P032 Distinct immune cell trigger responses in Ulcerative Colitis – Results from an in vivo human intestinal injury model
Bronze, M.(1,2)*;Vilstrup Johansen, J.(3);Attauabi, M.(1);Tveiten Bjerrum, J.(1);Ramírez Galera, M.(2);Woetmann, A.(2);Benedict Seidelin, J.(1);
(1)Herlev and Gentofte Hospital, Department of Gastroenterology and Hepatology, Herlev, Denmark;(2)University of Copenhagen, Department of Immunology and Microbiology, Copenhagen, Denmark;(3)University of Copenhagen, BRIC Bioinformatics Core Facility, Copenhagen, Denmark;
Background
Ulcerative colitis (UC) is characterized by alternated periods of active inflammation and quiescent disease. The mechanisms behind flare-up reactions are elusive, but it is hypothesized that normally unharmful factors can initiate flares in genetically susceptible individuals with a dysfunctional mucosal barrier and hyper-responsive immune system, leading to sustained inflammation. We aimed to describe the early cellular responses to injury in the normal intestine and in UC patients in remission.
Methods
Experimental injuries were performed in six UC patients in remission (endoscopic Mayo sub-score 0 and total Mayo score below 3) and in six control subjects1. During the initial sigmoidoscopy, six experimental wounds were made. After 24 and 48 hours, the subjects were re-endoscoped and new biopsies were taken across the experimental injury by angling the biopsy forceps 90° (Figure 1), thus including the mucosa of the injury edge and the wound bed. Biopsies from each time point were sequenced (bulk RNA-sequencing) and the frequencies of different cell types were inferred using deconvolution (Cellanneal)2
Results
Type 1-conventional dendritic cells (cDC) and macrophages decreased in both UC and controls after injury (p<0.05). Inflammatory monocytes increased in controls only at 48h post-injury, while in UC, these cells increased at 24h and decreased at 48h post-injury. There were no significant changes in natural killer cells or T and B cells frequencies between UC and controls both pre- and post-injury. The frequency of ILCs, mast cells, and type 2-cDC continuously increased in UC patients from pre-injury to 48h post-injury, in contrast to controls, where they decreased (Figure 2). ILC marker CD117 (expressed by ILC3 and ILC2) was overexpressed in UC pre-injury, however both CRTH2 (expressed only by ILC2) and CD127 were similar pre- and post-injury. Finally, the cytokines required for ILC3 stimulation (interleukin (IL)-1β, IL-1α and IL-23) and IL-17A, produced by ILC3 during inflammation, were increased.
Conclusion
UC patients in complete remission show an increased innate inflammatory response to mucosal injuries compared to healthy individuals, highlighted by the early engagement of inflammatory monocytes, mast cells, and ILCs, particularly ILC3s. Our data show a UC-specific innate cellular hyper-response that may explain the initial mechanisms of flares and could be targeted in future anti-flare therapies.
1.Seidelin JB et al. Acute Experimental Barrier Injury Triggers Ulcerative Colitis-Specific Innate Hyperresponsiveness and Ulcerative Colitis-Type Microbiome Changes in Humans. Cell Mol Gastroenterol Hepatol 2021;12:1281-1296.2. Buchauer L, Itzkovitz S. cellanneal: A User-Friendly Deconvolution Software for Omics Data, 2021.