IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice

Myrto Andreadou; Florian Ingelfinger; Donatella De Feo; Teresa L.M. Cramer; Selma Tuzlak; Ekaterina Friebel; Bettina Schreiner; Pascale Eede; Shirin Schneeberger; Maria Geesdorf; Frederike Ridder; Christina A. Welsh; Laura Power; Daniel Kirschenbaum; Shiva K. Tyagarajan; Melanie Greter; Frank L. Heppner; Sarah Mundt; Burkhard Becher

doi:10.1038/s41593-023-01435-z

IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice

Myrto Andreadou, Florian Ingelfinger, Donatella De Feo, Teresa L.M. Cramer, Selma Tuzlak, Ekaterina Friebel, Bettina Schreiner, Pascale Eede, Shirin Schneeberger, Maria Geesdorf, Frederike Ridder, Christina A. Welsh, Laura Power, Daniel Kirschenbaum, Shiva K. Tyagarajan, Melanie Greter, Frank L. Heppner, Sarah Mundt^*, Burkhard Becher^*

^*Corresponding author for this work

Department of Systems Immunology

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

Interleukin-12 (IL-12) is a potent driver of type 1 immunity. Paradoxically, in autoimmune conditions, including of the CNS, IL-12 reduces inflammation. The underlying mechanism behind these opposing properties and the involved cellular players remain elusive. Here we map IL-12 receptor (IL-12R) expression to NK and T cells as well as neurons and oligodendrocytes. Conditionally ablating the IL-12R across these cell types in adult mice and assessing their susceptibility to experimental autoimmune encephalomyelitis revealed that the neuroprotective role of IL-12 is mediated by neuroectoderm-derived cells, specifically neurons, and not immune cells. In human brain tissue from donors with multiple sclerosis, we observe an IL-12R distribution comparable to mice, suggesting similar mechanisms in mice and humans. Combining flow cytometry, bulk and single-nucleus RNA sequencing, we reveal an IL-12-induced neuroprotective tissue adaption preventing early neurodegeneration and sustaining trophic factor release during neuroinflammation, thereby maintaining CNS integrity in mice.

Original language	English
Pages (from-to)	1701-1712
Number of pages	12
Journal	Nature Neuroscience
Volume	26
Issue number	10
Early online date	25 Sept 2023
DOIs	https://doi.org/10.1038/s41593-023-01435-z
Publication status	Published - Oct 2023

Bibliographical note

We thank L. Robinson from Insight Editing London for paper editing; A. Sethi, S. Marti, M. Lutz, N. Puertas, P. Hähne, A. Fonseca da Silva, R. Lindemann, S. Da Costa Pereira and L. Oberbichler for technical support; H. Rehrauer, L. Opitz, A. Cabral de Gouvea, D. Popovic, Q. Zhang, F. Noe and T. Sykes for technical and computational advice on sequencing experiments; the Center for Microscopy and Image Analysis, University of Zurich (ZMB) and the Functional Genomics Center Zurich (FGCZ) for providing equipment. We thank A. Saab (UZH) for the Plp1 strain. The schematic representations of human MS lesions and neuroectodermal cell types were created with BioRender.com . This work has received funding from the Swiss National Science Foundation (Ambizione grant PZ00P3_193330 to S.M. and 733 310030_170320, 310030_188450 and CRSII5_183478 to B.B.), European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 882424 to B.B.), Research Talent Development Fund zur Förderung des akademischen Nachwuchses (FAN; to S.M.), Forschungskredit Postdoc fellowship University of Zurich grant no. K-41302-11-01 (to S.M.), Dr. Wilhelm Hurka Foundation (to B.B. and S.M.) and the Swiss Multiple Sclerosis Society (to S.M. and F.I.). F.I. received a PhD fellowship from Studienstiftung des deutschen Volkes. CreER

All Science Journal Classification (ASJC) codes

General Neuroscience

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Andreadou, M., Ingelfinger, F., De Feo, D., Cramer, T. L. M., Tuzlak, S., Friebel, E., Schreiner, B., Eede, P., Schneeberger, S., Geesdorf, M., Ridder, F., Welsh, C. A., Power, L., Kirschenbaum, D., Tyagarajan, S. K., Greter, M., Heppner, F. L., Mundt, S., & Becher, B. (2023). IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice. Nature Neuroscience, 26(10), 1701-1712. https://doi.org/10.1038/s41593-023-01435-z

