title: Enhanced microglial pro-inflammatory response to lipopolysaccharide correlates with brain infiltration and blood-brain barrier dysregulation in a mouse model of telomere shortening.
abstract: Microglia are a proliferative population of resident brain macrophages that under physiological conditions self-renew independent of hematopoiesis. Microglia are innate immune cells actively surveying the brain and are the earliest responders to injury. During aging, microglia elicit an enhanced innate immune response also referred to as 'priming'. To date, it remains unknown whether telomere shortening affects the proliferative capacity and induces priming of microglia. We addressed this issue using early (first-generation G1 mTerc(-/-) )- and late-generation (third-generation G3 and G4 mTerc(-/-) ) telomerase-deficient mice, which carry a homozygous deletion for the telomerase RNA component gene (mTerc). Late-generation mTerc(-/-) microglia show telomere shortening and decreased proliferation efficiency. Under physiological conditions, gene expression and functionality of G3 mTerc(-/-) microglia are comparable with microglia derived from G1 mTerc(-/-) mice despite changes in morphology. However, after intraperitoneal injection of bacterial lipopolysaccharide (LPS), G3 mTerc(-/-) microglia mice show an enhanced pro-inflammatory response. Nevertheless, this enhanced inflammatory response was not accompanied by an increased expression of genes known to be associated with age-associated microglia priming. The increased inflammatory response in microglia correlates closely with increased peripheral inflammation, a loss of blood-brain barrier integrity, and infiltration of immune cells in the brain parenchyma in this mouse model of telomere shortening.
authors.affiliation: Section Medical Physiology, Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Divya D A
authors.initials: DD
authors.lastname: Raj
authors.affiliation: Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands.|Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Jill
authors.initials: J
authors.lastname: Moser
authors.affiliation: Blood-Brain Barrier Research Group, Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Centre, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.
authors.forename: Susanne M A
authors.initials: SM
authors.lastname: van der Pol
authors.affiliation: Department of Cell Biology, European Research Institute on the Biology of Aging, University of Groningen, University Medical Center, Groningen, 9713 AV, The Netherlands.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: van Os
authors.affiliation: Section Medical Physiology, Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Inge R
authors.initials: IR
authors.lastname: Holtman
authors.affiliation: Section Medical Physiology, Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Nieske
authors.initials: N
authors.lastname: Brouwer
authors.affiliation: Department of Cardiology, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Hisko
authors.initials: H
authors.lastname: Oeseburg
authors.affiliation: Section Medical Physiology, Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Wandert
authors.initials: W
authors.lastname: Schaafsma
authors.affiliation: Section Medical Physiology, Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Evelyn M
authors.initials: EM
authors.lastname: Wesseling
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Wilfred
authors.initials: W
authors.lastname: den Dunnen
authors.affiliation: Section Medical Physiology, Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands.|Department of Psychiatry and Psychotherapy, University Medical Center, Freiburg, 79104, Germany.
authors.forename: Knut P H
authors.initials: KP
authors.lastname: Biber
authors.affiliation: Blood-Brain Barrier Research Group, Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Centre, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
authors.affiliation: Section Medical Physiology, Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Bart J L
authors.initials: BJ
authors.lastname: Eggen
authors.affiliation: Section Medical Physiology, Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Hendrikus W G M
authors.initials: HW
authors.lastname: Boddeke
mesh_terms: D000375:Aging / Q000276:immunology; D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D001921:Brain / Q000166:cytology / Q000503:physiopathology*; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology*; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000235:genetics; D059506:Telomere Shortening / Q000235:genetics*
chemical_list: D008070:Lipopolysaccharides; D019098:Telomerase
keywords: aging; blood-brain barrier; microglia; neuroimmune response; priming; telomerase; telomere