A GDF-15–GFRAL axis controls autoimmune T cell responses during neuroinflammation
Inflammatory activity during multiple sclerosis (MS) often improves during pregnancy, suggesting that pregnancy-related immune adaptations affect the disease. Here we show that growth/differentiation factor-15 (GDF-15) increases during pregnancy and correlates with a reduced rate of MS relapses. GDF-15 also accumulates in the inflamed central nervous system, and its absence impairs inflammation resolution in a mouse model of MS. GDF-15 suppresses autoimmune T cell responses through an indirect signaling pathway involving the activation of GDNF family receptor α-like (GFRAL) on brainstem neurons. Therapeutic approaches, including neuronal gene delivery, recombinant GDF-15 administration and targeted chemogenetic activation of GFRAL-positive neurons induce β-adrenergic signaling and norepinephrine synthesis in the spleen, leading to decreased expression of integrins on T cells required for transmigration across the blood-brain barrier and confer protection against neuroinflammation in preclinical models of MS. These findings position GDF-15 as a crucial neuroimmune mediator and the GDF-15-GFRAL axis as promising target for MS.
Authors
- Jan Broder Engler (ORCID: https://orcid.org/0000-0002-3169-2076)
- Christina Zeiler (ORCID: https://orcid.org/0000-0002-3006-9004)
- Manuel Alexander Friese (ORCID: https://orcid.org/0000-0001-6380-2420)
- Stefan M. Gold (ORCID: https://orcid.org/0000-0001-5188-4799)
- Aneta Kolakowska
- Nicola Rothammer (ORCID: https://orcid.org/0000-0002-5137-389X)
- Simone Bauer (ORCID: https://orcid.org/0000-0003-1780-231X)
- Sebastian B. Jørgensen (ORCID: https://orcid.org/0000-0002-9648-0971)
- Vanessa Vieira (ORCID: https://orcid.org/0000-0002-0205-9669)
- Petra Arck (ORCID: https://orcid.org/0000-0002-2932-926X)
- Nina Meurs (ORCID: https://orcid.org/0000-0001-5366-0123)
- J Wischhusen
- Christina Mayer (ORCID: https://orcid.org/0000-0002-4148-2822)
- Caren Ramien (ORCID: https://orcid.org/0000-0002-3949-1359)
- Beatrice Haack
- Giovanni Almanzar (ORCID: https://orcid.org/0000-0002-9430-7921)
- Jana K. Sonner (ORCID: https://orcid.org/0000-0002-4700-272X)
- Ingo Winschel (ORCID: https://orcid.org/0000-0001-9487-7070)
- Audrey Kahn
- Martina Prelog
- Lars Binkle-Ladisch (ORCID: https://orcid.org/0000-0001-6168-3210)
- Vincent Thiemann
- Markus Heine (ORCID: https://orcid.org/0000-0001-9761-8250)
- Mark Walkenhorst (ORCID: https://orcid.org/0000-0002-2277-9532)
- Randy John Seeley
- Anke Diemert
- L Unger
- JOERG HEEREN
- Sebastian Graute (ORCID: https://orcid.org/0009-0002-1007-6298)
- Thomas Renné
- Verena Horneffer-van der Sluis
Institutions
- Royal College of Surgeons in Ireland (IE)
- Universität Hamburg (DE)
- Johannes Gutenberg University Mainz (DE)
- University of Michigan (US)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Novo Nordisk (United States) (US)
- University Medical Center Hamburg-Eppendorf (DE)
- Universitätsklinikum Würzburg (DE)
- Institute of Neuroimmunology of the Slovak Academy of Sciences (SK)
- Franklin University (US)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Nature Immunology
- Published
- 2026-01-15
- DOI
- https://doi.org/10.1038/s41590-025-02406-1
- Citations
- 2
- Primary Topic
- GDF15 and Related Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 93.60