JAK inhibitors disrupt T cell-induced proinflammatory macrophage activation

Nyirenda, M. H., Nijjar, J. S., Frleta-Gilchrist, M., Gilchrist, D. S., Porter, D., Siebert, S. , Goodyear, C. S. and McInnes, I. B. (2023) JAK inhibitors disrupt T cell-induced proinflammatory macrophage activation. RMD Open, 9(1), e002671. (doi: 10.1136/rmdopen-2022-002671) (PMID:36599629) (PMCID:PMC9815080)

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Abstract

Objectives: Macrophage subsets, activated by T cells, are increasingly recognised to play a central role in rheumatoid arthritis (RA) pathogenesis. Janus kinase (JAK) inhibitors have proven beneficial clinical effects in RA. In this study, we investigated the effect of JAK inhibitors on the generation of cytokine-activated T (Tck) cells and the production of cytokines and chemokines induced by Tck cell/macrophage interactions. Methods: CD14+ monocytes and CD4+ T cells were purified from peripheral blood mononuclear cells from buffy coats of healthy donors. As representative JAK inhibitors, tofacitinib or ruxolitinib were added during Tck cell differentiation. Previously validated protocols were used to generate macrophages and Tck cells from monocytes and CD4+ T cells, respectively. Cytokine and chemokine including TNF, IL-6, IL-15, IL-RA, IL-10, MIP1α, MIP1β and IP10 were measured by ELISA. Results: JAK inhibitors prevented cytokine-induced maturation of Tck cells and decreased the production of proinflammatory cytokines TNF, IL-6, IL-15, IL-1RA and the chemokines IL-10, MIP1α, MIP1β, IP10 by Tck cell-activated macrophages in vitro (p<0.05). Conclusions: Our findings show that JAK inhibition disrupts T cell-induced macrophage activation and reduces downstream proinflammatory cytokine and chemokine responses, suggesting that suppressing the T cell-macrophage interaction contributes to the therapeutic effect of JAK inhibitors.

Item Type:Articles
Additional Information:Funding was provided by vs Arthritis, UK and the Scottish Clinical Pharmacology and Pathology Programme (SCP3), Medical Research Council (Ref: G1000419).
Status:Published
Refereed:No
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Porter, Dr Duncan and Nyirenda, Dr Mukanthu and Frleta-Gilchrist, Dr Marina and Siebert, Professor Stefan and Gilchrist, Dr Derek and Nijjar, Dr Jagtar and Goodyear, Professor Carl
Authors: Nyirenda, M. H., Nijjar, J. S., Frleta-Gilchrist, M., Gilchrist, D. S., Porter, D., Siebert, S., Goodyear, C. S., and McInnes, I. B.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Research Centre:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
Journal Name:RMD Open
Publisher:BMJ Publishing Group
ISSN:2056-5933
ISSN (Online):2056-5933
Published Online:04 January 2023
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in RMD Open 9(1): e002671
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190485Scottish Clinical Pharmacology and Pathology Programme (SCP3)Iain McInnesMedical Research Council (MRC)G1000419III - Immunology