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 Leppert; Jens Kuhle; Seunghee Kim-Schulze; Matthias Nahrendorf; Benjamin P Kleinstiver; Fay Probert; Panos Roussos; Filip K Swirski; Cameron S McAlpine

doi:10.1016/j.immuni.2023.04.013

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

Immunity. 2023 Jul 11;56(7):1502-1514.e8. doi: 10.1016/j.immuni.2023.04.013. Epub 2023 May 8.

Authors

Máté G Kiss¹, John E Mindur², Abi G Yates³, Donghoon Lee⁴, John F Fullard⁴, Atsushi Anzai², Wolfram C Poller⁵, Kathleen A Christie⁶, Yoshiko Iwamoto², Vladimir Roudko⁷, Jeffrey Downey⁵, Christopher T Chan², Pacific Huynh³, Henrike Janssen⁵, Achilles Ntranos⁸, Jan D Hoffmann³, Walter Jacob³, Sukanya Goswami³, Sumnima Singh⁵, David Leppert⁹, Jens Kuhle⁹, Seunghee Kim-Schulze⁷, Matthias Nahrendorf², Benjamin P Kleinstiver⁶, Fay Probert¹⁰, Panos Roussos¹¹, Filip K Swirski¹², Cameron S McAlpine¹³

Affiliations

¹ Cardiovascular Research Institute and the Department of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute and the Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Systems Biology and the Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
² Center for Systems Biology and the Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³ Cardiovascular Research Institute and the Department of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute and the Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Friedman Brain Institute and the Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Disease Neurogenomics and the Icahn Institute for Data Science and Genomic Technology and the Departments of Psychiatry and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Cardiovascular Research Institute and the Department of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Systems Biology and the Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Center for Genomic Medicine, Department of Pathology, Massachusetts General Hospital, Boston, MA, USA; Department of Pathology, Harvard Medical School, Boston, MA, USA.
⁷ Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸ Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹ Departments of Medicine, Clinical Research and Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
¹⁰ Department of Pharmacology and Department Chemistry, University of Oxford, Oxford, UK.
¹¹ Friedman Brain Institute and the Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Disease Neurogenomics and the Icahn Institute for Data Science and Genomic Technology and the Departments of Psychiatry and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mental Illness Research Education and Clinical Center, James J. Peters VA Medical Center, New York, NY, USA; Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
¹² Cardiovascular Research Institute and the Department of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Systems Biology and the Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹³ Cardiovascular Research Institute and the Department of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute and the Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Systems Biology and the Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: [email protected].

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 CD44^hiCD4⁺ 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.

Keywords: astrocyte; chemokine; interleukin-3; microglia; monocyte; multiple sclerosis; neuroinflammation; recruitment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Central Nervous System
Humans
Interleukin-3
Mice
Microglia
Multiple Sclerosis*
Neuroglia / metabolism

Substances

Interleukin-3
Il3 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding