IL4I1 augments CNS remyelination and axonal protection by modulating T cell driven inflammation

Psachoulia, Konstantina; Chamberlain, Kelly A.; Heo, Dongeun; Davis, Stephanie E; Paskus, Jeremiah D.; Nanescu, Sonia E.; Dupree, Jeffrey L.; Wynn, Thomas A.; Huang, Jeffrey K.

doi:10.1093/brain/aww254

Cited by 59 publications

(62 citation statements)

References 64 publications

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“…They are also responsible for the production of cytokines such as Interleukin-1 (IL-1), IL-6, IL-8, IL-12, IL-10, tumoral necrosis factor-alpha (TNF-α), and transforming growth factor beta (TGF-β) 32 . In addition, gliosis has been linked to the presence of foamy macrophages in infections and inflammatory diseases of the central nervous system 33 .…”

Section: Discussionmentioning

confidence: 99%

“…The lipidic corpuscles within macrophages are related to several inflammatory conditions and may function as storage sites and for the synthesis of inflammatory mediators 32 . On the other hand, the first line of defense against microorganism composed by PMN cells are attracted to the infection site and produce chemokines when activated, attracting other immune cells 33,36 . This local inflammation may have been the cause of the periventricular and parenchymatous demyelination observed in our results.…”

Section: Discussionmentioning

confidence: 99%

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Demyelination in experimental intraventricular neurocysticercosis

Moura

Milhomem

Lima

et al. 2020

Arq. Neuro-Psiquiatr.

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Neurocysticercosis (NCC) is classified as a neglected tropical disease, which affects mainly Latin America and Africa in spite of some reports in North America and Europe. NCC represents the cause of up to 30% of the reported cases of epilepsy in endemic countries. The NCC injuries present direct relation to the development stage, location, and number of parasites as well as to the host immune response. This study aimed the characterization of the inflammatory response and tissue injuries by means of the analyses of the periventricular and parenchymatous demyelination through the experimental intraventricular NCC infection. Therefore, BALB/c mice were submitted to experimental NCC inoculation with Taenia crassiceps cysticerci. Their brains were removed at 7, 30, 60, and 90 days after the inoculation (DAI), and analyzed after staining with hematoxylin and eosin (HE), Luxol Fast Blue, and Nissl. It was possible to observe ventriculomegaly, inflammatory infiltration composed by polymorphonuclear and mononuclear cells, and foamy macrophages. The presence of inflammatory cells was associated with neurodegeneration detected by the areas with demyelination observed initially in the periventricular area and lately in the parenchyma. In conclusion, the presence of cysticerci and the consequent inflammation were able to promote initial periventricular demyelination followed by parenchymatous demyelination as the infection progressed.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Demyelination in experimental intraventricular neurocysticercosis

Moura

Milhomem

Lima

et al. 2020

Arq. Neuro-Psiquiatr.

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“…Several macrophages/microglia populations have been shown to secrete the enzyme interleukin-four induced one (IL4I1), which is upregulated at the onset of inflammation resolution and remyelination [155]. Mice lacking Il4i1 or its receptor show increased proinflammatory macrophage density, remyelination impairment, and axonal injury in the CNS lesions.…”

Section: Role Of Inflammation In Oligodendrocyte Cell Lineage Progresmentioning

confidence: 99%

“…Mice lacking Il4i1 or its receptor show increased proinflammatory macrophage density, remyelination impairment, and axonal injury in the CNS lesions. Conversely, recombinant IL4I1 administration reduces proinflammatory macrophage density, enhances remyelination, and rescues remyelination impairment [155]. Remarkably, intravenous injection of IL4I1 into mice with experimental autoimmune encephalomyelitis (a widely used inflammatory mouse model of MS) at disease onset significantly reversed disease severity, resulting in motor function recovery [155].…”

Section: Role Of Inflammation In Oligodendrocyte Cell Lineage Progresmentioning

confidence: 99%

“…Conversely, recombinant IL4I1 administration reduces proinflammatory macrophage density, enhances remyelination, and rescues remyelination impairment [155]. Remarkably, intravenous injection of IL4I1 into mice with experimental autoimmune encephalomyelitis (a widely used inflammatory mouse model of MS) at disease onset significantly reversed disease severity, resulting in motor function recovery [155]. These studies suggest that manipulating M2 polarization and secretion of pro-myelinating factors in the CNS lesion may present a complementary regenerative strategy to support remyelination and clinical recovery in MS.…”

Section: Role Of Inflammation In Oligodendrocyte Cell Lineage Progresmentioning

confidence: 99%

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Extrinsic Factors Driving Oligodendrocyte Lineage Cell Progression in CNS Development and Injury

et al. 2020

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Oligodendrocytes (OLs) generate myelin membranes for the rapid propagation of electrical signals along axons in the central nervous system (CNS) and provide metabolites to support axonal integrity and function. Differentiation of OLs from oligodendrocyte progenitor cells (OPCs) is orchestrated by a multitude of intrinsic and extrinsic factors in the CNS. Disruption of this process, or OL loss in the developing or adult brain, as observed in various neurological conditions including hypoxia/ ischemia, stroke, and demyelination, results in axonal dystrophy, neuronal dysfunction, and severe neurological impairments. While much is known regarding the intrinsic regulatory signals required for OL lineage cell progression in development, studies from pathological conditions highlight the importance of the CNS environment and external signals in regulating OL genesis and maturation. Here, we review the recent findings in OL biology in the context of the CNS physiological and pathological conditions, focusing on extrinsic factors that facilitate OL development and regeneration.

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Immunosuppressive enzymes in the tumor microenvironment

Molinier‐Frenkel

Castellano

2017

FEBS Letters

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Antigen encounter by T lymphocytes induces important metabolic changes. Antitumor T lymphocytes enter in a metabolic competition with tumors, which divert feedback mechanisms of the immune response. Immunosuppressive enzymes, modifying the nutrient availability and leading to the production of toxic catabolites, represent one of these mechanisms, contributing to the metabolic halo in which T lymphocytes evolve during immune responses. Two classes of immunosuppressive enzymes, expressed by the tumor cells or by cells of the microenvironment, have been described: those catabolizing essential or semiessential amino acids, tryptophan, arginine, and phenylalanine and the ectoenzymes, which degrade the ATP to produce adenosine. These enzymes are described, as well as some of the ongoing clinical trials aiming to block them in cancer treatment.

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IL4I1 augments CNS remyelination and axonal protection by modulating T cell driven inflammation

Cited by 59 publications

References 64 publications

Demyelination in experimental intraventricular neurocysticercosis

Demyelination in experimental intraventricular neurocysticercosis

Extrinsic Factors Driving Oligodendrocyte Lineage Cell Progression in CNS Development and Injury

Immunosuppressive enzymes in the tumor microenvironment

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