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

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 LeppertJens Kuhle, Seunghee Kim-Schulze, Matthias Nahrendorf, Benjamin P. Kleinstiver, Fay Probert, Panos Roussos, Filip K. Swirski, Cameron S. McAlpine

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1502-1514.e8
JournalImmunity
Volume56
Issue number7
DOIs
StatePublished - 11 Jul 2023

Keywords

  • astrocyte
  • chemokine
  • interleukin-3
  • microglia
  • monocyte
  • multiple sclerosis
  • neuroinflammation
  • recruitment

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