title: Sustained IL-1β expression impairs adult hippocampal neurogenesis independent of IL-1 signaling in nestin+ neural precursor cells.
abstract: Alterations in adult hippocampal neurogenesis have been observed in numerous neurological diseases that contain a neuroinflammatory component. Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that contributes to neuroinflammation in many CNS disorders. Our previous results reveal a severe reduction in adult hippocampal neurogenesis due to focal and chronic expression of IL-1β in a transgenic mouse model, IL-1β(XAT), that evokes a complex neuroinflammatory response. Other investigators have shown that IL-1β can bind directly to neural precursors to cause cell cycle arrest in vitro. In order to observe if IL-1 signaling is necessary in vivo, we conditionally knocked out MyD88, an adapter protein essential for IL-1 signaling, in nestin(+) neural precursor cells (NPCs) in the presence of IL-1β-dependent inflammation. Our results show that conditional knockout of MyD88 does not prevent IL-1β-induced reduction in neuroblasts using a genetic fate mapping model. Interestingly, MyD88 deficiency in nestin(+) NPCs causes an increase in the number of astrocytes in the presence of IL-1β, suggesting that MyD88-dependent signaling is important in limiting astroglial differentiation due to inflammation. MyD88 deficiency does not alter the fate of NPCs in the absence of inflammation. Furthermore, the inflammatory milieu due to IL-1β is not affected by the absence of MyD88 in nestin(+) NPCs. These results show that sustained IL-1β causes a reduction in adult hippocampal neurogenesis that is independent of MyD88-dependent signaling in nestin(+) NPCs, suggesting an indirect negative effect of IL-1β on neurogenesis.
authors.affiliation: Department of Neurobiology & Anatomy, University of Rochester School of Medicine & Dentistry, Rochester, NY 14642, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wu
authors.forename: Sara L
authors.initials: SL
authors.lastname: Montgomery
authors.forename: Fatima
authors.initials: F
authors.lastname: Rivera-Escalera
authors.forename: John A
authors.initials: JA
authors.lastname: Olschowka
authors.forename: M Kerry
authors.initials: MK
authors.lastname: O'Banion
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000633:toxicity; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D000229:Dependovirus / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development*; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000096:biosynthesis / Q000235:genetics; D064231:Nestin / Q000235:genetics / Q000502:physiology*; D058953:Neural Stem Cells / Q000378:metabolism / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D060888:Real-Time Polymerase Chain Reaction; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis; D015398:Signal Transduction / Q000502:physiology; D013629:Tamoxifen / Q000633:toxicity
chemical_list: D018931:Antineoplastic Agents, Hormonal; D053583:Interleukin-1beta; D053594:Myeloid Differentiation Factor 88; D064231:Nestin; D017472:Receptors, Interleukin-1; D013629:Tamoxifen; D012313:RNA