RXRA in Paneth cells as driver of intestinal inflammation

Introduction The global rise in Crohn’s disease (CD) parallels the Westernization of dietary habits. A diet rich in polyunsaturated fatty acids (PUFAs), characteristic of a Western diet (WD), negatively affects the course of CD. Mice lacking the antioxidant enzyme GPX4 in their intestinal epithelial cells (IECs) (Gpx4+/-IEC) develop CD-like enteritis when fed a PUFA-enriched WD. This study investigates how PUFA signaling in Paneth cells (PC) via the transcription factor retinoid x receptor alpha (RXRα) fuels intestinal inflammation that can be pharmacologically targeted.

Material and Methods RNA-sequencing was performed on ileal samples from 176 CD patients across three independent cohorts. Single-cell sequencing was used to analyze small intestinal cells from Gpx4+/-IEC mice fed a PUFA-enriched WD. MODE-K cells (mouse IECs) were stimulated with PUFAs and analyzed using RNA-seq and ELISA. Mice lacking GPX4 specifically in Paneth cells (Gpx4ΔPC mice) or both, GPX4 and RXRα, were fed a PUFA-enriched WD. Additionally, Gpx4ΔPC mice were treated with either an RXRα antagonist (HX531) or a neutralizing CXCL1 antibody.

Results RXRα transcription factor activity was increased in ileal samples from patients with small intestinal CD compared to non-IBD controls. This is paralleled by an increased transcription of pro-inflammatory cytokines such as IL-8. Single-cell sequencing of Gpx4+/-IEC mice on a PUFA-enriched WD revealed heightened RXRα activity specifically in IECs. In vitro, MODE-K cells lacking Gpx4 exhibited increased RXRα activity when stimulated with PUFAs and produced high levels of CXCL1, the murine homologue of IL-8. Gpx4ΔPC mice developed CD-like enteritis upon PUFA WD feeding, which was alleviated by RXRα deletion in PCs or the treatment with HX531, or a neutralizing CXCL1 antibody.

Conclusion RXRα activity is upregulated in patients with small intestinal CD. RXRα in Paneth cells senses and translates PUFA-induced stress into CXCL1 production, fueling intestinal inflammation in experimental enteritis. Targeting this pathway may offer therapeutic strategies for preventing or treating CD.

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Artikel online veröffentlicht:
13. Mai 2025