{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T06:55:16Z","timestamp":1793256916578,"version":"4.5.0"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T00:00:00Z","timestamp":1768435200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T00:00:00Z","timestamp":1768435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["255154572, 534829736, 405358801"],"award-info":[{"award-number":["255154572, 534829736, 405358801"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["523862973"],"award-info":[{"award-number":["523862973"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["255154572, 534829736"],"award-info":[{"award-number":["255154572, 534829736"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["255154572, 534829736"],"award-info":[{"award-number":["255154572, 534829736"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["534829736"],"award-info":[{"award-number":["534829736"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["255154572, 534829736"],"award-info":[{"award-number":["255154572, 534829736"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Werner Otto-Stiftung"},{"DOI":"10.13039\/501100003493","name":"Gemeinn\u00fctzige Hertie-Stiftung","doi-asserted-by":"publisher","award":["P1200009"],"award-info":[{"award-number":["P1200009"]}],"id":[{"id":"10.13039\/501100003493","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["01KT2310"],"award-info":[{"award-number":["01KT2310"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["ERA-NET \u2013 JTC 2021, iParaCyts"],"award-info":[{"award-number":["ERA-NET \u2013 JTC 2021, iParaCyts"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Immunol"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats: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 \u03b1-like (GFRAL) on brainstem neurons. Therapeutic approaches, including neuronal gene delivery, recombinant GDF-15 administration and targeted chemogenetic activation of GFRAL-positive neurons induce \u03b2-adrenergic signaling and norepinephrine synthesis in the spleen, leading to decreased expression of integrins on T cells required for transmigration across the blood\u2013brain 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\u2013GFRAL axis as promising target for MS.<\/jats:p>","DOI":"10.1038\/s41590-025-02406-1","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T10:05:44Z","timestamp":1768471544000},"page":"503-515","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["A GDF-15\u2013GFRAL axis controls autoimmune T cell responses during neuroinflammation"],"prefix":"10.1038","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4700-272X","authenticated-orcid":false,"given":"Jana K.","family":"Sonner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Kahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6168-3210","authenticated-orcid":false,"given":"Lars","family":"Binkle-Ladisch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3169-2076","authenticated-orcid":false,"given":"Jan Broder","family":"Engler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Haack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Zeiler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Unger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Fischbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Almanzar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Walkenhorst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Mayer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aneta","family":"Kolakowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1007-6298","authenticated-orcid":false,"given":"Sebastian","family":"Graute","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3949-1359","authenticated-orcid":false,"given":"Caren","family":"Ramien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9487-7070","authenticated-orcid":false,"given":"Ingo","family":"Winschel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Rothammer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Heine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Horneffer-van der Sluis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Thiemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Vieira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5366-0123","authenticated-orcid":false,"given":"Nina","family":"Meurs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Renn\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Prelog","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian