title: Teriflunomide and monomethylfumarate target HIV-induced neuroinflammation and neurotoxicity.
abstract: HIV-associated neurocognitive disorders (HAND) affect about 50% of infected patients despite combined antiretroviral therapy (cART). Ongoing compartmentalized inflammation mediated by microglia which are activated by HIV-infected monocytes has been postulated to contribute to neurotoxicity independent from viral replication. Here, we investigated effects of teriflunomide and monomethylfumarate on monocyte/microglial activation and neurotoxicity. Human monocytoid cells (U937) transduced with a minimal HIV-Vector were co-cultured with human microglial cells (HMC3). Secretion of pro-inflammatory/neurotoxic cytokines (CXCL10, CCL5, and CCL2: p < 0.001; IL-6: p < 0.01) by co-cultures was strongly increased compared to microglia in contact with HIV-particles alone. Upon treatment with teriflunomide, cytokine secretion was decreased (CXCL10, 3-fold; CCL2, 2.5-fold; IL-6, 2.2-fold; p < 0.001) and monomethylfumarate treatment led to 2.9-fold lower CXCL10 secretion (p < 0.001). Reduced toxicity of co-culture conditioned media on human fetal neurons by teriflunomide (29%, p < 0.01) and monomethylfumarate (27%, p < 0.05) indicated functional relevance. Modulation of innate immune functions by teriflunomide and monomethylfumarate may target neurotoxic inflammation in the context of HAND.
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany. Bjoern.Ambrosius@ruhr-uni-bochum.de.
authors.forename: Björn
authors.identifier: 0000-0003-3679-7907
authors.initials: B
authors.lastname: Ambrosius
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany.|Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Faissner
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany.|Department of Neurology, University Hospital Bern and University of Bern, Bern, Switzerland.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Guse
authors.affiliation: Department of Neurosurgery, Knappschaftskrankenhaus Bochum, In der Schornau 22-25, 44892, Bochum, Germany.
authors.forename: Marec
authors.initials: M
authors.lastname: von Lehe
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Grunwald
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.affiliation: Department of Molecular and Medical Virology, Ruhr-University Bochum, Universitätsstr. 150, 44801, Bochum, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Grewe
authors.affiliation: Department of Neurology, University Hospital Bern and University of Bern, Bern, Switzerland. Andrew.Chan@insel.ch.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chan
mesh_terms: D018920:Coculture Techniques; D003437:Crotonates / Q000494:pharmacology*; D017077:Culture Media, Conditioned / Q000633:toxicity; D003879:Dermatologic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005333:Fetus; D005650:Fumarates / Q000494:pharmacology*; D015497:HIV-1; D006801:Humans; D006885:Hydroxybutyrates; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D008298:Maleates / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D009570:Nitriles; D014052:Toluidines / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: D003437:Crotonates; D017077:Culture Media, Conditioned; D003879:Dermatologic Agents; D005650:Fumarates; D006885:Hydroxybutyrates; D018836:Inflammation Mediators; D008298:Maleates; D009570:Nitriles; D014052:Toluidines; C073341:citraconic acid; C527525:teriflunomide
keywords: Dimethyl fumarate; Glial activation; HAND; HIV-associated neurocognitive disorder; Leflunomide; Microglia; Neuroinflammation