title: IL4I1 augments CNS remyelination and axonal protection by modulating T cell driven inflammation.
abstract: SEE PLUCHINO AND PERUZZOTTI-JAMETTI DOI101093/AWW266 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Myelin regeneration (remyelination) is a spontaneous process that occurs following central nervous system demyelination. However, for reasons that remain poorly understood, remyelination fails in the progressive phase of multiple sclerosis. Emerging evidence indicates that alternatively activated macrophages in central nervous system lesions are required for oligodendrocyte progenitor differentiation into remyelinating oligodendrocytes. Here, we show that an alternatively activated macrophage secreted enzyme, interleukin-four induced one (IL4I1), is upregulated at the onset of inflammation resolution and remyelination in mouse central nervous system lesions after lysolecithin-induced focal demyelination. Focal demyelination in mice lacking IL4I1 or interleukin 4 receptor alpha (IL4Rα) results in increased proinflammatory macrophage density, remyelination impairment, and axonal injury in central nervous system lesions. Conversely, recombinant IL4I1 administration into central nervous system lesions reduces proinflammatory macrophage density, enhances remyelination, and rescues remyelination impairment in IL4Rα deficient mice. We find that IL4I1 does not directly affect oligodendrocyte differentiation, but modulates inflammation by reducing interferon gamma and IL17 expression in lesioned central nervous system tissues, and in activated T cells from splenocyte cultures. Remarkably, intravenous injection of IL4I1 into mice with experimental autoimmune encephalomyelitis at disease onset significantly reversed disease severity, resulting in recovery from hindlimb paralysis. Analysis of post-mortem tissues reveals reduced axonal dystrophy in spinal cord, and decreased CD4+T cell populations in spinal cord and spleen tissues. These results indicate that IL4I1 modulates inflammation by regulating T cell expansion, thereby permitting the formation of a favourable environment in the central nervous system tissue for remyelination. Therefore, IL4I1 is a potentially novel therapeutic for promoting central nervous system repair in multiple sclerosis.
authors: 1 Department of Biology, Georgetown University, Washington, DC 20057, USA.
authors: Konstantina
authors: K
authors: Psachoulia
authors: 1 Department of Biology, Georgetown University, Washington, DC 20057, USA.
authors: Kelly A
authors: KA
authors: Chamberlain
authors: 1 Department of Biology, Georgetown University, Washington, DC 20057, USA.
authors: Dongeun
authors: D
authors: Heo
authors: 1 Department of Biology, Georgetown University, Washington, DC 20057, USA.
authors: Stephanie E
authors: SE
authors: Davis
authors: 1 Department of Biology, Georgetown University, Washington, DC 20057, USA.
authors: Jeremiah D
authors: JD
authors: Paskus
authors: 1 Department of Biology, Georgetown University, Washington, DC 20057, USA.
authors: Sonia E
authors: SE
authors: Nanescu
authors: 2 Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Jeffrey L
authors: JL
authors: Dupree
authors: 3 Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Thomas A
authors: TA
authors: Wynn
authors: 1 Department of Biology, Georgetown University, Washington, DC 20057, USA jeffrey.huang@georgetown.edu.
authors: Jeffrey K
authors: JK
authors: Huang
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control*; D005260:Female; D005420:Flavoproteins / Q000494:pharmacology / Q000502:physiology*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D050830:L-Amino Acid Oxidase; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000378:metabolism*; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*
chemical_list: D005420:Flavoproteins; C484538:Il4i1 protein, mouse; D050830:L-Amino Acid Oxidase
keywords: experimental autoimmune encephalomyelitis (EAE); inflammation; interleukin-4 induced 1 (IL4I1); macrophages; remyelination