Beck","family":"J\u00f8rgensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3721-5625","authenticated-orcid":false,"given":"Randy J.","family":"Seeley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"Diemert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2932-926X","authenticated-orcid":false,"given":"Petra C.","family":"Arck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan M.","family":"Gold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5647-1034","authenticated-orcid":false,"given":"Joerg","family":"Heeren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Wischhusen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6380-2420","authenticated-orcid":false,"given":"Manuel A.","family":"Friese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,15]]},"reference":[{"key":"2406_CR1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41583-024-00823-z","volume":"25","author":"MS Woo","year":"2024","unstructured":"Woo, M. S., Engler, J. B. & Friese, M. A. The neuropathobiology of multiple sclerosis. Nat. Rev. Neurosci. 25, 493\u2013513 (2024).","journal-title":"Nat. Rev. Neurosci."},{"key":"2406_CR2","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1038\/s41577-022-00718-z","volume":"22","author":"KE Attfield","year":"2022","unstructured":"Attfield, K. E., Jensen, L. T., Kaufmann, M., Friese, M. A. & Fugger, L. The immunology of multiple sclerosis. Nat. Rev. Immunol. 22, 734\u2013750 (2022).","journal-title":"Nat. Rev. Immunol."},{"key":"2406_CR3","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1136\/jnnp-2022-330533","volume":"94","author":"C Schubert","year":"2023","unstructured":"Schubert, C. et al. Postpartum relapse risk in multiple sclerosis: a systematic review and meta-analysis. J. Neurol. Neurosurg. Psychiatry 94, 718\u2013725 (2023).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"2406_CR4","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1007\/s00281-016-0584-y","volume":"38","author":"SM Gold","year":"2016","unstructured":"Gold, S. M. & Voskuhl, R. R. Pregnancy and multiple sclerosis: from molecular mechanisms to clinical application. Semin. Immunopathol. 38, 709\u2013718 (2016).","journal-title":"Semin. Immunopathol."},{"key":"2406_CR5","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/s12948-016-0048-x","volume":"14","author":"MP Piccinni","year":"2016","unstructured":"Piccinni, M. P. et al. How pregnancy can affect autoimmune diseases progression?. Clin. Mol. Allergy 14, 11 (2016).","journal-title":"Clin. Mol. Allergy"},{"key":"2406_CR6","doi-asserted-by":"publisher","first-page":"J103","DOI":"10.1016\/j.jaut.2011.09.007","volume":"38\u2013178","author":"A Munoz-Suano","year":"2012","unstructured":"Munoz-Suano, A., Kallikourdis, M., Sarris, M. & Betz, A. G. Regulatory T cells protect from autoimmune arthritis during pregnancy. J. Autoimmun. 38\u2013178, J103\u2013J108 (2012).","journal-title":"J. Autoimmun."},{"key":"2406_CR7","doi-asserted-by":"publisher","first-page":"J88","DOI":"10.1016\/j.jaut.2011.07.001","volume":"38","author":"MA Landek-Salgado","year":"2012","unstructured":"Landek-Salgado, M. A., Rose, N. R. & Caturegli, P. Placenta suppresses experimental autoimmune hypophysitis through soluble TNF receptor 1. J. Autoimmun. 38, J88\u2013J96 (2012).","journal-title":"J. Autoimmun."},{"key":"2406_CR8","doi-asserted-by":"publisher","first-page":"E181","DOI":"10.1073\/pnas.1617115114","volume":"114","author":"JB Engler","year":"2017","unstructured":"Engler, J. B. et al. Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy. Proc. Natl Acad. Sci. USA 114, E181\u2013E190 (2017).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2406_CR9","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.yfrne.2011.12.001","volume":"33","author":"RD Spence","year":"2012","unstructured":"Spence, R. D. & Voskuhl, R. R. Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration. Front. Neuroendocrinol. 33, 105\u2013115 (2012).","journal-title":"Front. Neuroendocrinol."},{"key":"2406_CR10","first-page":"35","volume":"15","author":"RR Voskuhl","year":"2016","unstructured":"Voskuhl, R. R. et al. