What question did this study set out to answer?

This research aims to clarify how interleukin-1β signalling alters chromatin structure and affects transcription factor occupancy in cystic fibrosis.

May 20, 2026

B28-08 Interleukin-1β Signalling Regulates NF-κB-dependent Chromatin Remodelling and NKX2-1 Repression in Cystic Fibrosis Small Airway Epithelial Cells

Key Points

This research aims to clarify how interleukin-1β signalling alters chromatin structure and affects transcription factor occupancy in cystic fibrosis.
Primary human small airway epithelial cells were treated with IL-1β for 48 hours or 14 days.
Chromatin accessibility and transcription factor binding were analyzed using ATAC-seq and CUT&RUN-seq.
Gene expression and protein levels were assessed by qRT-PCR and western blotting, respectively.
IL-1β exposure increased chromatin accessibility at NF-κB-binding sites, enhancing MUC5B and MUC5AC expression.
Repression of SCGB3A2 and SFTPB was observed due to reduced NKX2-1 occupancy and H3K27ac levels.
Chronically treated cells exhibited sustained mucin secretion and a significant decrease in DASC markers.

Abstract

Abstract Rationale Distal airway secretory cells (DASCs), characterized by expression of SCGB3A2 and SFTPB, are essential for mucociliary homeostasis and host defence in the bronchiolar epithelium. Their selective depletion in muco-obstructive lung diseases (MOLDs), including cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease (COPD), highlights a shared mechanism of inflammation-induced epithelial remodelling. Chronic airway inflammation in CF, predominantly driven by interleukin-1β (IL-1β) promotes mucin overproduction and impairs DASC identity. However, the molecular basis by which IL-1β signalling alters chromatin structure and transcription factor (TF) occupancy to repress distal-airway programs remains unclear. We hypothesized that IL-1β triggers NF-κB-dependent chromatin remodelling that disrupts NKX2-1 regulatory networks, leading to persistent mucin hypersecretion and DASC loss in CF small airways. Methods Primary human small airway epithelial (SAE) cells from previously healthy transplant donors were differentiated at air-liquid interface and treated with IL-1β (1 ng/mL) for 48 hours (acute) or 14 days (chronic). Chromatin accessibility and TF binding were analysed by ATAC-seq and CUT&RUN-seq targeting NF-κB (RELA/p65), NKX2-1, SPDEF, CTCF, and H3K27ac. Gene expression was assessed by qRT-PCR, and western blotting for MUC5B, MUC5AC, SCGB3A2, and SFTPB. Chromatin architecture was further analysed by CTCF occupancy mapping to evaluate enhancer-promoter binding at the MUC5B and SCGB3A2 loci. Results Acute (48 h) IL-1β exposure selectively increased chromatin accessibility at NF-κB-binding sites upstream of MUC5B and MUC5AC, correlating with robust transcriptional activation and nuclear SPDEF accumulation. In addition, IL-1β treatment repressed SCGB3A2 and SFTPB through loss of NKX2-1 occupancy and reduced H3K27ac at distal airway enhancer elements. These IL-1β-induced chromatin alterations were maintained in chronically stimulated SAE cultures, indicating stable reprogramming of mucin-regulatory and distal-airway enhancer landscapes. Functionally, IL-1β-treated cultures displayed elevated mucin secretion and a marked reduction in SCGB3A2+/SFTPB+ DASCs. Conclusions Our findings uncover a previously unrecognized epigenetic axis by which IL-1β signalling remodels the chromatin landscape of the distal airway epithelium, linking persistent inflammation to mucin overproduction and DASC depletion. Our data provide mechanistic insight into the persistence of mucin-dominant airway remodelling in CF small airways and identify NF-κB and NKX2-1 as key epigenetic nodes for therapeutic target to restore distal-airway homeostasis in CF and other relevant chronic lung diseases. This abstract is funded by: NIH, NHLBI, CFF

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