JAK inhibitors disrupt T cell-induced proinflammatory macrophage activation (original) (raw)

Nyirenda, Mukanthu H., Nijjar, Jagtar Singh, Frleta-Gilchrist, Marina, Gilchrist, Derek S., Porter, Duncan, Siebert, Stefan ORCID: https://orcid.org/0000-0002-1802-7311, Goodyear, Carl S. ORCID: https://orcid.org/0000-0001-5926-5941 and McInnes, Iain B. ORCID: https://orcid.org/0000-0002-6462-4280(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)

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.

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Funder and Project Information

Scottish Clinical Pharmacology and Pathology Programme (SCP3)

Iain McInnes

G1000419

III - Immunology

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