Variability in Macrophage Activation by Tofacitinib Explains UC Treatment Response
Overview
Tofacitinib shows variable efficacy in ulcerative colitis (UC), with 40% of patients responding. This study reveals that responders have higher baseline JAK-STAT activity, whereas non-responders exhibit increased NF-kB pathway activation and macrophage hyperactivation driven by IL-10-dependent mechanisms.
Background
Ulcerative colitis is a chronic inflammatory bowel disease characterized by mucosal inflammation of the colon. Despite biologic therapies, a significant proportion of patients remain refractory, necessitating alternative treatments such as JAK inhibitors. Tofacitinib, a JAK1/3 inhibitor, targets multiple cytokine pathways but shows incomplete response rates. Understanding cellular and molecular mechanisms underlying response variability is critical to improving therapeutic strategies.
40% of UC patients responded to tofacitinib treatment, showing higher baseline JAK-STAT signaling.
Non-responders exhibited increased baseline NF-kB pathway activation and macrophage hyperactivation after treatment.
Resident macrophages in responders downregulated inflammatory markers such as S100A9, FCGR3A, and MMP12 post-treatment.
Non-responders showed increased macrophage and fibroblast activation with upregulation of pro-inflammatory genes including MMP9, IL1B, IL6, CXCL1, CXCL8, and S100A9.
In vitro, tofacitinib induced macrophage hyperactivation in response to LPS via inhibition of IL-10 signaling, but not in response to TNF or IFNγ.
Fibroblasts, which do not produce IL-10, did not show hyperactivation with tofacitinib treatment.
Clinical Implications
Baseline assessment of JAK-STAT and NF-kB pathway activity may help predict patient response to tofacitinib in UC. Monitoring macrophage activation states could guide therapeutic decisions. Targeting IL-10-dependent macrophage hyperactivation may represent a novel strategy to overcome tofacitinib resistance.
Conclusion
Resistance to tofacitinib in ulcerative colitis is mediated by IL-10-dependent macrophage hyperactivation, highlighting the importance of macrophage biology in treatment outcomes. These insights provide a rationale for personalized approaches and potential combination therapies to improve efficacy.
References
Original Article -- Variability in Macrophage Activation by Tofacitinib May Explain Insufficient Responses in Ulcerative Colitis Patients
by Elisa Melón-Ardanaz, Marisol Veny, Ana M Corraliza, Victoria Gudiño, Alba Garrido-Trigo, Ángela Sanzo-Machuca, Marc Buendia, Miriam Esteller, Lisseth Robbins-Moreno, Maite Rodrigo, M Carme Masamunt, Ángel Giner, Marta Gallego, Ingrid Ordás, Agnès Fernández-Clotet, Berta Caballol, Ángel Corbí, Bram Verstockt, Severine Vermeire, Julian Panés, Elena Ricart, Azucena Salas
