IL-3 receptor signalling suppresses chronic intestinal inflammation by controlling mechanobiology and tissue egress of regulatory T cells.

Abstract

IL-3 has been reported to be involved in various inflammatory disorders, but its role in inflammatory bowel disease (IBD) has not been addressed so far. Here, we determined IL-3 expression in samples from patients with IBD and studied the impact of Il3 or Il3r deficiency on T cell-dependent experimental colitis. We explored the mechanical, cytoskeletal and migratory properties of Il3r -/- and Il3r +/+ T cells using real-time deformability cytometry, atomic force microscopy, scanning electron microscopy, fluorescence recovery after photobleaching and in vitro and in vivo cell trafficking assays. We observed that, in patients with IBD, the levels of IL-3 in the inflamed mucosa were increased. In vivo, experimental chronic colitis on T cell transfer was exacerbated in the absence of Il-3 or Il-3r signalling. This was attributable to Il-3r signalling-induced changes in kinase phosphorylation and actin cytoskeleton structure, resulting in increased mechanical deformability and enhanced egress of Tregs from the inflamed colon mucosa. Similarly, IL-3 controlled mechanobiology in human Tregs and was associated with increased mucosal Treg abundance in patients with IBD. Collectively, our data reveal that IL-3 signaling exerts an important regulatory role at the interface of biophysical and migratory T cell features in intestinal inflammation and suggest that this might be an interesting target for future intervention.

• Authors: Karen Anne-Marie Ullrich, Julia Derdau, Carsten Baltes, Alice Battistella, Gonzalo Rosso, Stefan Uderhardt, Lisa Lou Schulze, Li-Juan Liu, Mark Dedden, Marta Spocinska, Lucina Kainka, Markéta Kubánková, Tanja Martina Müller, Nina-Maria Schmidt, Emily Becker, Oumaima Ben Brahim, Imke Atreya, Susetta Finotto, Iryna Prots, Stefan Wirtz, Benno Weigmann, Rocío López-Posadas, Raja Atreya, Arif Bülent Ekici, Franziska Lautenschläger, Jochen Guck, Markus F Neurath, Sebastian Zundler
• Journal: Gut (Gut) Vol. 72 Issue 11 Pg. 2081-2094 (11 2023) ISSN: 1468-3288 [Electronic] England
• PMID: 37541770 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Receptors, Interleukin-3
• Interleukin-3

Topics

• Humans
• T-Lymphocytes, Regulatory
• Receptors, Interleukin-3 (metabolism)
• Interleukin-3 (metabolism)
• Inflammation (metabolism)
• Colitis (metabolism)
• Inflammatory Bowel Diseases (metabolism)
• Intestinal Mucosa (metabolism)