title: Resolution of TLR2-induced inflammation through manipulation of metabolic pathways in Rheumatoid Arthritis.
abstract: During inflammation, immune cells activated by toll-like receptors (TLRs) have the ability to undergo a bioenergetic switch towards glycolysis in a manner similar to that observed in tumour cells. While TLRs have been implicated in the pathogenesis of rheumatoid arthritis (RA), their role in regulating cellular metabolism in synovial cells, however, is still unknown. In this study, we investigated the effect of TLR2-activation on mitochondrial function and bioenergetics in primary RA-synovial fibroblast cells (RASFC), and further determined the role of glycolytic blockade on TLR2-induced inflammation in RASFC using glycolytic inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). We observed an increase in mitochondrial mutations, ROS and lipid peroxidation, paralleled by a decrease in the mitochondrial membrane potential in TLR2-stimulated RASFC. This was mirrored by differential regulation of key mitochondrial genes, coupled with alteration in mitochondrial morphology. TLR2-activation also regulated changes in the bioenergetic profile of RASFC, inducing PKM2 nuclear translocation, decreased mitochondrial respiration and ATP synthesis and increased glycolysis:respiration ratio, suggesting a metabolic switch. Finally, using 3PO, we demonstrated that glycolytic blockade reversed TLR2-induced pro-inflammatory mechanisms including invasion, migration, cytokine/chemokine secretion and signalling pathways. These findings support the concept of complex interplay between innate immunity, oxidative damage and oxygen metabolism in RA pathogenesis.
authors.affiliation: Molecular Rheumatology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.|Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital, Dublin, Ireland.
authors.forename: Trudy
authors.initials: T
authors.lastname: McGarry
authors.affiliation: Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital, Dublin, Ireland.
authors.forename: Monika
authors.initials: M
authors.lastname: Biniecka
authors.affiliation: Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital, Dublin, Ireland.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Deborah
authors.initials: D
authors.lastname: Cluxton
authors.affiliation: Molecular Rheumatology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.|Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital, Dublin, Ireland.
authors.forename: Mary
authors.initials: M
authors.lastname: Canavan
authors.affiliation: Molecular Rheumatology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Wade
authors.affiliation: Molecular Rheumatology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.|Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital, Dublin, Ireland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wade
authors.affiliation: Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital, Dublin, Ireland.
authors.forename: Lorna
authors.initials: L
authors.lastname: Gallagher
authors.affiliation: Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital, Dublin, Ireland.
authors.forename: Carl
authors.initials: C
authors.lastname: Orr
authors.affiliation: Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital, Dublin, Ireland.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Veale
authors.affiliation: Molecular Rheumatology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Fearon
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D019069:Cell Respiration; D002478:Cells, Cultured; D005347:Fibroblasts / Q000473:pathology; D020869:Gene Expression Profiling; D050259:Genes, Mitochondrial; D006801:Humans; D015227:Lipid Peroxidation; D053078:Membrane Potential, Mitochondrial; D053858:Metabolic Networks and Pathways; D008928:Mitochondria / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D000255:Adenosine Triphosphate