Epithelial NF-κB shapes protective Treg cell responses to restrain intestinal inflammation
Abstract
Inflammation resolution depends on coordinated communication between tissue compartments, yet how the intestinal epithelium shapes its immune microenvironment remains poorly understood. Here, using colonic biopsies from patients with ulcerative colitis (UC) and mouse models enabling tissue-wide visualization of NF-κB activity, we combine single-cell RNA sequencing and secretome analysis to define epithelial communication during colitis. We show that, paradoxically, the NF-κB-driven pro-inflammatory secretome of intestinal epithelial cells (IECs) is essential for recovery and prevents unrestrained inflammation. Mechanistically, epithelial NF-κB promotes CCL22-dependent regulatory T cell (Treg cell) recruitment and promotes a tolerogenic, pro-repair cell state, accompanied by induction of the lipid-metabolism-associated GDPD3 and CCR4. In UC, epithelial NF-κB is not uniformly activated but instead induces a selective pro-inflammatory transcriptional program while repressing targets regulating T cell recruitment. Thus, we identify dynamic epithelial–immune communication and demonstrate a protective IEC NF-κB–Treg cell axis important for resolution of intestinal inflammation.
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BibTeX
@article{barleben2026epithelial,
title = {{Epithelial NF-κB shapes protective Treg cell responses to restrain intestinal inflammation}},
author = {Luisa Barleben and Antony Julián Schneegans and Bora Uyar and Alix Bruneau and Giomar Vasileva and Franziska Flohr and Eleni Kabrani and Thomas Vasilakis and Linda Hammann and Pimrapat Gebert and Carola Dietrich and Bettina Bochow-Fitzner and Alexander Arnold and Somesh Sai and Florentine Gröne and Maike Sander and Thomas Conrad and Audrey Gérard and Ignazio Piseddu and David Anz and Christoph Jochum and Altuna Akalin and Linda Hammerich and Christoph S. N. Klose and Frank Tacke and Michela Di Virgilio and Marina Kolesnichenko},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78796-z},
url = {https://www.nature.com/articles/s41467-026-78796-z},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Epithelial NF-κB shapes protective Treg cell responses to restrain intestinal inflammation
AU - Luisa Barleben
AU - Antony Julián Schneegans
AU - Bora Uyar
AU - Alix Bruneau
AU - Giomar Vasileva
AU - Franziska Flohr
AU - Eleni Kabrani
AU - Thomas Vasilakis
AU - Linda Hammann
AU - Pimrapat Gebert
AU - Carola Dietrich
AU - Bettina Bochow-Fitzner
AU - Alexander Arnold
AU - Somesh Sai
AU - Florentine Gröne
AU - Maike Sander
AU - Thomas Conrad
AU - Audrey Gérard
AU - Ignazio Piseddu
AU - David Anz
AU - Christoph Jochum
AU - Altuna Akalin
AU - Linda Hammerich
AU - Christoph S. N. Klose
AU - Frank Tacke
AU - Michela Di Virgilio
AU - Marina Kolesnichenko
PY - 2026
DA - 2026/10/20
JO - Nature Communications
DO - 10.1038/s41467-026-78796-z
UR - https://www.nature.com/articles/s41467-026-78796-z
AB - Inflammation resolution depends on coordinated communication between tissue compartments, yet how the intestinal epithelium shapes its immune microenvironment remains poorly understood. Here, using colonic biopsies from patients with ulcerative colitis (UC) and mouse models enabling tissue-wide visualization of NF-κB activity, we combine single-cell RNA sequencing and secretome analysis to define epithelial communication during colitis. We show that, paradoxically, the NF-κB-driven pro-inflammatory secretome of intestinal epithelial cells (IECs) is essential for recovery and prevents unrestrained inflammation. Mechanistically, epithelial NF-κB promotes CCL22-dependent regulatory T cell (Treg cell) recruitment and promotes a tolerogenic, pro-repair cell state, accompanied by induction of the lipid-metabolism-associated GDPD3 and CCR4. In UC, epithelial NF-κB is not uniformly activated but instead induces a selective pro-inflammatory transcriptional program while repressing targets regulating T cell recruitment. Thus, we identify dynamic epithelial–immune communication and demonstrate a protective IEC NF-κB–Treg cell axis important for resolution of intestinal inflammation.
SN - 2041-1723
ER -