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title = "IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice",

abstract = "Interleukin-12 (IL-12) is a potent driver of type 1 immunity. Paradoxically, in autoimmune conditions, including of the CNS, IL-12 reduces inflammation. The underlying mechanism behind these opposing properties and the involved cellular players remain elusive. Here we map IL-12 receptor (IL-12R) expression to NK and T cells as well as neurons and oligodendrocytes. Conditionally ablating the IL-12R across these cell types in adult mice and assessing their susceptibility to experimental autoimmune encephalomyelitis revealed that the neuroprotective role of IL-12 is mediated by neuroectoderm-derived cells, specifically neurons, and not immune cells. In human brain tissue from donors with multiple sclerosis, we observe an IL-12R distribution comparable to mice, suggesting similar mechanisms in mice and humans. Combining flow cytometry, bulk and single-nucleus RNA sequencing, we reveal an IL-12-induced neuroprotective tissue adaption preventing early neurodegeneration and sustaining trophic factor release during neuroinflammation, thereby maintaining CNS integrity in mice.",

author = "Myrto Andreadou and Florian Ingelfinger and {De Feo}, Donatella and Cramer, {Teresa L.M.} and Selma Tuzlak and Ekaterina Friebel and Bettina Schreiner and Pascale Eede and Shirin Schneeberger and Maria Geesdorf and Frederike Ridder and Welsh, {Christina A.} and Laura Power and Daniel Kirschenbaum and Tyagarajan, {Shiva K.} and Melanie Greter and Heppner, {Frank L.} and Sarah Mundt and Burkhard Becher",

note = "We thank L. Robinson from Insight Editing London for paper editing; A. Sethi, S. Marti, M. Lutz, N. Puertas, P. H{\"a}hne, A. Fonseca da Silva, R. Lindemann, S. Da Costa Pereira and L. Oberbichler for technical support; H. Rehrauer, L. Opitz, A. Cabral de Gouvea, D. Popovic, Q. Zhang, F. Noe and T. Sykes for technical and computational advice on sequencing experiments; the Center for Microscopy and Image Analysis, University of Zurich (ZMB) and the Functional Genomics Center Zurich (FGCZ) for providing equipment. We thank A. Saab (UZH) for the Plp1 strain. The schematic representations of human MS lesions and neuroectodermal cell types were created with BioRender.com . This work has received funding from the Swiss National Science Foundation (Ambizione grant PZ00P3_193330 to S.M. and 733 310030_170320, 310030_188450 and CRSII5_183478 to B.B.), European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation program (grant agreement no. 882424 to B.B.), Research Talent Development Fund zur F{\"o}rderung des akademischen Nachwuchses (FAN; to S.M.), Forschungskredit Postdoc fellowship University of Zurich grant no. K-41302-11-01 (to S.M.), Dr. Wilhelm Hurka Foundation (to B.B. and S.M.) and the Swiss Multiple Sclerosis Society (to S.M. and F.I.). F.I. received a PhD fellowship from Studienstiftung des deutschen Volkes. CreER",

year = "2023",

month = oct,

doi = "10.1038/s41593-023-01435-z",

language = "English",

volume = "26",

pages = "1701--1712",

journal = "Nature Neuroscience",

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Andreadou, M, Ingelfinger, F, De Feo, D, Cramer, TLM, Tuzlak, S, Friebel, E, Schreiner, B, Eede, P, Schneeberger, S, Geesdorf, M, Ridder, F, Welsh, CA, Power, L, Kirschenbaum, D, Tyagarajan, SK, Greter, M, Heppner, FL, Mundt, S & Becher, B 2023, 'IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice', Nature Neuroscience, vol. 26, no. 10, pp. 1701-1712. https://doi.org/10.1038/s41593-023-01435-z

TY - JOUR

T1 - IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice

AU - Andreadou, Myrto

AU - Ingelfinger, Florian

AU - De Feo, Donatella

AU - Cramer, Teresa L.M.

