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The alarmin interleukin-1α triggers secondary degeneration through reactive astrocytes and endothelium after spinal cord injury

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  • Floriane Bretheau

    (Axe neurosciences du Centre de recherche du Centre hospitalier universitaire (CHU) de Québec–Université Laval et Département de médecine moléculaire de l’Université Laval)

  • Adrian Castellanos-Molina

    (Axe neurosciences du Centre de recherche du Centre hospitalier universitaire (CHU) de Québec–Université Laval et Département de médecine moléculaire de l’Université Laval)

  • Dominic Bélanger

    (Axe neurosciences du Centre de recherche du Centre hospitalier universitaire (CHU) de Québec–Université Laval et Département de médecine moléculaire de l’Université Laval)

  • Maxime Kusik

    (Axe neurosciences du Centre de recherche du Centre hospitalier universitaire (CHU) de Québec–Université Laval et Département de médecine moléculaire de l’Université Laval)

  • Benoit Mailhot

    (Axe neurosciences du Centre de recherche du Centre hospitalier universitaire (CHU) de Québec–Université Laval et Département de médecine moléculaire de l’Université Laval)

  • Ana Boisvert

    (Axe neurosciences du Centre de recherche du Centre hospitalier universitaire (CHU) de Québec–Université Laval et Département de médecine moléculaire de l’Université Laval)

  • Nicolas Vallières

    (Axe neurosciences du Centre de recherche du Centre hospitalier universitaire (CHU) de Québec–Université Laval et Département de médecine moléculaire de l’Université Laval)

  • Martine Lessard

    (Axe neurosciences du Centre de recherche du Centre hospitalier universitaire (CHU) de Québec–Université Laval et Département de médecine moléculaire de l’Université Laval)

  • Matthias Gunzer

    (University Hospital Essen, University of Duisburg-Essen
    Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V.)

  • Xiaoyu Liu

    (Florida Atlantic University)

  • Éric Boilard

    (Axe maladies infectieuses et immunitaires du Centre de recherche du CHU de Québec–Université Laval et Centre de recherche en arthrite de l’Université Laval)

  • Ning Quan

    (Florida Atlantic University)

  • Steve Lacroix

    (Axe neurosciences du Centre de recherche du Centre hospitalier universitaire (CHU) de Québec–Université Laval et Département de médecine moléculaire de l’Université Laval)

Abstract

Spinal cord injury (SCI) triggers neuroinflammation, and subsequently secondary degeneration and oligodendrocyte (OL) death. We report that the alarmin interleukin (IL)−1α is produced by damaged microglia after SCI. Intra-cisterna magna injection of IL-1α in mice rapidly induces neutrophil infiltration and OL death throughout the spinal cord, mimicking the injury cascade seen in SCI sites. These effects are abolished through co-treatment with the IL-1R1 antagonist anakinra, as well as in IL-1R1-knockout mice which demonstrate enhanced locomotor recovery after SCI. Conditional restoration of IL-1R1 expression in astrocytes or endothelial cells (ECs), but not in OLs or microglia, restores IL-1α-induced effects, while astrocyte- or EC-specific Il1r1 deletion reduces OL loss. Conditioned medium derived from IL-1α-stimulated astrocytes results in toxicity for OLs; further, IL-1α-stimulated astrocytes generate reactive oxygen species (ROS), and blocking ROS production in IL-1α-treated or SCI mice prevented OL loss. Thus, after SCI, microglia release IL-1α, inducing astrocyte- and EC-mediated OL degeneration.

Suggested Citation

  • Floriane Bretheau & Adrian Castellanos-Molina & Dominic Bélanger & Maxime Kusik & Benoit Mailhot & Ana Boisvert & Nicolas Vallières & Martine Lessard & Matthias Gunzer & Xiaoyu Liu & Éric Boilard & Ni, 2022. "The alarmin interleukin-1α triggers secondary degeneration through reactive astrocytes and endothelium after spinal cord injury," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33463-x
    DOI: 10.1038/s41467-022-33463-x
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