Myeloid cell-associated aromatic amino acid metabolism facilitates CNS myelin regeneration.

Autor: Hu J; Department of Biology, Georgetown University, Washington, DC, 20007, USA., Melchor GS; Department of Biology, Georgetown University, Washington, DC, 20007, USA.; Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, 20007, USA., Ladakis D; Division of Neuroimmunology and Neurological Infections, Johns Hopkins University, Baltimore, MD, 21287, USA., Reger J; Department of Biology, Georgetown University, Washington, DC, 20007, USA.; National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, 20892, USA., Kim HW; Department of Biology, Georgetown University, Washington, DC, 20007, USA., Chamberlain KA; Department of Biology, Georgetown University, Washington, DC, 20007, USA.; Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, 20007, USA., Shults NV; Department of Biology, Georgetown University, Washington, DC, 20007, USA., Oft HC; Department of Biology, Georgetown University, Washington, DC, 20007, USA., Smith VN; Department of Biology, Georgetown University, Washington, DC, 20007, USA., Rosko LM; Department of Biology, Georgetown University, Washington, DC, 20007, USA.; Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, 20007, USA., Li E; Department of Biology, Georgetown University, Washington, DC, 20007, USA., Baydyuk M; Department of Biology, Georgetown University, Washington, DC, 20007, USA., Fu MM; National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, 20892, USA., Bhargava P; Division of Neuroimmunology and Neurological Infections, Johns Hopkins University, Baltimore, MD, 21287, USA., Huang JK; Department of Biology, Georgetown University, Washington, DC, 20007, USA. jh1659@georgetown.edu.; Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, 20007, USA. jh1659@georgetown.edu.
Jazyk: angličtina
Zdroj: NPJ Regenerative medicine [NPJ Regen Med] 2024 Jan 02; Vol. 9 (1), pp. 1. Date of Electronic Publication: 2024 Jan 02.
DOI: 10.1038/s41536-023-00345-9
Abstrakt: Regulation of myeloid cell activity is critical for successful myelin regeneration (remyelination) in demyelinating diseases, such as multiple sclerosis (MS). Here, we show aromatic alpha-keto acids (AKAs) generated from the amino acid oxidase, interleukin-4 induced 1 (IL4I1), promote efficient remyelination in mouse models of MS. During remyelination, myeloid cells upregulated the expression of IL4I1. Conditionally knocking out IL4I1 in myeloid cells impaired remyelination efficiency. Mice lacking IL4I1 expression exhibited a reduction in the AKAs, phenylpyruvate, indole-3-pyruvate, and 4-hydroxyphenylpyruvate, in remyelinating lesions. Decreased AKA levels were also observed in people with MS, particularly in the progressive phase when remyelination is impaired. Oral administration of AKAs modulated myeloid cell-associated inflammation, promoted oligodendrocyte maturation, and enhanced remyelination in mice with focal demyelinated lesions. Transcriptomic analysis revealed AKA treatment induced a shift in metabolic pathways in myeloid cells and upregulated aryl hydrocarbon receptor activity in lesions. Our results suggest myeloid cell-associated aromatic amino acid metabolism via IL4I1 produces AKAs in demyelinated lesions to enable efficient remyelination. Increasing AKA levels or targeting related pathways may serve as a strategy to facilitate the regeneration of myelin in inflammatory demyelinating conditions.
(© 2024. The Author(s).)
Databáze: MEDLINE
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