title: Janus kinase inhibitors prevent migration of rheumatoid arthritis neutrophils towards interleukin-8, but do not inhibit priming of the respiratory burst or reactive oxygen species production.
abstract: Neutrophils play a crucial role in the pathophysiology of rheumatoid arthritis (RA) via the release of reactive oxygen species (ROS), proteases and cytokines. Orally active Janus kinase (JAK) inhibitors (JAKi), e.g. baricitinib and tofacitinib, have high clinical efficacy in RA but are linked with neutropenia and increased infections. Our aim was to determine the effect of JAK inhibition with baricitinib and tofacitinib on healthy control and RA neutrophil lifespan and function. RA (n = 7) and healthy control (n = 7) neutrophils were treated with baricitinib or tofacitinib for 30 min, prior to incubation in the absence or presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) or interferon (IFN)-γ. JAKi prevented GM-CSF- and IFN-γ-induced apoptosis delay in RA and healthy control neutrophils in a dose-dependent manner. Baricitinib decreased the rate of chemotaxis towards interleukin (IL)-8, but not f-Met-Leu-Phe (fMLP) in RA neutrophils. While healthy control neutrophils incubated with GM-CSF became primed to produce ROS in response to stimulation with fMLP and phorbol-12-myristate-12-acetate (PMA), RA neutrophils produced increased levels of ROS without the need for priming. JAKi prevented ROS release from primed healthy control neutrophils in response to fMLP, but had no effect on ROS production by RA neutrophils. Baricitinib reversed GM-CSF priming of ROS production in response to fMLP in healthy control, but not RA, neutrophils. We conclude that incubation with JAKi prevents chemotaxis of RA neutrophils towards IL-8, but does not prevent the production of ROS or increase the level of apoptosis. This may be due to the in-vivo exposure of RA neutrophils to priming agents other than those that activate JAK/signal transducer and activator of transcription (STAT) signalling.
authors.affiliation: Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
authors.forename: T S
authors.initials: TS
authors.lastname: Mitchell
authors.affiliation: Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
authors.forename: R J
authors.initials: RJ
authors.lastname: Moots
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
authors.forename: H L
authors.identifier: 0000-0003-0442-3134
authors.initials: HL
authors.lastname: Wright
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001384:Azetidines / Q000494:pharmacology; D016022:Case-Control Studies; D002465:Cell Movement; D002478:Cells, Cultured; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016897:Respiratory Burst / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D006113:United Kingdom
chemical_list: D001384:Azetidines; C508606:CXCL8 protein, human; D016209:Interleukin-8; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D011758:Pyrroles; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C479163:tofacitinib; D053612:Janus Kinases; C000596027:baricitinib; D013755:Tetradecanoylphorbol Acetate
keywords: JAK inhibitors; ROS; apoptosis; baricitinib; neutrophils; rheumatoid arthritis; tofacitinib