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Arthritis Career Development Fellowship","doi-asserted-by":"publisher","award":["200605\/Z\/16\/Z"],"award-info":[{"award-number":["200605\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/501100012041","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012041","name":"Versus Arthritis Career Development Fellowship","doi-asserted-by":"publisher","award":["21430"],"award-info":[{"award-number":["21430"]}],"id":[{"id":"10.13039\/501100012041","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>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 &lt; 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.<\/jats:p>","DOI":"10.3390\/metabo12070650","type":"journal-article","created":{"date-parts":[[2022,7,17]],"date-time":"2022-07-17T22:57:06Z","timestamp":1658098626000},"page":"650","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Metabolic Profiling of Rheumatoid Arthritis Neutrophils Reveals Altered Energy Metabolism That Is Not Affected by JAK Inhibition"],"prefix":"10.3390","volume":"12","author":[{"given":"Susama","family":"Chokesuwattanaskul","sequence":"first","affiliation":[{"name":"Institute of Integrative Biology, University of Liverpool, Liverpool L69 7BE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3566-9244","authenticated-orcid":false,"given":"Michele","family":"Fresneda Alarcon","sequence":"additional","affiliation":[{"name":"Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangeetha","family":"Mangalakumaran","sequence":"additional","affiliation":[{"name":"School of Life Sciences, University of Liverpool, Liverpool L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudi","family":"Grosman","sequence":"additional","affiliation":[{"name":"Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7BE, UK"},{"name":"High Field NMR Facility, Liverpool Shared Research Facilities University of Liverpool, Liverpool L69 7TX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew L.","family":"Cross","sequence":"additional","affiliation":[{"name":"Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4398-1705","authenticated-orcid":false,"given":"Elinor A.","family":"Chapman","sequence":"additional","affiliation":[{"name":"Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8773-5274","authenticated-orcid":false,"given":"David","family":"Mason","sequence":"additional","affiliation":[{"name":"Centre for Cell Imaging, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7TX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7019-6211","authenticated-orcid":false,"given":"Robert J.","family":"Moots","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Aintree University Hospital, Liverpool L9 7AL, UK"},{"name":"Faculty of Health, Social Care and Medicine, Edge Hill University, Ormskirk L39 4QP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0708-2964","authenticated-orcid":false,"given":"Marie M.","family":"Phelan","sequence":"additional","affiliation":[{"name":"Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7BE, UK"},{"name":"High Field NMR Facility, Liverpool Shared Research Facilities University of Liverpool, Liverpool L69 7TX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0442-3134","authenticated-orcid":false,"given":"Helen L.","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Edwards, S.W. 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