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 15, 35\u201346 (2016).","journal-title":"Neurol."},{"key":"2406_CR11","doi-asserted-by":"publisher","first-page":"3425","DOI":"10.1016\/j.neuron.2022.10.016","volume":"110","author":"T Koren","year":"2022","unstructured":"Koren, T. & Rolls, A. Immunoception: defining brain-regulated immunity. Neuron 110, 3425\u20133428 (2022).","journal-title":"Neuron"},{"key":"2406_CR12","doi-asserted-by":"publisher","first-page":"5902","DOI":"10.1016\/j.cell.2021.10.013","volume":"184","author":"T Koren","year":"2021","unstructured":"Koren, T. et al. Insular cortex neurons encode and retrieve specific immune responses. Cell 184, 5902\u20135915 (2021).","journal-title":"Cell"},{"key":"2406_CR13","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1016\/j.immuni.2021.04.007","volume":"54","author":"M Schiller","year":"2021","unstructured":"Schiller, M. et al. Optogenetic activation of local colonic sympathetic innervations attenuates colitis by limiting immune cell extravasation. Immunity 54, 1022\u20131036 (2021).","journal-title":"Immunity"},{"key":"2406_CR14","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1146\/annurev-neuro-111020-105359","volume":"45","author":"RGJ Klein Wolterink","year":"2022","unstructured":"Klein Wolterink, R. G. J., Wu, G. S., Chiu, I. M. & Veiga-Fernandes, H. Neuroimmune interactions in peripheral organs. Annu. Rev. Neurosci. 45, 339\u2013360 (2022).","journal-title":"Annu. Rev. Neurosci."},{"key":"2406_CR15","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1038\/s41586-024-07469-y","volume":"630","author":"H Jin","year":"2024","unstructured":"Jin, H., Li, M., Jeong, E., Castro-Martinez, F. & Zuker, C. S. A body\u2013brain circuit that regulates body inflammatory responses. Nature 630, 695\u2013703 (2024).","journal-title":"Nature"},{"key":"2406_CR16","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/s41586-024-08474-x","volume":"638","author":"MA Wheeler","year":"2025","unstructured":"Wheeler, M. A. & Quintana, F. J. The neuroimmune connectome in health and disease. Nature 638, 333\u2013342 (2025).","journal-title":"Nature"},{"key":"2406_CR17","doi-asserted-by":"publisher","first-page":"951","DOI":"10.3389\/fimmu.2020.00951","volume":"11","author":"J Wischhusen","year":"2020","unstructured":"Wischhusen, J., Melero, I. & Fridman, W. H. Growth\/differentiation factor-15 (GDF-15): from biomarker to novel targetable immune checkpoint. Front. Immunol. 11, 951 (2020).","journal-title":"Front. Immunol."},{"key":"2406_CR18","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1038\/s41586-023-06921-9","volume":"625","author":"M Fejzo","year":"2023","unstructured":"Fejzo, M. et al. GDF15 linked to maternal risk of nausea and vomiting during pregnancy. Nature 625, 760\u2013767 (2023).","journal-title":"Nature"},{"key":"2406_CR19","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/S0140-6736(03)15265-8","volume":"363","author":"S Tong","year":"2004","unstructured":"Tong, S. et al. Serum concentrations of macrophage inhibitory cytokine 1 (MIC 1) as a predictor of miscarriage. Lancet 363, 129\u2013130 (2004).","journal-title":"Lancet"},{"key":"2406_CR20","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1159\/000523991","volume":"14","author":"G Lorenz","year":"2022","unstructured":"Lorenz, G. et al. GDF15 suppresses lymphoproliferation and humoral autoimmunity in a murine model of systemic lupus erythematosus. J. Innate Immun. 14, 673\u2013689 (2022).","journal-title":"J. Innate Immun."},{"key":"2406_CR21","doi-asserted-by":"publisher","first-page":"1150","DOI":"10.1038\/nm.4392","volume":"23","author":"SE Mullican","year":"2017","unstructured":"Mullican, S. E. et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat. Med. 23, 1150\u20131157 (2017).","journal-title":"Nat. Med."},{"key":"2406_CR22","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.1038\/nm.4394","volume":"23","author":"L Yang","year":"2017","unstructured":"Yang, L. et al. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat. Med. 23, 1158\u20131166 (2017).","journal-title":"Nat. Med."