AU - Tuzlak, Selma

AU - Friebel, Ekaterina

AU - Schreiner, Bettina

AU - Eede, Pascale

AU - Schneeberger, Shirin

AU - Geesdorf, Maria

AU - Ridder, Frederike

AU - Welsh, Christina A.

AU - Power, Laura

AU - Kirschenbaum, Daniel

AU - Tyagarajan, Shiva K.

AU - Greter, Melanie

AU - Heppner, Frank L.

AU - Mundt, Sarah

AU - Becher, Burkhard

N1 - We thank L. Robinson from Insight Editing London for paper editing; A. Sethi, S. Marti, M. Lutz, N. Puertas, P. Hähne, A. Fonseca da Silva, R. Lindemann, S. Da Costa Pereira and L. Oberbichler for technical support; H. Rehrauer, L. Opitz, A. Cabral de Gouvea, D. Popovic, Q. Zhang, F. Noe and T. Sykes for technical and computational advice on sequencing experiments; the Center for Microscopy and Image Analysis, University of Zurich (ZMB) and the Functional Genomics Center Zurich (FGCZ) for providing equipment. We thank A. Saab (UZH) for the Plp1 strain. The schematic representations of human MS lesions and neuroectodermal cell types were created with BioRender.com . This work has received funding from the Swiss National Science Foundation (Ambizione grant PZ00P3_193330 to S.M. and 733 310030_170320, 310030_188450 and CRSII5_183478 to B.B.), European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 882424 to B.B.), Research Talent Development Fund zur Förderung des akademischen Nachwuchses (FAN; to S.M.), Forschungskredit Postdoc fellowship University of Zurich grant no. K-41302-11-01 (to S.M.), Dr. Wilhelm Hurka Foundation (to B.B. and S.M.) and the Swiss Multiple Sclerosis Society (to S.M. and F.I.). F.I. received a PhD fellowship from Studienstiftung des deutschen Volkes. CreER

PY - 2023/10

Y1 - 2023/10

N2 - Interleukin-12 (IL-12) is a potent driver of type 1 immunity. Paradoxically, in autoimmune conditions, including of the CNS, IL-12 reduces inflammation. The underlying mechanism behind these opposing properties and the involved cellular players remain elusive. Here we map IL-12 receptor (IL-12R) expression to NK and T cells as well as neurons and oligodendrocytes. Conditionally ablating the IL-12R across these cell types in adult mice and assessing their susceptibility to experimental autoimmune encephalomyelitis revealed that the neuroprotective role of IL-12 is mediated by neuroectoderm-derived cells, specifically neurons, and not immune cells. In human brain tissue from donors with multiple sclerosis, we observe an IL-12R distribution comparable to mice, suggesting similar mechanisms in mice and humans. Combining flow cytometry, bulk and single-nucleus RNA sequencing, we reveal an IL-12-induced neuroprotective tissue adaption preventing early neurodegeneration and sustaining trophic factor release during neuroinflammation, thereby maintaining CNS integrity in mice.

AB - Interleukin-12 (IL-12) is a potent driver of type 1 immunity. Paradoxically, in autoimmune conditions, including of the CNS, IL-12 reduces inflammation. The underlying mechanism behind these opposing properties and the involved cellular players remain elusive. Here we map IL-12 receptor (IL-12R) expression to NK and T cells as well as neurons and oligodendrocytes. Conditionally ablating the IL-12R across these cell types in adult mice and assessing their susceptibility to experimental autoimmune encephalomyelitis revealed that the neuroprotective role of IL-12 is mediated by neuroectoderm-derived cells, specifically neurons, and not immune cells. In human brain tissue from donors with multiple sclerosis, we observe an IL-12R distribution comparable to mice, suggesting similar mechanisms in mice and humans. Combining flow cytometry, bulk and single-nucleus RNA sequencing, we reveal an IL-12-induced neuroprotective tissue adaption preventing early neurodegeneration and sustaining trophic factor release during neuroinflammation, thereby maintaining CNS integrity in mice.

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DO - 10.1038/s41593-023-01435-z

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AN - SCOPUS:85172702206

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JO - Nature Neuroscience

JF - Nature Neuroscience

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ER -

IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice

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