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Nature. 2018 Apr;556(7701):332-338. doi: 10.1038/s41586-018-0023-4. Epub 2018 Apr 11.

Innate immune memory in the brain shapes neurological disease hallmarks.

Author information

1
German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
2
Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
3
Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany.
4
Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
5
Department for Systems Medicine and Epigenetics in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
6
Genomics and Immunoregulation, LIMES-Institute, University of Bonn, Bonn, Germany.
7
Bioinformatics Unit, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
8
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
9
Platform for Single Cell Genomics and Epigenomics at the University of Bonn and the German Center for Neurodegenerative Diseases, Bonn, Germany.
10
Molecular Immunology in Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
11
BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
12
German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. jonas.neher@dzne.de.
13
Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. jonas.neher@dzne.de.

Abstract

Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished-training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer's pathology, immune training exacerbates cerebral β-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.

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PMID:
29643512
PMCID:
PMC6038912
DOI:
10.1038/s41586-018-0023-4
[Indexed for MEDLINE]
Free PMC Article

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