},{"key":"2406_CR23","doi-asserted-by":"publisher","first-page":"e2021357118","DOI":"10.1073\/pnas.2021357118","volume":"118","author":"PV Sabatini","year":"2021","unstructured":"Sabatini, P. V. et al. GFRAL-expressing neurons suppress food intake via aversive pathways. Proc. Natl Acad. Sci. USA 118, e2021357118 (2021).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2406_CR24","doi-asserted-by":"publisher","first-page":"4253","DOI":"10.1038\/s41467-023-39817-3","volume":"14","author":"M Haake","year":"2023","unstructured":"Haake, M. et al. Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment. Nat. Commun. 14, 4253 (2023).","journal-title":"Nat. Commun."},{"key":"2406_CR25","doi-asserted-by":"publisher","first-page":"12281","DOI":"10.1073\/pnas.1918508117","volume":"117","author":"I Santos","year":"2020","unstructured":"Santos, I. et al. CXCL5-mediated recruitment of neutrophils into the peritoneal cavity of Gdf15-deficient mice protects against abdominal sepsis. Proc. Natl. Acad. Sci. USA 117, 12281\u201312287 (2020).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2406_CR26","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1084\/jem.20100370","volume":"208","author":"SCA de Jager","year":"2011","unstructured":"de Jager, S. C. A. et al. Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis. J. Exp. Med. 208, 217\u2013225 (2011).","journal-title":"J. Exp. Med."},{"key":"2406_CR27","doi-asserted-by":"publisher","first-page":"3796","DOI":"10.1172\/JCI91561","volume":"127","author":"NM Ratnam","year":"2017","unstructured":"Ratnam, N. M. et al. NF-\u03baB regulates GDF-15 to suppress macrophage surveillance during early tumor development. J. Clin. Invest. 127, 3796\u20133809 (2017).","journal-title":"J. Clin. Invest."},{"key":"2406_CR28","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1038\/s42255-021-00366-y","volume":"3","author":"J-H Weng","year":"2021","unstructured":"Weng, J. -H. et al. Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation. Nat. Metab. 3, 513\u2013522 (2021).","journal-title":"Nat. Metab."},{"key":"2406_CR29","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1038\/s42255-022-00606-9","volume":"4","author":"W Cheng","year":"2022","unstructured":"Cheng, W. et al. Hindbrain circuits in the control of eating behaviour and energy balance. Nat. Metab. 4, 826\u2013835 (2022).","journal-title":"Nat. Metab."},{"key":"2406_CR30","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1038\/s41574-021-00529-7","volume":"17","author":"D Wang","year":"2021","unstructured":"Wang, D. et al. GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease. Nat. Rev. Endocrinol. 17, 592\u2013607 (2021).","journal-title":"Nat. Rev. Endocrinol."},{"key":"2406_CR31","first-page":"4781","volume":"85","author":"AG Moore","year":"2000","unstructured":"Moore, A. G. et al. The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women. J. Clin. Endocrinol. Metab. 85, 4781\u20134788 (2000).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2406_CR32","doi-asserted-by":"publisher","first-page":"1913","DOI":"10.1038\/s42255-024-01135-3","volume":"6","author":"AM Gurtan","year":"2024","unstructured":"Gurtan, A. M. et al. Identification and characterization of human GDF15 knockouts. Nat. Metab. 6, 1913\u20131921 (2024).","journal-title":"Nat. Metab."},{"key":"2406_CR33","doi-asserted-by":"publisher","first-page":"eadf5681","DOI":"10.1126\/scitranslmed.adf5681","volume":"15","author":"KA Walker","year":"2023","unstructured":"Walker, K. A. et al. Proteomics analysis of plasma from middle-aged adults identifies protein markers of dementia risk in later life. Sci. Transl. Med. 15, eadf5681 (2023).","journal-title":"Sci. Transl. Med."},{"key":"2406_CR34","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1038\/s43587-023-00565-0","volume":"4","author":"Y Guo","year":"2024","unstructured":"Guo, Y. et al. Plasma proteomic profiles predict future dementia in healthy adults. Nat. Aging 4, 247\u2013260 (2024).","journal-title":"Nat. Aging"},{"key":"2406_CR35","doi-asserted-by":"publisher","first-page":"e675","DOI":"10.1212\/NXI.0000000000000675","volume":"7","author":"A Amstad","year":"2020","unstructured":"Amstad, A. et al. Growth differentiation factor 15 is increased in stable MS. Neurol. Neuroimmunol. Neuroinflamm. 