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

Lößlein L, Linnerbauer M, Zuber F, Tsaktanis T, Vandrey O, Peter A, Panier F, Zissler J, Riekher V, Bäuerle T, Hanspach J, Laun FB, Nagel L, Mészáros L, Zunke F, Winkler J, Naumann U, Schwingen NR, Neumaier E, Liesz A, Quintana F, Rothhammer V (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 16

Article Number: 5344

Journal Issue: 1

DOI: 10.1038/s41467-025-60363-7

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.

Authors with CRIS profile

Lena Lößlein Department of Neurology Mathias Linnerbauer Department of Neurology Thanos Tsaktanis Department of Neurology Oliver Vandrey Department of Neurology Anne Peter Department of Neurology Vivienne Tschurl Department of Medicine 3 – Rheumatology and Immunology Tobias Bäuerle Professur für Multimodale Bildgebung in der präklinischen Forschung Jannis Hanspach Institute of Radiology Jürgen Winkler Professur für Molekulare Neurologie Ulrike Naumann Department of Neurology Nora Rebecca Schwingen Department of Medicine 5 – Haematology and Oncology Emely Neumaier Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology

Involved external institutions

Klinikum der Universität München DE Germany (DE) Harvard University US United States (USA) (US)

How to cite

APA:

Lößlein, L., Linnerbauer, M., Zuber, F., Tsaktanis, T., Vandrey, O., Peter, A.,... Rothhammer, V. (2025). TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation. Nature Communications, 16(1). https://doi.org/10.1038/s41467-025-60363-7

MLA:

Lößlein, Lena, et al. "TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation." Nature Communications 16.1 (2025).

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