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, Chapman, Elinor ORCID: 0000-0002-4398-1705, Mason, David ORCID: 0000-0002-8773-5274, Moots, Robert, Phelan, Marie and Wright, Helen ORCID: 0000-0003-0442-3134 (2022) Metabolic profiling of rheumatoid arthritis neutrophils reveals altered energy metabolism that is not affected by JAK inhibition. [Preprint]

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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 has 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 200ng/mL) for 2h. Metabolites were extracted and 1 H 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 0h (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 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:	Preprint
Uncontrolled Keywords:	Clinical Research, Autoimmune Disease, Arthritis, Rheumatoid Arthritis, 6 Evaluation of treatments and therapeutic interventions, 5 Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, 6.1 Pharmaceuticals, Inflammatory and immune system
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:	01 Jun 2022 13:40
Last Modified:	14 Mar 2024 17:37
DOI:	10.1101/2022.05.30.22275773
Related URLs:	Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3155792