Sonner JK, Kahn A, Binkle-Ladisch L, Engler JB, Haack B, Zeiler C, Unger L, Bauer S, Fischbach F, Almanzar G, Walkenhorst M, Mayer C, Kolakowska A, Graute S, Ramien C, Winschel I, Rothammer N, Heine M, Horneffer-van der Sluis V, Thiemann V, Vieira V, Meurs N, Renné T, Prelog M, Jørgensen SB, Seeley RJ, Diemert A, Arck PC, Gold SM, Heeren J, Wischhusen J, Friese MA.
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.Nat Immunol. 2026 Jan 15.
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