Metabolic Profiling of Rheumatoid Arthritis Neutrophils Reveals Altered Energy Metabolism That Is Not Affected by JAK Inhibition

Chokesuwattanaskul, Susama, Alarcon, Michele Fresneda, Mangalakumaran, Sangeetha, Grosman, Rudi ORCID: 0000-0002-0233-7112, Cross, Andrew L, Chapman, Elinor A ORCID: 0000-0002-4398-1705, Mason, David, Moots, Robert J ORCID: 0000-0001-7019-6211, Phelan, Marie M and Wright, Helen L ORCID: 0000-0003-0442-3134 (2022) Metabolic Profiling of Rheumatoid Arthritis Neutrophils Reveals Altered Energy Metabolism That Is Not Affected by JAK Inhibition. METABOLITES, 12 (7). 650-.

Access the full-text of this item by clicking on the Open Access link.

Text
JAKI_author_acceoted.pdf - Author Accepted Manuscript
Download (7MB) | Preview

Official URL: http://dx.doi.org/10.3390/metabo12070650

Abstract

Neutrophils play a key role in the pathophysiology of rheumatoid arthritis (RA) where release of ROS and proteases directly causes damage to joints and tissues. Neutrophil function can be modulated by Janus Kinase (JAK) inhibitor drugs, including tofacitinib and baricitinib, which are clinically effective treatments for RA. However, clinical trials have reported increased infection rates and transient neutropenia during therapy. The subtle differences in the mode of action, efficacy and safety of JAK inhibitors have been the primary research topic of many clinical trials and systematic reviews, to provide a more precise and targeted treatment to patients. The aim of this study was to determine both the differences in the metabolome of neutrophils from healthy controls and people with RA, and the effect of different JAK inhibitors on the metabolome of healthy and RA neutrophils. Isolated neutrophils from healthy controls (HC) (n = 6) and people with RA (n = 7) were incubated with baricitinib, tofacitinib or a pan-JAK inhibitor (all 200 ng/mL) for 2 h. Metabolites were extracted, and 1H nuclear magnetic resonance (NMR) was applied to study the metabolic changes. Multivariate analyses and machine learning models showed a divergent metabolic pattern in RA neutrophils compared to HC at 0 h (F1 score = 86.7%) driven by energy metabolites (ATP, ADP, GTP and glucose). No difference was observed in the neutrophil metabolome when treated with JAK inhibitors. However, JAK inhibitors significantly inhibited ROS production and baricitinib decreased NET production (p < 0.05). Bacterial killing was not impaired by JAK inhibitors, indicating that the effect of JAK inhibitors on neutrophils can inhibit joint damage in RA without impairing host defence. This study highlights altered energy metabolism in RA neutrophils which may explain the cause of their dysregulation in inflammatory disease.

Item Type:	Article
Uncontrolled Keywords:	JAK inhibitors, metabolomics, NMR, rheumatoid arthritis, host defence, neutrophils, NETs
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences
Depositing User:	Symplectic Admin
Date Deposited:	12 Jul 2022 07:58
Last Modified:	16 Mar 2023 20:46
DOI:	10.3390/metabo12070650
Open Access URL:	https://doi.org/10.3390/metabo12070650
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3158263