IL-1-driven stromal-neutrophil interaction in deep ulcers defines a pathotype of therapy non-responsive inflammatory bowel disease

Abstract

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 localisation, we describe heterogeneity of the tissular inflammatory response in IBD treatment failure. Among inflammatory pathotypes, we found high neutrophil infiltration, activation of fibroblasts, and vascular remodelling at sites of deep ulceration was a feature of non-response to several anti-inflammatory therapies. Activated fibroblasts in the ulcer bed display neutrophil chemoattractant properties that are IL-1R- but not TNF-dependent. The identification of distinct, localised, tissular pathotypes associated with treatment non-response will aid precision targeting of current therapeutics and provide a biological rationale for IL-1 signalling blockade in ulcerating disease.

Competing Interest Statement

Fiona Powrie, PhD, FRS, FMedSci Grants/Research support: Roche and Janssen Consulting fees: GSK and Genentech Simon Travis, DPhil FRCP Grants/Research Support: AbbVie, Buhlmann, Celgene, IOIBD, Janssen, Lilly, Pfizer, Takeda, UCB, Vifor and Norman Collisson Foundation. Consulting Fees: AbbVie, Allergan, Αbiomics, Amgen, Arena, Asahi, Astellas, Biocare, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Buhlmann, Celgene, Chemocentryx, Cosmo, Enterome, Ferring, Giuliani SpA, GSK, Genentech, Immunocore, Immunometabolism, Indigo, Janssen, Lexicon, Lilly, Merck, MSD, Neovacs, Novartis, NovoNordisk, NPS Pharmaceuticals, Pfizer, Proximagen, Receptos, Roche, Sensyne, Shire, Sigmoid Pharma, SynDermix, Takeda, Theravance, Tillotts, Topivert, UCB, VHsquared, Vifor, Zeria. Speaker fees: AbbVie, Amgen, Biogen, Ferring, Janssen, Pfizer, Shire, Takeda, UCB. No stocks or share options. K.G. L. and A.P.F. are employees of Roche Ltd. All authors declare no commercial or financial conflict of interest.

Footnotes

* ↵11 Oxford IBD cohort investigators: Dr Carolina Arancibia, Dr Adam Bailey, Professor Ellie Barnes, Dr Elizabeth Bird-Lieberman, Dr Oliver Brain, Dr Barbara Braden, Dr Jane Collier, Professor James East, Dr Lucy Howarth, Professor Paul Klenerman, Professor Simon Leedham, Dr Rebecca Palmer, Dr Fiona Powrie, Dr Astor Rodrigues, Professor Alison Simmons, Dr Peter Sullivan, Professor Holm Uhlig, Professor Jack Satsangi, Dr Philip Allan, Dr Timothy Ambrose, Dr Jan Bornschein, Dr Jeremy Cobbold, Dr Emma Culver, Dr Michael Pavlides, Dr Alissa Walsh

* ↵12 Roche Fibroblast Network Consortium: Kevin Wei, Ilya Korsunsky, Francesca Barone, Michael Brenner, Chris Buckley, Mark Coles, Andreas P. Frei, Kara G. Lassen, Fiona Powrie, Soumya Raychaudhuri

* ↵17 Lead contact