title: The farnesoid-X-receptor in myeloid cells controls CNS autoimmunity in an IL-10-dependent fashion.
abstract: Innate immune responses by myeloid cells decisively contribute to perpetuation of central nervous system (CNS) autoimmunity and their pharmacologic modulation represents a promising strategy to prevent disease progression in Multiple Sclerosis (MS). Based on our observation that peripheral immune cells from relapsing-remitting and primary progressive MS patients exhibited strongly decreased levels of the bile acid receptor FXR (farnesoid-X-receptor, NR1H4), we evaluated its potential relevance as therapeutic target for control of established CNS autoimmunity. Pharmacological FXR activation promoted generation of anti-inflammatory macrophages characterized by arginase-1, increased IL-10 production, and suppression of T cell responses. In mice, FXR activation ameliorated CNS autoimmunity in an IL-10-dependent fashion and even suppressed advanced clinical disease upon therapeutic administration. In analogy to rodents, pharmacological FXR activation in human monocytes from healthy controls and MS patients induced an anti-inflammatory phenotype with suppressive properties including control of effector T cell proliferation. We therefore, propose an important role of FXR in control of T cell-mediated autoimmunity by promoting anti-inflammatory macrophage responses.
authors.affiliation: Department of Neurology, University of Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hucke
authors.affiliation: Department of Neurology, University of Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Herold
authors.affiliation: Institute of Immunology, University of Muenster, Muenster, Germany.
authors.forename: Marie
authors.initials: M
authors.lastname: Liebmann
authors.affiliation: Institute of Immunology, University of Muenster, Muenster, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Freise
authors.affiliation: Department of Neurology, University of Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Lindner
authors.affiliation: Department of Neurology, University of Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.
authors.forename: Ann-Katrin
authors.initials: AK
authors.lastname: Fleck
authors.affiliation: Institute of Immunology, University of Muenster, Muenster, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Zenker
authors.affiliation: Institute of Experimental Immunology and Imaging, University Duisburg-Essen, Essen, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Thiebes
authors.affiliation: Department of Neurology, University of Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.
authors.forename: Juncal
authors.initials: J
authors.lastname: Fernandez-Orth
authors.affiliation: Department of Neurology, Technische Universität München, Munich, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Buck
authors.affiliation: Department of Neurology, University of Mainz, Mainz, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Luessi
authors.affiliation: Department of Neurology, University of Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.|Cluster of Excellence Cells in Motion, University of Muenster, Muenster, Germany.
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.affiliation: Department of Neurology, University of Mainz, Mainz, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Zipp
authors.affiliation: Department of Neurology, Technische Universität München, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hemmer
authors.affiliation: Institute of Experimental Immunology and Imaging, University Duisburg-Essen, Essen, Germany.
authors.forename: Daniel Robert
authors.initials: DR
authors.lastname: Engel
authors.affiliation: Institute of Immunology, University of Muenster, Muenster, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.affiliation: Institute of Neuropathology, University of Muenster, Muenster, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Kuhlmann
authors.affiliation: Department of Neurology, University of Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.|Cluster of Excellence Cells in Motion, University of Muenster, Muenster, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.affiliation: Department of Neurology, University of Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany. luisa.klotz@ukmuenster.de.
authors.forename: Luisa
authors.initials: L
authors.lastname: Klotz
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D016753:Interleukin-10; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C556062:IL10 protein, mouse
keywords: CNS autoimmunity; EAE; Farnesoid-X-receptor; IL-10; Myeloid cells