Innate immune memory in the brain shapes neurological disease hallmarks
Ann-Christin Wendeln1,2,3,11, Karoline Degenhardt1,2,3,11, Lalit Kaurani4,5, Michael Gertig4,5, Thomas Ulas6, Gaurav Jain4,5, Jessica Wagner1,2,3, Lisa M. Häsler1,2, Katleen Wild1,2, Angelos Skodras1,2, Thomas Blank7, Ori Staszewski7, Moumita Datta7, Tonatiuh Pena Centeno5, Vincenzo Capece5, Md. Rezaul Islam5, Cemil Kerimoglu5, Matthias Staufenbiel1,2, Joachim L. Schultze6,8, Marc Beyer9, Marco Prinz7,10, Mathias Jucker1,2, André Fischer4,5 & Jonas J. Neher1,2*
1German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; 2Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; 3Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany; 4Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany; 5Department for Systems Medicine and Epigenetics in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany; 6Genomics and Immunoregulation, LIMES-Institute, University of Bonn, Bonn, Germany; 7Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; 8Platform for Single Cell Genomics and Epigenomics at the University of Bonn and the German Center for Neurodegenerative Diseases, Bonn, Germany.
9Molecular Immunology in Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; 10BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany
11These authors contributed equally: Ann-Christin Wendeln, Karoline Degenhardt
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.