IL-1-driven stromal–neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies
Matthias Friedrich, Mathilde Pohin, Matthew Jackson, Ilya Korsunsky, Samuel J. Bullers, Kévin Rue-Albrecht, Zoe Christoforidou, Dharshan Sathananthan, Tom Thomas, Rahul Ravindran, Ruchi Tandon, Raphael Sanches Peres, Hannah Sharpe, Kevin Wei, Gerald F. Watts, Elizabeth H. Mann, Alessandra Geremia, Moustafa Attar, Oxford IBD Cohort Investigators, Francesca Barone, Michael B. Brenner, Christopher D. Buckley, Mark Coles, Andreas P. Frei, Kara G. Lassen, Fiona M. Powrie, Sarah McCuaig, Lloyd Thomas, Elena Collantes, Holm H. Uhlig, Stephen N. Sansom, Alistair Easton, Soumya Raychaudhuri, Simon Travis, Fiona M. Powrie
Abstract
Current inflammatory bowel disease (IBD) therapies are ineffective in a high proportion of patients. Combining bulk and single-cell transcriptomics, quantitative histopathology and in situ localization across three cohorts of patients with IBD (total n = 376), we identify coexpressed gene modules within the heterogeneous tissular inflammatory response in IBD that map to distinct histopathological and cellular features (pathotypes). One of these pathotypes is defined by high neutrophil infiltration, activation of fibroblasts and vascular remodeling at sites of deep ulceration. Activated fibroblasts in the ulcer bed display neutrophil-chemoattractant properties that are IL-1R, but not TNF, dependent. Pathotype-associated neutrophil and fibroblast signatures are increased in nonresponders to several therapies across four independent cohorts (total n = 343). The identification of distinct, localized, tissular pathotypes will aid precision targeting of current therapeutics and provides a biological rationale for IL-1 signaling blockade in ulcerating disease.