Interleukin-3 coordinates glial-peripheral immune crosstalk to incite multiple sclerosis.

Glial cells and central nervous system (CNS)-infiltrating leukocytes contribute to multiple sclerosis (MS). However, the networks that govern crosstalk among these ontologically distinct populations remain unclear. Here, we show that, in mice and humans, CNS-resident astrocytes and infiltrating CD44hiCD4+ T cells generated interleukin-3 (IL-3), while microglia and recruited myeloid cells expressed interleukin-3 receptor-ɑ (IL-3Rɑ). Astrocytic and T cell IL-3 elicited an immune migratory and chemotactic program by IL-3Rɑ+ myeloid cells that enhanced CNS immune cell infiltration, exacerbating MS and its preclinical model. Multiregional snRNA-seq of human CNS tissue revealed the appearance of IL3RA-expressing myeloid cells with chemotactic programming in MS plaques. IL3RA expression by plaque myeloid cells and IL-3 amount in the cerebrospinal fluid predicted myeloid and T cell abundance in the CNS and correlated with MS severity. Our findings establish IL-3:IL-3RA as a glial-peripheral immune network that prompts immune cell recruitment to the CNS and worsens MS. Copyright © 2023 Elsevier Inc. All rights reserved.

Citation

Máté G Kiss, John E Mindur, Abi G Yates, Donghoon Lee, John F Fullard, Atsushi Anzai, Wolfram C Poller, Kathleen A Christie, Yoshiko Iwamoto, Vladimir Roudko, Jeffrey Downey, Christopher T Chan, Pacific Huynh, Henrike Janssen, Achilles Ntranos, Jan D Hoffmann, Walter Jacob, Sukanya Goswami, Sumnima Singh, David Leppert, Jens Kuhle, Seunghee Kim-Schulze, Matthias Nahrendorf, Benjamin P Kleinstiver, Fay Probert, Panos Roussos, Filip K Swirski, Cameron S McAlpine. Interleukin-3 coordinates glial-peripheral immune crosstalk to incite multiple sclerosis. Immunity. 2023 Jul 11;56(7):1502-1514.e8

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PMID: 37160117

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