7, e675 (2020).","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"2406_CR36","doi-asserted-by":"publisher","first-page":"2165","DOI":"10.1016\/j.cmet.2023.11.003","volume":"35","author":"JF Lu","year":"2023","unstructured":"Lu, J. F. et al. GDF15 is a major determinant of ketogenic diet-induced weight loss. Cell Metab. 35, 2165\u20132182 (2023).","journal-title":"Cell Metab."},{"key":"2406_CR37","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1016\/j.cmet.2018.12.016","volume":"29","author":"S Patel","year":"2019","unstructured":"Patel, S. et al. GDF15 provides an endocrine signal of nutritional stress in mice and humans. Cell Metab. 29, 707\u2013718 (2019).","journal-title":"Cell Metab."},{"key":"2406_CR38","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/nm.2354","volume":"17","author":"T Kempf","year":"2011","unstructured":"Kempf, T. et al. GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat. Med. 17, 581\u2013588 (2011).","journal-title":"Nat. Med."},{"key":"2406_CR39","doi-asserted-by":"publisher","first-page":"e20210420","DOI":"10.1084\/jem.20210420","volume":"219","author":"A Patsalos","year":"2022","unstructured":"Patsalos, A. et al. A growth factor-expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15. J. Exp. Med. 219, e20210420 (2022).","journal-title":"J. Exp. Med."},{"key":"2406_CR40","doi-asserted-by":"publisher","first-page":"13640","DOI":"10.1523\/JNEUROSCI.1133-09.2009","volume":"29","author":"J Strelau","year":"2009","unstructured":"Strelau, J. et al. Progressive postnatal motoneuron loss in mice lacking GDF-15. J. Neurosci. 29, 13640\u201313648 (2009).","journal-title":"J. Neurosci."},{"key":"2406_CR41","doi-asserted-by":"publisher","first-page":"2730","DOI":"10.1093\/brain\/awac102","volume":"145","author":"G Di Liberto","year":"2022","unstructured":"Di Liberto, G. et al. Neurodegenerative phagocytes mediate synaptic stripping in Neuro-HIV. Brain 145, 2730\u20132741 (2022).","journal-title":"Brain"},{"key":"2406_CR42","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1038\/s41586-023-06249-4","volume":"619","author":"D Wang","year":"2023","unstructured":"Wang, D. et al. GDF15 promotes weight loss by enhancing energy expenditure in muscle. Nature 619, 143\u2013150 (2023).","journal-title":"Nature"},{"key":"2406_CR43","doi-asserted-by":"publisher","first-page":"e2106868118","DOI":"10.1073\/pnas.2106868118","volume":"118","author":"I Cimino","year":"2021","unstructured":"Cimino, I. et al. Activation of the hypothalamic\u2013pituitary\u2013adrenal axis by exogenous and endogenous GDF15. Proc. Natl Acad. Sci. USA 118, e2106868118 (2021).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2406_CR44","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1016\/j.cmet.2023.06.016","volume":"35","author":"KA Sj\u00f8berg","year":"2023","unstructured":"Sj\u00f8berg, K. A. et al. GDF15 increases insulin action in the liver and adipose tissue via a \u03b2-adrenergic receptor-mediated mechanism. Cell. Metab. 35, 1327\u20131340 (2023).","journal-title":"Cell. Metab."},{"key":"2406_CR45","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1038\/nri2156","volume":"7","author":"K Ley","year":"2007","unstructured":"Ley, K., Laudanna, C., Cybulsky, M. I. & Nourshargh, S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat. Rev. Immunol. 7, 678\u2013689 (2007).","journal-title":"Nat. Rev. Immunol."},{"key":"2406_CR46","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.smim.2012.04.010","volume":"24","author":"F Carrette","year":"2012","unstructured":"Carrette, F. & Surh, C. D. IL-7 signaling and CD127 receptor regulation in the control of T cell homeostasis. Semin. Immunol. 24, 209\u2013217 (2012).","journal-title":"Semin. Immunol."},{"key":"2406_CR47","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.1126\/science.1100747","volume":"306","author":"R Zimmermann","year":"2004","unstructured":"Zimmermann, R. et al. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306, 1383\u20131386 (2004).","journal-title":"Science"},{"key":"2406_CR48","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1007\/s004240050525","volume":"435","author":"T Yamauchi","year":"1998","unstructured":"Yamauchi, T., Iwai, M., Kobayashi, N. & Shimazu, T. Noradrenaline and ATP decrease the secretion of triglyceride and apoprotein B from perfused rat liver. Pfl\u00fcgers Arch. 435, 368\u2013374 (1998).","journal-title":"Pfl\u00fcgers Arch."