Biology subjects

Masamunt, M. C.

Publications and source records attributed to Masamunt, M. C..

2 recordsLinked to original sources

bioRxiv2024

Understanding the mechanisms underlying the lack of response to Janus kinase inhibition in ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. About one-third of UC patients failed to respond to available drugs, including tofacitinib, a broad Janus kinase (JAK) inhibitor. However, the mechanisms underlying patient response or resistance to oral JAK inhibitors remain unknown. To elucidate the molecular and cellular pathways activated by tofacitinib in responder and non-responder patients, we generated a longitudinal single-cell RNA sequence dataset profiling both immune and non-immune cell populations from colonic biopsies of UC patients. Our analysis revealed that responders exhibited higher baseline JAK-STAT activity, while non-responders had increased baseline NF-kB pathway activation. Longitudinal comparisons showed that disease progression in non-responders was associated with increased abundance and enhanced activation of macrophages and fibroblasts. Our data suggest that resistance to tofacitinib is mediated by the hyperactivation of myeloid cells, and we identified IL-10-dependent macrophages as a cellular subset contributing to this resistance.

immunology↗

bioRxiv2022

Macrophage and neutrophil heterogeneity at single-cell spatial resolution in inflammatory bowel disease

Ulcerative colitis (UC) and Crohns disease (CD) are chronic inflammatory intestinal diseases that show a perplexing heterogeneity in manifestations and response to treatment. The molecular basis for this heterogeneity remains uncharacterized. We applied single-cell RNA sequencing and CosMx Spatial Molecular Imaging to human colon and found the highest diversity in cellular composition in the myeloid compartment of UC and CD patients. Besides resident macrophage subsets (M0 and M2), patients showed a variety of activated macrophages including classical (M1 CXCL5 and M1 ACOD1) and new inflammation-dependent alternative (IDA) macrophages. In addition, we captured intestinal neutrophils in three transcriptional states. Subepithelial IDA macrophages expressed NRG1, which promotes epithelial differentiation. In contrast, NRG1low IDA macrophages were expanded within the submucosa and in granulomas, in proximity to abundant inflammatory fibroblasts, which we suggest may promote macrophage activation. We conclude that macrophages sense and respond to unique tissue microenvironments, potentially contributing to patient-to-patient heterogeneity.

immunology↗