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

View ORCID ProfileMatthias Friedrich, Mathilde Pohin, View ORCID ProfileMatthew A. Jackson, View ORCID ProfileIlya Korsunsky, Samuel Bullers, Kevin Rue-Albrecht, Zoe Christoforidou, Dharshan Sathananthan, Rahul Ravindran, Raphael Sanches Peres, Hannah Sharpe, Kevin Wei, Gerald F. M. Watts, Elizabeth H. Mann, Alessandra Geremia, Tom Thomas, Moustafa Attar, Oxford IBD Cohort Investigators, Roche Fibroblast Network Consortium, Sarah McCuaig, Lloyd Thomas, Elena Collantes, Holm H. Uhlig, Stephen Sansom, Alistair Easton, View ORCID ProfileSoumya Raychaudhuri, Simon P. Travis, Fiona M. Powrie
doi: https://doi.org/10.1101/2021.02.05.429804
Matthias Friedrich
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford OX3 7FY, United Kingdom
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Mathilde Pohin
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford OX3 7FY, United Kingdom
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Matthew A. Jackson
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford OX3 7FY, United Kingdom
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Ilya Korsunsky
2Center for Data Sciences, Brigham and Women’s Hospital, Boston, MA 02115, USA
3Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
4Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA
5Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Samuel Bullers
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford OX3 7FY, United Kingdom
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Kevin Rue-Albrecht
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford OX3 7FY, United Kingdom
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Zoe Christoforidou
6MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom
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Dharshan Sathananthan
7Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
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Rahul Ravindran
7Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
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Raphael Sanches Peres
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford OX3 7FY, United Kingdom
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Hannah Sharpe
8Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FY, United Kingdom
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Kevin Wei
9Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
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Gerald F. M. Watts
9Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
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Elizabeth H. Mann
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford OX3 7FY, United Kingdom
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Alessandra Geremia
7Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
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Tom Thomas
7Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
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Moustafa Attar
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford OX3 7FY, United Kingdom
10The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7FY, United Kingdom
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13Roche Pharma Research and Early Development, Immunology, Infectious Diseases and Ophthalmology (I2O) Discovery and Translational Area, Roche Innovation Center Basel, Basel, Switzerland
Sarah McCuaig
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford OX3 7FY, United Kingdom
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Lloyd Thomas
7Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
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Elena Collantes
7Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
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Holm H. Uhlig
7Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
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Stephen Sansom
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford OX3 7FY, United Kingdom
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Alistair Easton
14Old Road Campus Research Building, Department of Oncology, Medical Sciences Division, University of Oxford, Oxford OX3 7FY, United Kingdom
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Soumya Raychaudhuri
2Center for Data Sciences, Brigham and Women’s Hospital, Boston, MA 02115, USA
3Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
4Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA
5Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
9Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
15Centre for Genetics and Genomics Versus Arthritis, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
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Simon P. Travis
7Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
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Fiona M. Powrie
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford OX3 7FY, United Kingdom
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  • For correspondence: fiona.powrie@kennedy.ox.ac.uk
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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

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted February 06, 2021.
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IL-1-driven stromal-neutrophil interaction in deep ulcers defines a pathotype of therapy non-responsive inflammatory bowel disease
Matthias Friedrich, Mathilde Pohin, Matthew A. Jackson, Ilya Korsunsky, Samuel Bullers, Kevin Rue-Albrecht, Zoe Christoforidou, Dharshan Sathananthan, Rahul Ravindran, Raphael Sanches Peres, Hannah Sharpe, Kevin Wei, Gerald F. M. Watts, Elizabeth H. Mann, Alessandra Geremia, Tom Thomas, Moustafa Attar, Oxford IBD Cohort Investigators, Roche Fibroblast Network Consortium, Sarah McCuaig, Lloyd Thomas, Elena Collantes, Holm H. Uhlig, Stephen Sansom, Alistair Easton, Soumya Raychaudhuri, Simon P. Travis, Fiona M. Powrie
bioRxiv 2021.02.05.429804; doi: https://doi.org/10.1101/2021.02.05.429804
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IL-1-driven stromal-neutrophil interaction in deep ulcers defines a pathotype of therapy non-responsive inflammatory bowel disease
Matthias Friedrich, Mathilde Pohin, Matthew A. Jackson, Ilya Korsunsky, Samuel Bullers, Kevin Rue-Albrecht, Zoe Christoforidou, Dharshan Sathananthan, Rahul Ravindran, Raphael Sanches Peres, Hannah Sharpe, Kevin Wei, Gerald F. M. Watts, Elizabeth H. Mann, Alessandra Geremia, Tom Thomas, Moustafa Attar, Oxford IBD Cohort Investigators, Roche Fibroblast Network Consortium, Sarah McCuaig, Lloyd Thomas, Elena Collantes, Holm H. Uhlig, Stephen Sansom, Alistair Easton, Soumya Raychaudhuri, Simon P. Travis, Fiona M. Powrie
bioRxiv 2021.02.05.429804; doi: https://doi.org/10.1101/2021.02.05.429804

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