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Metabolic profiling of rheumatoid arthritis neutrophils reveals altered energy metabolism that is not affected by JAK inhibition

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 is directly affected 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 1H nuclear magnetic resonance (NMR) was applied to study the metabolic changes. Multivariate analyses and machine learning models show a divergent metabolic pattern in RA neutrophils compared to HC at baseline (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-value<0.05). Bacterial killing was not inhibited by JAK inhibitors, indicating their effect on neutrophils is beneficial to 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.

INSTRUMENT(S): Nuclear Magnetic Resonance (NMR) -

SUBMITTER: Michele Fresneda Alarcon

PROVIDER: MTBLS4766 | MetaboLights | 2023-07-11

REPOSITORIES: MetaboLights

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

Chokesuwattanaskul Susama S Fresneda Alarcon Michele M Mangalakumaran Sangeetha S Grosman Rudi R Cross Andrew L AL Chapman Elinor A EA Mason David D Moots Robert J RJ Phelan Marie M MM Wright Helen L HL

Metabolites 20220715 7

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 o ...[more]

PMID: 35888774

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Project description:An expansion of neutrophils often marks cancer. To date, neutrophils are assumed to be a relatively homogenous population, but recent studies describe both pro- and anti-tumor functions in neutrophils. This suggests there is more heterogeneity in neutrophils than previously appreciated. To better understand and target neutrophil functions in cancer, we must dissect neutrophil heterogeneity and how it changes from health to disease. To this end, we employed single-cell transcriptome technology to profile immature neutrophils from bone marrow of healthy individuals. Intriguingly, we identified a new neutrophil subset that expresses several B cell markers, including CD79a/b, components of the B cell receptors and PAX5, a lineage-specific transcriptional factor. We termed this population the BNeut. Using flow cytometry, we found that BNeuts are confined to the bone marrow of healthy individuals but expand into the blood of melanoma patients at an early stage, suggesting BNeuts might be a biomarker for disease. Additionally, we find BNeuts in the mouse models of different cancer types, including breast and lung carcinoma. The BNeut appears and functions more similar to a neutrophil than a B cell. BNeuts possess a neutrophil-like transcriptional profile, large cytoplasm with segmented nucleus, and produce ROS and NETs. Using imaging, we show that the BNeuts are single cells co-expressing both CD66b and CD79b, and lack the B cell surface marker CD19. To understand why neutrophils might use a B cell program, we explored different B cell functions including antigen presentation, a function that is usually absent from neutrophils. We show BNeuts are excellent at phagocytosis, including uptake of tumor cells. Further, BNeuts have increased expression of antigen presentation-related genes compared to other neutrophils and can modulate CD4+ T cell responses. Together, we have identified a novel neutrophil subset expressing B cell markers that is preferentially expanded in the blood of melanoma patients and poised to control T cell responses during disease.

			Action	DRS
	MTBLS4766	Other
	FILES	Other
	a_MTBLS4766_NMR___metabolite_profiling.txt	Txt
	files-all.json	Other
	i_Investigation.txt	Txt