Interleukin-3 coordinates glial-peripheral immune crosstalk to incite multiple sclerosis.
Kiss MG., Mindur JE., Yates AG., Lee D., Fullard JF., Anzai A., Poller WC., Christie KA., Iwamoto Y., Roudko V., Downey J., Chan CT., Huynh P., Janssen H., Ntranos A., Hoffmann JD., Jacob W., Goswami S., Singh S., Leppert D., Kuhle J., Kim-Schulze S., Nahrendorf M., Kleinstiver BP., Probert F., Roussos P., Swirski FK., McAlpine CS.
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.