Emergency barriers in Inflammatory Bowel Diseases - Neutrophil-epithelial crosstalk shapes epithelial restitution in the ulcer microenvironment (SFB/TRR 241)

Third Party Funds Group - Sub project


Acronym: SFB/TRR 241

Start date : 01.07.2022

End date : 30.06.2026

Extension date: 30.06.2030

Website: https://www.transregio241.de/


Overall project details

Overall project

TRR 241: Immun-Epitheliale Signalwege bei chronisch entzündlichen Darmerkrankungen

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Project details

Short description

Therapy-refractory subgroups of patients suffering from IBD often feature deep ulcerations and neutrophil granulocyte-related molecular signatures. We propose that the interplay between neutrophils and wound-associated intestinal epithelial cells determines successful epithelial restitution and will shed light on this conflicted intercellular crosstalk. We focus on how wound-associated epithelia are imprinted by neutrophils in the ulcer microenvironment and which protective mechanisms are used by these specialized cells in order to shape the innate immune response and support mucosal healing in IBD-related ulcers.


Scientific Abstract

Many patients suffering from inflammatory bowel disease (IBD) are successfully treated with existing immune
modulators, yet therapy-refractory subgroups exist. Recent studies have identified neutrophil-related molecular signatures and deep ulcers as predictive for therapeutic failure. This calls for specialized approaches to these patients with complicated courses of disease. Surprisingly little is known about the ulcer microenvironment in IBD. In the first funding period, the project has studied structure and function of fibrinoid layers which cover mucosal ulcers and focused on the remodeling of blood clots to an immunothrombus by neutrophils. We found that neutrophils form neutrophil extracellular traps on mucosal erosions and prevent rectal bleeding in ulcerative colitis by peptidyl-arginine deiminase-4 (PAD4) - dependent immunothrombosis. PAD4 regulates both clot remodeling by proteases and serpins and the formation of neutrophil extracellular traps in mucosal ulcerations. We further observed that proper formation of immunothrombi directs epithelial restitution by wound-associated epithelial cells. In preliminary data, we uncover how restituting epithelia shape neutrophil functional plasticity and that neutrophils shape epithelial restitution. This cellular crosstalk crucially decides ulcer fate. It is our central hypothesis that epithelial defects lead to a dysregulated immune response in the ulcer microenvironment. For the next funding period, we thus aim to further decipher the cellular crosstalk in the ulcer microenvironment using advanced imaging technology, flow cytometric and functional analyses in genetically modified mouse strains. Based on previous work by us and others, including analyses of the IBDome and SEPIA databases, we will focus on mediators associated to resistance to therapy which are also related to neutrophils like IL-1 family members and its interplay with the pro-resolving action of TGF-b. In our previous work, the IL-1 family members IL-36alpha and IL-36gamma were identified as critical mediators in the immune-epithelial interplay. Preliminary data now shows that TGF-beta importantly shapes epithelial restitution by wound-associated epithelia, thus shapes neutrophils and vice versa. We join forces to synergistically exploit neutrophil expertise (Leppkes) and epithelial expertise (Scheibe) coming from a medical (Leppkes) and biological (Scheibe) background in our studies of cellular crosstalk in the ulcer microenvironment. Our work will employ epithelial organoid culture systems and detailed immunophenotyping of stimulated neutrophil populations in various activation states. Furthermore, we aim to identify immune checkpoints and mucosal stressors that disturb epithelial restitution in the ulcer microenvironment. This mechanistic work will be complemented by multi-labeling immunohistochemistry and transcriptomics of human IBD ulcerations. Taken together, we aim to identify critical checkpoints of immune-epithelial crosstalk inside the dysregulated IBD ulcer microenvironment in order to pave the way for future therapies in therapy-refractory patient cohorts.

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