title: Loss of Presenilin 2 Function Is Associated with Defective LPS-Mediated Innate Immune Responsiveness.
abstract: The importance of presenilin-dependent γ-secretase protease activities in the development, neurogenesis, and immune system is highlighted by the diversity of its substrates and characterization of Psen1- and Psen2-deficient transgenic animals. Functional differences between presenilin 1 (PS1) and presenilin 2 (PS2) are incompletely understood. In this study, we have identified a Psen2-specific function, not shared by Psen1 in Toll-like receptor signaling. We show that immortalized fibroblasts and bone marrow-derived macrophages from Psen2- but not Psen1-deficient mice display reduced responsiveness to lipopolysaccharide (LPS) with decreased nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) activity and diminished pro-inflammatory cytokine production. In whole animal in vivo responses, Psen2-deficient animals have abnormal systemic production of LPS-stimulated pro-inflammatory cytokines. Mechanistically, we demonstrate that Psen2 deficiency is paralleled by reduced transcription of tlr4 mRNA and loss of LPS-induced tlr4 mRNA transcription regulation. These observations illustrate a novel PS2-dependent means of modulating LPS-mediated immune responses and identify a functional distinction between PS1 and PS2 in innate immunity.
authors.affiliation: Signal Transduction Laboratory, School of Biochemistry & Cell Biology, ABCRF, University College Cork, 3.41 Western Gateway Building, Western Road, Cork, Ireland.
authors.forename: Vishal
authors.initials: V
authors.lastname: Agrawal
authors.affiliation: Signal Transduction Laboratory, School of Biochemistry & Cell Biology, ABCRF, University College Cork, 3.41 Western Gateway Building, Western Road, Cork, Ireland.
authors.forename: Neha
authors.initials: N
authors.lastname: Sawhney
authors.affiliation: Signal Transduction Laboratory, School of Biochemistry & Cell Biology, ABCRF, University College Cork, 3.41 Western Gateway Building, Western Road, Cork, Ireland.
authors.forename: Emer
authors.initials: E
authors.lastname: Hickey
authors.affiliation: Signal Transduction Laboratory, School of Biochemistry & Cell Biology, ABCRF, University College Cork, 3.41 Western Gateway Building, Western Road, Cork, Ireland. jv.mccarthy@ucc.ie.
authors.forename: Justin V
authors.initials: JV
authors.lastname: McCarthy
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D053766:Presenilin-2 / Q000172:deficiency* / Q000378:metabolism; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D053766:Presenilin-2; D051197:Toll-Like Receptor 4; D020928:Mitogen-Activated Protein Kinases
keywords: Cell signaling; Gamma-secretase; Innate immunity; Presenilin; Toll-like receptor 4 (TLR4)