Differential effects of tofacitinib on macrophage activation contribute to lack of response in ulcerative colitis patients
Year: 2025
Type: article
Abstract: BACKGROUND AND AIMS: Tofacitinib, a Janus kinase inhibitor, is approved for the treatment of moderate-to-severe ulcerative colitis. Nonetheless, 40-60% of patients will not respond adequately. The mechanisms underlying responses to tofacitinib remain unknown. METHODS: We applied single-cell and/or bulk RNA analysis to biopsies (n = 23 and 63, respectively) from ulcerative colitis patients (n = 31) before and after tofacitinib treatment. Response was assessed using endoscopic and clinical criteria. In vitro-derived macrophages and primary intestinal fibroblasts were used to validate our findings. RESULTS: Forty percent of patients responded to tofacitinib. Responders exhibited higher baseline JAK-STAT activity, while non-responders had increased baseline NF-kB pathway activation. Response was associated with significant changes in the abundance and/or activation of immune, epithelial, and stromal cells and the downregulation of S100A9, FCGR3A, MMP12 in resident macrophages. In contrast, non-responders showed a significant increase in the number and activation of macrophages and fibroblasts following tofacitinib treatment, including upregulation of MMP9, IL1B, IL6, CXCL1, CXCL8, and S100A9 compared to baseline. In monocyte-derived macrophages tofacitinib drove the hyperactivation of macrophages in response to lipopolysaccharide, but not TNF or IFNγ. This effect is dependent on the inhibition of IL-10 signaling, which is abundantly induced in response to LPS, but not to TNF or IFNγ. In contrast, cultured fibroblasts, which produced no IL-10 regardless of the stimuli, showed no hyperactivation when pre-treated with tofacitinib. CONCLUSIONS: We conclude that resistance to tofacitinib is mediated by the hyperactivation of myeloid cells and we identify IL-10-dependent macrophages as one cellular subset contributing to this resistance.
Source: Journal of Crohn s and Colitis
Authors: 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
Institutions: Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Consejo Superior de Investigaciones Científicas, Centro de Investigaciones Biológicas Margarita Salas, KU Leuven
Language: English
Topic: Inflammatory Bowel Disease
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,790
Awards: G1175115578, G1650125035, G1855990336, G202859282, G2262748287, G2309174360, G2601397997, G2660406951, G300979063, G3480869486, G3518538256, G3681454997, G4042783231, G425668148, G430777504, Identification of the Molecular Mechanisms of non-response to Treatments, Relapses and Remission in Autoimmune, Inflammatory, and Allergic Conditions, G434337789, G4753549704, G5080475149, G5195188938, G526084217, G5421974903, G574669212, G5789413810, G7084143925, G7434936867, G99296377
OpenAlex ID: W4410101956