The rheumatoid synovial environment alters fatty acid metabolism in human monocytes and enhances CCL20 secretion

Rodgers, L. C., Cole, J., Rattigan, K. M., Barrett, M. P. , Kurian, N., McInnes, I. B. and Goodyear, C. S. (2020) The rheumatoid synovial environment alters fatty acid metabolism in human monocytes and enhances CCL20 secretion. Rheumatology, 59(4), pp. 869-878. (doi: 10.1093/rheumatology/kez378) (PMID:31497857)

Abstract

Objectives: Fatty acid oxidation (FAO) and glycolysis have been implicated in immune regulation and activation of macrophages. However, investigation of human monocyte intracellular metabolism in the context of the hypoxic and inflammatory rheumatoid arthritis (RA) synovium is lacking. We hypothesized that exposure of monocytes to the hypoxic and inflammatory RA environment would have a profound impact on their metabolic state, and potential to contribute to disease pathology. Methods: Human monocytes were isolated from buffy coats and exposed to hypoxia. Metabolic profiling of monocytes was carried out by LC-MS metabolomics. Inflammatory mediator release after LPS or RA-synovial fluid (RA-SF) stimulation was analysed by ELISA. FAO was inhibited by etomoxir or enhanced with exogenous carnitine supplementation. Transcriptomics of RA blood monocytes and RA-SF macrophages was carried out by microarray. Results: Hypoxia exacerbated monocyte-derived CCL20 and IL-1β release in response to LPS, and increased glycolytic intermediates at the expense of carnitines. Modulation of carnitine identified a novel role for FAO in the production of CCL20 in response to LPS. Transcriptional analysis of RA blood monocytes and RA-SF macrophages revealed that fatty acid metabolism was altered and CCL20 increased when monocytes enter the synovial environment. In vitro analysis of monocytes showed that RA-SF increases carnitine abundance and CCL20 production in hypoxia, which was exacerbated by exogenous carnitine. Conclusion: This work has revealed a novel inflammatory mechanism in RA that links FAO to CCL20 production in human monocytes, which could subsequently contribute to RA disease pathogenesis by promoting the recruitment of Th17 cells and osteoclastogenesis.

• Item Type: Articles
• Additional Information: This work was funded by the GLAZgo Discovery Centre.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McInnes, Professor Iain and Cole, Mr John and Rattigan, Dr Kevin and Barrett, Professor Michael and Goodyear, Professor Carl and Rodgers, Mr Lewis
• Authors: Rodgers, L. C., Cole, J., Rattigan, K. M., Barrett, M. P., Kurian, N., McInnes, I. B., and Goodyear, C. S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Rheumatology
• Publisher: Oxford University Press
• ISSN: 1462-0324
• ISSN (Online): 1462-0332
• Published Online: 08 September 2019
• Copyright Holders: Copyright © The Author(s) 2019
• First Published: First published in Rheumatology 59(4):869-878
• Publisher Policy: Reproduced in accordance with the publisher copyright policy