title: Extracellular vesicle-mediated transfer of genetic information between the hematopoietic system and the brain in response to inflammation.
abstract: Mechanisms behind how the immune system signals to the brain in response to systemic inflammation are not fully understood. Transgenic mice expressing Cre recombinase specifically in the hematopoietic lineage in a Cre reporter background display recombination and marker gene expression in Purkinje neurons. Here we show that reportergene expression in neurons is caused by intercellular transfer of functional Cre recombinase messenger RNA from immune cells into neurons in the absence of cell fusion. In vitro purified secreted extracellular vesicles (EVs) from blood cells contain Cre mRNA, which induces recombination in neurons when injected into the brain. Although Cre-mediated recombination events in the brain occur very rarely in healthy animals, their number increases considerably in different injury models, particularly under inflammatory conditions, and extend beyond Purkinje neurons to other neuronal populations in cortex, hippocampus, and substantia nigra. Recombined Purkinje neurons differ in their miRNA profile from their nonrecombined counterparts, indicating physiological significance. These observations reveal the existence of a previously unrecognized mechanism to communicate RNA-based signals between the hematopoietic system and various organs, including the brain, in response to inflammation.
authors.affiliation: Institute of Neurology (Edinger Institute), Frankfurt University Medical School Frankfurt, Frankfurt, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Ridder
authors.affiliation: Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Keller
authors.affiliation: Institute of Neurology (Edinger Institute), Frankfurt University Medical School Frankfurt, Frankfurt, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Dams
authors.affiliation: Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Anne-Kathleen
authors.initials: AK
authors.lastname: Rupp
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Frankfurt University Medical School Frankfurt, Frankfurt, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Schlaudraff
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Frankfurt University Medical School Frankfurt, Frankfurt, Germany.
authors.forename: Domenico
authors.initials: D
authors.lastname: Del Turco
authors.affiliation: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Unit Cancer Genome Research, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases, Heidelberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Starmann
authors.affiliation: Institute of Neurology (Edinger Institute), Frankfurt University Medical School Frankfurt, Frankfurt, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jadranka
authors.initials: J
authors.lastname: Macas
authors.affiliation: German Red Cross Blood Service Baden-Württemberg-Hessen and Institute for Transfusion Medicine and Immunohematology, Frankfurt University Medical School, Frankfurt, Germany.
authors.forename: Darja
authors.initials: D
authors.lastname: Karpova
authors.affiliation: Institute of Neurology (Edinger Institute), Frankfurt University Medical School Frankfurt, Frankfurt, Germany.
authors.forename: Kavi
authors.initials: K
authors.lastname: Devraj
authors.affiliation: Department of Neurology, Philipps University Marburg, Marburg, Germany.
authors.forename: Candan
authors.initials: C
authors.lastname: Depboylu
authors.affiliation: Institute of Neurology (Edinger Institute), Frankfurt University Medical School Frankfurt, Frankfurt, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Landfried
authors.affiliation: Division Molecular Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
authors.affiliation: Institute of Neurology (Edinger Institute), Frankfurt University Medical School Frankfurt, Frankfurt, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Karl H
authors.initials: KH
authors.lastname: Plate
authors.affiliation: Department of Neurology, Philipps University Marburg, Marburg, Germany; Department for Translational Neurodegeneration, German Center for Neurodegenerative Diseases e.V. (DZNE), Technical University Munich (TUM), Munich, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Höglinger
authors.affiliation: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Unit Cancer Genome Research, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases, Heidelberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Sültmann
authors.affiliation: Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Altevogt
authors.affiliation: Institute of Neurology (Edinger Institute), Frankfurt University Medical School Frankfurt, Frankfurt, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Momma
mesh_terms: D000818:Animals; D055354:Exosomes / Q000378:metabolism*; D006413:Hematopoietic System / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D019426:Integrases; D008822:Mice, Transgenic; D011689:Purkinje Cells / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D011995:Recombination, Genetic
chemical_list: D012333:RNA, Messenger; C045073:Cre recombinase; D019426:Integrases