title: TLR activation induces TNF-alpha production from adult neural stem/progenitor cells.
abstract: Adult neural stem cells (NSCs) are believed to facilitate CNS repair and tissue regeneration. However, it is not yet clear how these cells are influenced when the cellular environment is modified during neurotrauma or neuroinflammatory conditions. In this study, we determine how different proinflammatory cytokines modulate the expression of TLR2 and TLR4 in NSCs and how these cells respond to TLR2 and TLR4 agonists. Primary cultures of neural stem/progenitor cells isolated from the subventricular zone of brains from adult Dark Agouti rats were exposed to 1) supernatants from activated macrophages; 2) proinflammatory cytokines IFN-gamma, TNF-alpha, or both; and 3) agonists for TLR2 and TLR4. Both TLR2 and TLR4 were expressed during basal conditions and their mRNA levels were further increased following cytokine exposure. TLR4 was up-regulated by IFN-gamma and this effect was reversed by TNF-alpha. TLR2 expression was increased by supernatants from activated macrophages and by TNF-alpha, which synergized with IFN-gamma. TLR agonists induced the expression of TNF-alpha mRNA. Importantly, TNF-alpha could be translated into protein and released into the supernatants where it was quantified by cytokine ELISA. In conclusion, we demonstrate that NSCs constitutively express TLR2 and TLR4 and that their expression is increased as a consequence of exposure to proinflammatory mediators. Additionally, activation of these receptors can induce production of proinflammatory cytokines. These findings suggest that NSCs may be primed to participate in cytokine production during neuroinflammatory or traumatic conditions.
authors.affiliation: Department of Clinical Neurosciences, Division of Neuroimmunology, Division of Rheumatology, Karolinska Institutet, Stockholm, Sweden. Ruxandra.Covacu@ki.se
authors.forename: Ruxandra
authors.initials: R
authors.lastname: Covacu
authors.forename: Lisa
authors.initials: L
authors.lastname: Arvidsson
authors.forename: Asa
authors.initials: A
authors.lastname: Andersson
authors.forename: Mohsen
authors.initials: M
authors.lastname: Khademi
authors.forename: Helena
authors.initials: H
authors.lastname: Erlandsson-Harris
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.forename: Mikael A
authors.initials: MA
authors.lastname: Svensson
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.forename: Lou
authors.initials: L
authors.lastname: Brundin
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D019899:Paracrine Communication; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000235:genetics / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000235:genetics / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000494:pharmacology
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma