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<p>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.</p>

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A GDF-15–GFRAL axis controls autoimmune T cell responses during neuroinflammation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月15日

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  • Jana K. Sonner,
  • Audrey Kahn,
  • Lars Binkle-Ladisch,
  • Jan Broder Engler,
  • Beatrice Haack,
  • Christina Zeiler,
  • Lisa Unger,
  • Simone Bauer,
  • Felix Fischbach,
  • Giovanni Almanzar,
  • Mark Walkenhorst,
  • Christina Mayer,
  • Aneta Kolakowska,
  • Sebastian Graute,
  • Caren Ramien,
  • Ingo Winschel,
  • Nicola Rothammer,
  • Markus Heine,
  • Verena Horneffer-van der Sluis,
  • Vincent Thiemann,
  • Vanessa Vieira,
  • Nina Meurs,
  • Thomas Renné,
  • Martina Prelog,
  • Sebastian Beck Jørgensen,
  • Randy J. Seeley,
  • Anke Diemert,
  • Petra C. Arck,
  • Stefan M. Gold,
  • Joerg Heeren,
  • Jörg Wischhusen,
  • Manuel A. Friese

摘要

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.