},{"key":"2406_CR49","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1038\/s41586-023-06568-6","volume":"622","author":"A-M Globig","year":"2023","unstructured":"Globig, A. -M. et al. The \u03b21-adrenergic receptor links sympathetic nerves to T\u2009cell exhaustion. Nature 622, 383\u2013392 (2023).","journal-title":"Nature"},{"key":"2406_CR50","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.molmet.2019.01.003","volume":"21","author":"H Frikke-Schmidt","year":"2019","unstructured":"Frikke-Schmidt, H. et al. GDF15 acts synergistically with liraglutide but is not necessary for the weight loss induced by bariatric surgery in mice. Mol. Metab. 21, 13\u201321 (2019).","journal-title":"Mol. Metab."},{"key":"2406_CR51","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/nn.2467","volume":"13","author":"L Madisen","year":"2010","unstructured":"Madisen, L. et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat. Neurosci. 13, 133\u2013140 (2010).","journal-title":"Nat. Neurosci."},{"key":"2406_CR52","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1016\/j.neuron.2016.01.040","volume":"89","author":"BL Roth","year":"2016","unstructured":"Roth, B. L. DREADDs for neuroscientists. Neuron 89, 683\u2013694 (2016).","journal-title":"Neuron"},{"key":"2406_CR53","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1002\/dvg.22949","volume":"54","author":"H Zhu","year":"2016","unstructured":"Zhu, H. et al. Cre-dependent DREADD (designer receptors exclusively activated by designer drugs) mice. Genesis 54, 439\u2013446 (2016).","journal-title":"Genesis"},{"key":"2406_CR54","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1016\/j.immuni.2022.04.015","volume":"55","author":"A Eisenstein","year":"2022","unstructured":"Eisenstein, A. et al. Activation of the transcription factor NRF2 mediates the anti-inflammatory properties of a subset of over-the-counter and prescription NSAIDs. Immunity 55, 1082\u20131095 (2022).","journal-title":"Immunity"},{"key":"2406_CR55","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.bbi.2023.11.029","volume":"116","author":"J Reyes","year":"2024","unstructured":"Reyes, J., Zhao, Y., Pandya, K. & Yap, G. S. Growth differentiation factor-15 is an IFN-\u03b3 regulated mediator of infection-induced weight loss and the hepatic FGF21 response. Brain Behav. Immun. 116, 24\u201333 (2024).","journal-title":"Brain Behav. Immun."},{"key":"2406_CR56","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/j.cmet.2022.12.011","volume":"35","author":"O Benichou","year":"2023","unstructured":"Benichou, O. et al. Discovery, development, and clinical proof of mechanism of LY3463251, a long-acting GDF15 receptor agonist. Cell Metab. 35, 274\u2013286 (2023).","journal-title":"Cell Metab."},{"key":"2406_CR57","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1210\/clinem\/dgae550","volume":"110","author":"WB Smith","year":"2024","unstructured":"Smith, W. B. et al. A growth differentiation factor 15 receptor agonist in randomized placebo-controlled trials in healthy or obese persons. J. Clin. Endocrinol. Metab. 110, 771\u2013786 (2024).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2406_CR58","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1038\/s41586-024-08305-z","volume":"637","author":"I Melero","year":"2024","unstructured":"Melero, I. et al. Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours. Nature 637, 1218\u20131227 (2024).","journal-title":"Nature"},{"key":"2406_CR59","doi-asserted-by":"publisher","first-page":"113960","DOI":"10.1016\/j.celrep.2024.113960","volume":"43","author":"LE Ruud","year":"2024","unstructured":"Ruud, L. E. et al. Activation of GFRAL+ neurons induces hypothermia and glucoregulatory responses associated with nausea and torpor. Cell Rep. 43, 113960 (2024).","journal-title":"Cell Rep."},{"key":"2406_CR60","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1038\/nm1564","volume":"13","author":"T Korn","year":"2007","unstructured":"Korn, T. et al. Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat. Med. 13, 423\u2013431 (2007).","journal-title":"Nat. Med."