the spinal cord of IL-1α(-/-) mice showed a transient increase in mature oligodendrocyte numbers, coinciding with increased IL-1α expression in wild-type animals. In adult mice, IL-1α deletion is accompanied by increased oligodendrocyte survival after SCI. TOX3 overexpression in human oligodendrocytes reduced cellular death under conditions mimicking SCI. These results suggest that IL-1α-mediated Tox3 suppression during the early phase of CNS insult plays a crucial role in secondary degeneration.
  
  
  CONCLUSIONS
  The mechanisms underlying bystander degeneration of neurons and oligodendrocytes after CNS injury are ill defined. We show that microglia at sites of spinal cord injury (SCI) rapidly produce the danger signal interleukin (IL)-1α, which triggers neuroinflammation and locomotor defects. We uncovered that IL-1α(-/-) mice have markedly increased levels of the survival factor Tox3 in their oligodendrocytes, which correlates with the protection of this cell population, and reduced lesion volume, resulting in unprecedented speed, level, and persistence of functional recovery after SCI. Our data suggest that central inhibition of IL-1α or Tox3 overexpression during the acute phase of a CNS insult may be an effective means for preventing the loss of neurological function in SCI, or other acute injuries such as ischemia and traumatic brain injuries.
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-CHUL et Département de Médecine Moléculaire de l'Université Laval, Québec, Québec G1V 4G2, Canada, and.
authors.forename: Dominic
authors.initials: D
authors.lastname: Bastien
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-CHUL et Département de Médecine Moléculaire de l'Université Laval, Québec, Québec G1V 4G2, Canada, and.
authors.forename: Victor
authors.initials: V
authors.lastname: Bellver Landete
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-CHUL et Département de Médecine Moléculaire de l'Université Laval, Québec, Québec G1V 4G2, Canada, and.
authors.forename: Martine
authors.initials: M
authors.lastname: Lessard
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-CHUL et Département de Médecine Moléculaire de l'Université Laval, Québec, Québec G1V 4G2, Canada, and.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vallières
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-CHUL et Département de Médecine Moléculaire de l'Université Laval, Québec, Québec G1V 4G2, Canada, and.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Champagne
authors.affiliation: Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, Ohio 43614-5806.
authors.forename: Akira
authors.initials: A
authors.lastname: Takashima
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-CHUL et Département de Médecine Moléculaire de l'Université Laval, Québec, Québec G1V 4G2, Canada, and.
authors.forename: Marie-Ève
authors.initials: MÈ
authors.lastname: Tremblay
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-CHUL et Département de Médecine Moléculaire de l'Université Laval, Québec, Québec G1V 4G2, Canada, and.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Doyon
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-CHUL et Département de Médecine Moléculaire de l'Université Laval, Québec, Québec G1V 4G2, Canada, and steve.lacroix@crchul.ulaval.ca.
authors.forename: Steve
authors.identifier: http://orcid.org/0000-0003-0781-6371
authors.initials: S
authors.lastname: Lacroix
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D017353:Gene Deletion; D006609:High Mobility Group Proteins; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D053582:Interleukin-1alpha / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009410:Nerve Degeneration / Q000503:physiopathology*; D009836:Oligodendroglia / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D011980:Receptors, Progesterone / Q000096:biosynthesis*; D020127:Recovery of Function / Q000502:physiology; D013119:Spinal Cord Injuries / Q000378:metabolism*; D015534:Trans-Activators; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D006609:High Mobility Group Proteins; D053582:Interleukin-1alpha; D011980:Receptors, Progesterone; C521752:TOX3 protein, human; D015534:Trans-Activators
keywords: cytokine; microglia; neurodegeneration; neuroimmunology; neuroinflammation; neutrophil