TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation

Lena Lößlein, Mathias Linnerbauer, Finnja Zuber, Thanos Tsaktanis, Oliver Vandrey, Anne Peter, Franziska Panier, Julia Zissler, Vivienne Riekher, Tobias Bäuerle, Jannis Hanspach, Frederik B. Laun, Lisa Nagel, Lisa Mészáros, Friederike Zunke, Jürgen Winkler, Ulrike J. Naumann, Nora Schwingen, Emely Neumaier, Arthur Liesz, Francisco Quintana and Veit Rothhammer ()
Additional contact information
Lena Lößlein: Friedrich-Alexander University Erlangen Nuremberg
Mathias Linnerbauer: Friedrich-Alexander University Erlangen Nuremberg
Finnja Zuber: Friedrich-Alexander University Erlangen Nuremberg
Thanos Tsaktanis: Friedrich-Alexander University Erlangen Nuremberg
Oliver Vandrey: Friedrich-Alexander University Erlangen Nuremberg
Anne Peter: Friedrich-Alexander University Erlangen Nuremberg
Franziska Panier: Friedrich-Alexander University Erlangen Nuremberg
Julia Zissler: Friedrich-Alexander University Erlangen Nuremberg
Vivienne Riekher: Friedrich-Alexander University Erlangen Nuremberg
Tobias Bäuerle: Friedrich-Alexander University Erlangen Nuremberg
Jannis Hanspach: Friedrich-Alexander University Erlangen Nuremberg
Frederik B. Laun: Friedrich-Alexander University Erlangen Nuremberg
Lisa Nagel: Friedrich-Alexander University Erlangen Nuremberg
Lisa Mészáros: Friedrich-Alexander University Erlangen Nuremberg
Friederike Zunke: Friedrich-Alexander University Erlangen Nuremberg
Jürgen Winkler: Friedrich-Alexander University Erlangen Nuremberg
Ulrike J. Naumann: Friedrich-Alexander University Erlangen Nuremberg
Nora Schwingen: Friedrich-Alexander University Erlangen Nuremberg
Emely Neumaier: Friedrich-Alexander University Erlangen Nuremberg
Arthur Liesz: LMU Munich
Francisco Quintana: Harvard Medical School
Veit Rothhammer: Friedrich-Alexander University Erlangen Nuremberg

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-60363-7

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