title: CD14 is a key organizer of microglial responses to CNS infection and injury.
abstract: Microglia, innate immune cells of the CNS, sense infection and damage through overlapping receptor sets. Toll-like receptor (TLR) 4 recognizes bacterial lipopolysaccharide (LPS) and multiple injury-associated factors. We show that its co-receptor CD14 serves three non-redundant functions in microglia. First, it confers an up to 100-fold higher LPS sensitivity compared to peripheral macrophages to enable efficient proinflammatory cytokine induction. Second, CD14 prevents excessive responses to massive LPS challenges via an interferon β-mediated feedback. Third, CD14 is mandatory for microglial reactions to tissue damage-associated signals. In mice, these functions are essential for balanced CNS responses to bacterial infection, traumatic and ischemic injuries, since CD14 deficiency causes either hypo- or hyperinflammation, insufficient or exaggerated immune cell recruitment or worsened stroke outcomes. While CD14 orchestrates functions of TLR4 and related immune receptors, it is itself regulated by TLR and non-TLR systems to thereby fine-tune microglial damage-sensing capacity upon infectious and non-infectious CNS challenges.
authors.affiliation: Institute of Neuropathology, University of Göttingen, Göttingen, 37075, Germany.
authors.forename: Hana
authors.initials: H
authors.lastname: Janova
authors.affiliation: Department of Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité Universitätsmedizin Berlin, Berlin, 10117, Germany.
authors.forename: Chotima
authors.initials: C
authors.lastname: Böttcher
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, 9713AW, The Netherlands.
authors.forename: Inge R
authors.initials: IR
authors.lastname: Holtman
authors.affiliation: Institute of Neuropathology, University of Göttingen, Göttingen, 37075, Germany.|Institute of Molecular Medicine, University of Mainz, Mainz, 55131, Germany.
authors.forename: Tommy
authors.initials: T
authors.lastname: Regen
authors.affiliation: Institute of Neuropathology, University of Göttingen, Göttingen, 37075, Germany.|Sartorius-Stedim Biotech GmbH, Göttingen, 37079, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: van Rossum
authors.affiliation: Institute of Neuropathology, University of Göttingen, Göttingen, 37075, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Götz
authors.affiliation: Institute of Neuropathology, University of Göttingen, Göttingen, 37075, Germany.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Ernst
authors.affiliation: Institute of Neuropathology, University of Göttingen, Göttingen, 37075, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Fritsche
authors.affiliation: Institute of Neuropathology, University of Göttingen, Göttingen, 37075, Germany.
authors.forename: Ulla
authors.initials: U
authors.lastname: Gertig
authors.affiliation: Institute of Neuropathology, University of Göttingen, Göttingen, 37075, Germany.
authors.forename: Nasrin
authors.initials: N
authors.lastname: Saiepour
authors.affiliation: Institute of Neuropathology, University of Göttingen, Göttingen, 37075, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Gronke
authors.affiliation: Institute of Neuropathology, University of Göttingen, Göttingen, 37075, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wrzos
authors.affiliation: Institute of Neuropathology, University of Göttingen, Göttingen, 37075, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ribes
authors.affiliation: Department of Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité Universitätsmedizin Berlin, Berlin, 10117, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Rolfes
authors.affiliation: Department of Neurology, University of Washington, Seattle, 98195-6465.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Weinstein
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, 37075.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Ehrenreich
authors.affiliation: Department of Oncology and Hematology, University of Göttingen, Göttingen, 37075, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Pukrop
authors.affiliation: Department of Neural Regeneration, Institute of Reconstructive Neurobiology, University of Bonn, Bonn, 53127, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Kopatz
authors.affiliation: Institute of Neuropathology, University of Göttingen, Göttingen, 37075, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Stadelmann
authors.affiliation: Transcriptome Analysis Laboratory, University of Göttingen, Göttingen, 37077, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Salinas-Riester
authors.affiliation: Institute of Neuropathology, University of Göttingen, Göttingen, 37075, Germany.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Weber
authors.affiliation: Institute of Neuropathology and BIOSS Center for Biological Signaling, University of Freiburg, Freiburg, 79106, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.affiliation: Institute of Neuropathology, University of Göttingen, Göttingen, 37075, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, 9713AW, The Netherlands.
authors.forename: Bart J L
authors.initials: BJ
authors.lastname: Eggen
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, 9713AW, The Netherlands.
authors.forename: Hendrikus W G M
authors.initials: HW
authors.lastname: Boddeke
authors.affiliation: Department of Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité Universitätsmedizin Berlin, Berlin, 10117, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Priller
authors.affiliation: Institute of Neuropathology, University of Göttingen, Göttingen, 37075, Germany.|Paul-Flechsig-Institute for Brain Research, University of Leipzig, Leipzig, 04103, Germany.
authors.forename: Uwe-Karsten
authors.initials: UK
authors.lastname: Hanisch
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology; D001930:Brain Injuries / Q000150:complications / Q000276:immunology* / Q000473:pathology; D002545:Brain Ischemia / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D025461:Feedback, Physiological / Q000502:physiology; D020244:Infarction, Middle Cerebral Artery; D016899:Interferon-beta / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology*; D015213:Neuroimmunomodulation; D020521:Stroke / Q000276:immunology* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016899:Interferon-beta; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse
keywords: Toll-like receptor; chemokines; cytokines; damage; inflammation; monocytes; neutrophils