PMID- 33761362 OWN - NLM STAT- MEDLINE DCOM- 20220127 LR - 20220127 IS - 2211-1247 (Electronic) VI - 34 IP - 12 DP - 2021 Mar 23 TI - TNF-alpha and alpha-synuclein fibrils differently regulate human astrocyte immune reactivity and impair mitochondrial respiration. PG - 108895 LID - S2211-1247(21)00209-6 [pii] LID - 10.1016/j.celrep.2021.108895 [doi] AB - Here, we examine the cellular changes triggered by tumor necrosis factor alpha (TNF-alpha) and different alpha-synuclein (alphaSYN) species in astrocytes derived from induced pluripotent stem cells. Human astrocytes treated with TNF-alpha display a strong reactive pro-inflammatory phenotype with upregulation of pro-inflammatory gene networks, activation of the nuclear factor kappaB (NF-kappaB) pathway, and release of pro-inflammatory cytokines, whereas those treated with high-molecular-weight alphaSYN fibrils acquire a reactive antigen (cross)-presenting phenotype with upregulation of major histocompatibility complex (MHC) genes and increased human leukocyte antigen (HLA) molecules at the cell surface. Surprisingly, the cell surface location of MHC proteins is abrogated by larger F110 fibrillar polymorphs, despite the upregulation of MHC genes. Interestingly, TNF-alpha and alphaSYN fibrils compete to drive the astrocyte immune reactive response. The astrocyte immune responses are accompanied by an impaired mitochondrial respiration, which is exacerbated in Parkinson's disease (PD) astrocytes. Our data provide evidence for astrocytic involvement in PD pathogenesis and reveal their complex immune reactive responses to exogenous stressors. CI - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Russ, Kaspar AU - Russ K AD - Cell Stem Cell Laboratory for CNS Disease Modeling, Department of Experimental Medical Science, BMC D10, Lund University, 22184 Lund, Sweden; MultiPark and the Lund Stem Cell Center, Lund University, 22184 Lund, Sweden. FAU - Teku, Gabriel AU - Teku G AD - Protein Structure and Bioinformatics, Department of Experimental Medical Science, BMC B13, Lund University, 22184 Lund, Sweden. FAU - Bousset, Luc AU - Bousset L AD - Institut Francois Jacob (MIRCen), CEA and Laboratory of Neurodegenerative Diseases, CNRS, 18 Route du Panorama, 92265 Fontenay-Aux-Roses, France. FAU - Redeker, Virginie AU - Redeker V AD - Institut Francois Jacob (MIRCen), CEA and Laboratory of Neurodegenerative Diseases, CNRS, 18 Route du Panorama, 92265 Fontenay-Aux-Roses, France. FAU - Piel, Sara AU - Piel S AD - Mitochondrial Medicine, Department of Clinical Sciences Lund, Lund University, 22184 Lund, Sweden. FAU - Savchenko, Ekaterina AU - Savchenko E AD - Cell Stem Cell Laboratory for CNS Disease Modeling, Department of Experimental Medical Science, BMC D10, Lund University, 22184 Lund, Sweden; MultiPark and the Lund Stem Cell Center, Lund University, 22184 Lund, Sweden. FAU - Pomeshchik, Yuriy AU - Pomeshchik Y AD - Cell Stem Cell Laboratory for CNS Disease Modeling, Department of Experimental Medical Science, BMC D10, Lund University, 22184 Lund, Sweden; MultiPark and the Lund Stem Cell Center, Lund University, 22184 Lund, Sweden. FAU - Savistchenko, Jimmy AU - Savistchenko J AD - Institut Francois Jacob (MIRCen), CEA and Laboratory of Neurodegenerative Diseases, CNRS, 18 Route du Panorama, 92265 Fontenay-Aux-Roses, France. FAU - Stummann, Tina C AU - Stummann TC AD - H. Lundbeck A/S, Valby, Denmark. FAU - Azevedo, Carla AU - Azevedo C AD - Cell Stem Cell Laboratory for CNS Disease Modeling, Department of Experimental Medical Science, BMC D10, Lund University, 22184 Lund, Sweden; MultiPark and the Lund Stem Cell Center, Lund University, 22184 Lund, Sweden. FAU - Collin, Anna AU - Collin A AD - Office for Medical Services/division of Laboratory Medicine, Department of Clinical Genetics and Pathology, Lund, Sweden. FAU - Goldwurm, Stefano AU - Goldwurm S AD - Centro Parkinson/Parkinson Institute, ASST "Gaetano Pini/CTO," via Bignami 1, 20126 Milan, Italy. FAU - Fog, Karina AU - Fog K AD - H. Lundbeck A/S, Valby, Denmark. FAU - Elmer, Eskil AU - Elmer E AD - Mitochondrial Medicine, Department of Clinical Sciences Lund, Lund University, 22184 Lund, Sweden. FAU - Vihinen, Mauno AU - Vihinen M AD - Protein Structure and Bioinformatics, Department of Experimental Medical Science, BMC B13, Lund University, 22184 Lund, Sweden. FAU - Melki, Ronald AU - Melki R AD - Institut Francois Jacob (MIRCen), CEA and Laboratory of Neurodegenerative Diseases, CNRS, 18 Route du Panorama, 92265 Fontenay-Aux-Roses, France. FAU - Roybon, Laurent AU - Roybon L AD - Cell Stem Cell Laboratory for CNS Disease Modeling, Department of Experimental Medical Science, BMC D10, Lund University, 22184 Lund, Sweden; MultiPark and the Lund Stem Cell Center, Lund University, 22184 Lund, Sweden. Electronic address: laurent.roybon@med.lu.se. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Cell Rep JT - Cell reports JID - 101573691 RN - 0 (Cytokines) RN - 0 (HLA-DRB1 Chains) RN - 0 (Inflammation Mediators) RN - 0 (Peptides) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (alpha-Synuclein) RN - 8L70Q75FXE (Adenosine Triphosphate) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 2.3.2.27 (parkin protein) SB - IM MH - Adenosine Triphosphate/metabolism MH - Amino Acid Sequence MH - Antigen Presentation MH - Astrocytes/*immunology/metabolism MH - Cell Membrane/metabolism MH - Cell Respiration MH - Cytokines/metabolism MH - HLA-DRB1 Chains/chemistry MH - Humans MH - Induced Pluripotent Stem Cells/cytology/metabolism MH - Inflammation Mediators/metabolism MH - Mitochondria/*metabolism MH - Molecular Weight MH - Parkinson Disease/pathology MH - Peptides/chemistry/metabolism MH - Phenotype MH - Tumor Necrosis Factor-alpha/*metabolism MH - Ubiquitin-Protein Ligases/metabolism MH - alpha-Synuclein/*metabolism OTO - NOTNLM OT - HLA genes OT - Parkinson's disease OT - alpha-synuclein OT - astrocytes OT - iPSC OT - reactivity COIS- Declaration of interests The authors declare no competing interests EDAT- 2021/03/25 06:00 MHDA- 2022/01/28 06:00 CRDT- 2021/03/24 20:12 PHST- 2019/02/08 00:00 [received] PHST- 2020/12/23 00:00 [revised] PHST- 2021/03/02 00:00 [accepted] PHST- 2021/03/24 20:12 [entrez] PHST- 2021/03/25 06:00 [pubmed] PHST- 2022/01/28 06:00 [medline] AID - S2211-1247(21)00209-6 [pii] AID - 10.1016/j.celrep.2021.108895 [doi] PST - ppublish SO - Cell Rep. 2021 Mar 23;34(12):108895. doi: 10.1016/j.celrep.2021.108895.