The effect of baricitinib on pSTAT3 levels in IL-6 or IL-15 stimulated PBMCs isolated from SLE patients

Gábor Janos Szebeni¹Nikolett Gémes²Patrícia Neuperger²Enikő Szabó²József Á Balog²Dániel Honfi¹Attila Balog¹Gergely Toldi^1,3*

• ¹Szegedi Tudomanyegyetem, Szeged, Hungary
• ²HUN-REN Szegedi Biologiai Kutatokozpont, Szeged, Hungary
• ³Liggins Institute, The University of Auckland, Auckland, New Zealand

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease marked by multi-organ inflammation. Its pathogenesis involves profound T cell dysfunction, autoreactive B cell activation, impaired CD8+ T cell responses, myeloid cell abnormalities, and dysregulated cytokine secretion. Central to cytokine-driven immune activation is the JAK/STAT signaling pathway. Baricitinib, a selective oral JAK1/2 inhibitor approved for rheumatoid arthritis, has been extensively studied in SLE. We aimed to investigate STAT3 phosphorylation in CD4+ and CD8+ T cells, and CD11b+ myeloid cells from SLE patients using single-cell flow cytometry of PBMCs stimulated ex vivo with IL-6 or IL-15. We quantified pSTAT3 induction and assessed the inhibitory effect of baricitinib. Despite long-term immunomodulators, significant STAT3 activation was observed in T cells and myeloid cells upon IL-6 or IL-15 stimulation in SLE patients. Baricitinib effectively inhibited STAT3 phosphorylation in these cell types, though its inhibitory effect was notably weaker following IL-15 stimulation compared to IL-6. Notably, baricitinib did not affect the proportion of IFN-γ or IL-17-expressing cells. These findings highlight the cell-type and cytokine-specific effects of baricitinib and demonstrate its capacity to dampen IL-6– and IL-15–mediated STAT3 activation in key immune cell subsets. Our results support a precision medicine approach to JAK inhibition in SLE and reinforce the potential of baricitinib in modulating key inflammatory pathways.