TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation
After acute lesions in the central nervous system (CNS), the interaction of microglia, astrocytes, and infiltrating immune cells decides over their resolution or chronification. However, this CNS-intrinsic cross-talk is poorly characterized. Analyzing cerebrospinal fluid (CSF) samples of Multiple Sclerosis (MS) patients as well as CNS samples of female mice with experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we identify microglia-derived TGFα as key factor driving recovery. Through mechanistic in vitro studies, in vivo treatment paradigms, scRNA sequencing, CRISPR-Cas9 genetic perturbation models and MRI in the EAE model, we show that together with other glial and non-glial cells, microglia secrete TGFα in a highly regulated temporospatial manner in EAE. Here, TGFα contributes to recovery by decreasing infiltrating T cells, pro-inflammatory myeloid cells, oligodendrocyte loss, demyelination, axonal damage and neuron loss even at late disease stages. In a therapeutic approach in EAE, blood-brain barrier penetrating intranasal application of TGFα attenuates pro-inflammatory signaling in astrocytes and CNS infiltrating immune cells while promoting neuronal survival and lesion resolution. Together, microglia-derived TGFα is an important mediator of glial-immune crosstalk, highlighting its therapeutic potential in resolving acute CNS inflammation.
Authors
- Francisco J. Quintana (ORCID: https://orcid.org/0000-0001-8156-0736)
- Arthur Liesz (ORCID: https://orcid.org/0000-0002-9069-2594)
- Frederik Bernd Laun (ORCID: https://orcid.org/0000-0002-9269-5609)
- Lisa Mészáros
- Veit Rothhammer (ORCID: https://orcid.org/0000-0003-0296-843X)
- Jürgen Winkler (ORCID: https://orcid.org/0000-0003-0630-9204)
- Mathias Linnerbauer (ORCID: https://orcid.org/0000-0002-5528-5141)
- Jannis Hanspach (ORCID: https://orcid.org/0000-0001-5416-7752)
- Lena Lößlein (ORCID: https://orcid.org/0000-0001-5705-9175)
- Tobias Bäuerle (ORCID: https://orcid.org/0000-0002-0206-6199)
- Oliver Vandrey
- Lisa Nagel
- Friederike Zunke (ORCID: https://orcid.org/0000-0002-0408-6388)
- Thanos Tsaktanis
- Ulrike Naumann (ORCID: https://orcid.org/0000-0003-3555-5703)
- Emely Elisa Neumaier
- Nora Rebecca Schwingen
- Julia Zißler
- Finnja Zuber
- Anne Peter (ORCID: https://orcid.org/0009-0009-6419-985X)
- Vivienne Riekher
- Franziska Panier
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Khalifa University of Science and Technology (AE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Johannes Gutenberg University Mainz (DE)
- LMU Klinikum (DE)
- Universitätsklinikum Erlangen (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Munich Cluster for Systems Neurology (DE)
- Comprehensive Cancer Center Erlangen (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-06-19
- DOI
- https://doi.org/10.1038/s41467-025-60363-7
- Citations
- 1
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.84
Funders
- National Multiple Sclerosis Society
- Brigham and Women's Hospital
- Broad Institute
- International Progressive MS Alliance
- Friedrich-Alexander-Universität Erlangen-Nürnberg
- Deutsche Forschungsgemeinschaft
- Johannes Gutenberg-Universität Mainz
- Khalifa University of Science, Technology and Research
- Ludwig-Maximilians-Universität München
- National Institutes of Health