},{"key":"2406_CR61","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1016\/j.cell.2019.07.033","volume":"178","author":"HH Luan","year":"2019","unstructured":"Luan, H. H. et al. GDF15 is an inflammation-induced central mediator of tissue tolerance. Cell 178, 1231\u20131244 (2019).","journal-title":"Cell"},{"key":"2406_CR62","doi-asserted-by":"publisher","first-page":"29803","DOI":"10.1073\/pnas.2008213117","volume":"117","author":"AM Kressel","year":"2020","unstructured":"Kressel, A. M. et al. Identification of a brainstem locus that inhibits tumor necrosis factor. Proc. Natl Acad. Sci. USA 117, 29803\u201329810 (2020).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2406_CR63","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s42255-022-00529-5","volume":"4","author":"CFW Chow","year":"2022","unstructured":"Chow, C. F. W. et al. Body weight regulation via MT1-MMP-mediated cleavage of GFRAL. Nat. Metab. 4, 203\u2013212 (2022).","journal-title":"Nat. Metab."},{"key":"2406_CR64","doi-asserted-by":"publisher","first-page":"16701","DOI":"10.1074\/jbc.274.24.16701","volume":"274","author":"DK Rohrer","year":"1999","unstructured":"Rohrer, D. K., Chruscinski, A., Schauble, E. H., Bernstein, D. & Kobilka, B. K. Cardiovascular and metabolic alterations in mice lacking both \u03b21- and \u03b22-adrenergic receptors. J. Biol. Chem. 274, 16701\u201316708 (1999).","journal-title":"J. Biol. Chem."},{"key":"2406_CR65","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1038\/nn.4593","volume":"20","author":"KY Chan","year":"2017","unstructured":"Chan, K. Y. et al. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat. Neurosci. 20, 1172\u20131179 (2017).","journal-title":"Nat. Neurosci."},{"key":"2406_CR66","doi-asserted-by":"publisher","first-page":"eabm5500","DOI":"10.1126\/sciadv.abm5500","volume":"8","author":"N Rothammer","year":"2022","unstructured":"Rothammer, N. et al. G9a dictates neuronal vulnerability to inflammatory stress via transcriptional control of ferroptosis. Sci. Adv. 8, eabm5500 (2022).","journal-title":"Sci. Adv."},{"key":"2406_CR67","doi-asserted-by":"publisher","first-page":"2354","DOI":"10.1038\/s41596-022-00716-4","volume":"17","author":"I Scheyltjens","year":"2022","unstructured":"Scheyltjens, I. et al. Single-cell RNA and protein profiling of immune cells from the mouse brain and its border tissues. Nat. Protoc. 17, 2354\u20132388 (2022).","journal-title":"Nat. Protoc."},{"key":"2406_CR68","doi-asserted-by":"publisher","first-page":"1805","DOI":"10.1038\/nm.3015","volume":"18","author":"B Schattling","year":"2012","unstructured":"Schattling, B. et al. TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat. Med. 18, 1805\u20131811 (2012).","journal-title":"Nat. Med."}],"container-title":["Nature Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41590-025-02406-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41590-025-02406-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41590-025-02406-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T21:02:07Z","timestamp":1772571727000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41590-025-02406-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,15]]},"references-count":68,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["2406"],"URL":"https:\/\/doi.org\/10.1038\/s41590-025-02406-1","relation":{},"ISSN":["1529-2908","1529-2916"],"issn-type":[{"value":"1529-2908","type":"print"},{"value":"1529-2916","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,15]]},"assertion":[{"value":"9 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 December 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 January 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"S.B.J. is an employee of Novo Nordisk, a pharmaceutical company producing and selling medicine for the treatment of diabetes and obesity. R.J.S. has received research support from Novo Nordisk, Fractyl, Astra Zeneca, Congruence Therapeutics, Eli Lilly, Bullfrog AI, Glyscend Therapeutics and Amgen. R.J.S. has served as a paid consultant for Novo Nordisk, Eli Lilly, CinRx, Fractyl, Structure Therapeutics, Crinetics, Amgen, Congruence Therapeutics and Nuanced Health. R.J.S. has equity in Bullfrog AI, Nuanced Health, Coro Bio and Rewind. J.W. is an inventor on patents related to GDF-15 as a biomarker and therapeutic target in cancer, and a cofounder and shareholder of the biotech company CatalYm. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}