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: Trudy McGarry, Monika Biniecka, Wei Gao, Deborah Cluxton, Mary Canavan, Siobhan Wade, Sarah Wade, Lorna Gallagher, Carl Orr, Douglas J Veale, Ursula Fearon
• Journal: Scientific reports (Sci Rep) Vol. 7 Pg. 43165 (02 22 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28225071 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Reactive Oxygen Species
• TLR2 protein, human
• Toll-Like Receptor 2
• Adenosine Triphosphate

Topics

• Adenosine Triphosphate (biosynthesis)
• Arthritis, Rheumatoid (pathology)
• Cell Respiration
• Cells, Cultured
• Fibroblasts (pathology)
• Gene Expression Profiling
• Genes, Mitochondrial
• Humans
• Lipid Peroxidation
• Membrane Potential, Mitochondrial
• Metabolic Networks and Pathways
• Mitochondria (metabolism)
• Reactive Oxygen Species (metabolism)
• Toll-Like Receptor 2 (metabolism)