TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation
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 Mu...
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| Format: | Article |
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Nature Portfolio
2025-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60363-7 |
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| author | 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 Veit Rothhammer |
| author_facet | 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 Veit Rothhammer |
| author_sort | Lena Lößlein |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-908952fd22bb4f939d2a77196caf2eb2 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-908952fd22bb4f939d2a77196caf2eb22025-08-20T03:22:53ZengNature PortfolioNature Communications2041-17232025-06-0116111710.1038/s41467-025-60363-7TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammationLena Lößlein0Mathias Linnerbauer1Finnja Zuber2Thanos Tsaktanis3Oliver Vandrey4Anne Peter5Franziska Panier6Julia Zissler7Vivienne Riekher8Tobias Bäuerle9Jannis Hanspach10Frederik B. Laun11Lisa Nagel12Lisa Mészáros13Friederike Zunke14Jürgen Winkler15Ulrike J. Naumann16Nora Schwingen17Emely Neumaier18Arthur Liesz19Francisco Quintana20Veit Rothhammer21Department of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergDepartment of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergDepartment of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergDepartment of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergDepartment of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergDepartment of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergDepartment of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergDepartment of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergDepartment of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergInstitute of Radiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergInstitute of Radiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergInstitute of Radiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergInstitute of Radiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergDepartment of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergDepartment of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergDepartment of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergDepartment of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergDepartment of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergDepartment of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergInstitute for Stroke and Dementia Research (ISD), University Hospital, LMU MunichAnn Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical SchoolDepartment of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen NurembergAbstract 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.https://doi.org/10.1038/s41467-025-60363-7 |
| spellingShingle | 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 Veit Rothhammer TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation Nature Communications |
| title | TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation |
| title_full | TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation |
| title_fullStr | TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation |
| title_full_unstemmed | TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation |
| title_short | TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation |
| title_sort | tgfα controls checkpoints in cns resident and infiltrating immune cells to promote resolution of inflammation |
| url | https://doi.org/10.1038/s41467-025-60363-7 |
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