# TET1 deficiency amplifies macrophage inflammatory signaling associated with Crohn’s disease

## TL;DR

This study shows that reduced TET1 activity in macrophages increases inflammation and immune cell recruitment in Crohn’s disease.

## Contribution

The study identifies TET1 as a key regulator of macrophage inflammation in Crohn’s disease through integrated human and mechanistic analyses.

## Key findings

- TET1 is the most downregulated TET enzyme in Crohn’s disease tissues and correlates with increased inflammation.
- TET1-deficient macrophages show altered 5hmC patterns, heightened IFN signaling, and increased chemokine release.
- CD patient PBMCs exhibit reduced TET1 and exaggerated inflammatory responses, mirroring TET1-deficient macrophages.

## Abstract

To define the role of Ten-Eleven Translocation (TET) proteins in Crohn’s disease (CD)-associated inflammation through integrative human and mechanistic studies.

Publicly available CD transcriptomic and DNA methylation datasets, and primary mononuclear cells and ileal biopsies were analyzed for TET gene expression and signatures. TET1 and TET2 CRISPR/Cas9 knockout macrophage cell lines were generated.

Macrophages were stimulated with LPS in the presence or absence of kinase inhibitors. Conditioned media from macrophages were applied to primary human neutrophils. PBMCs from CD patients and healthy donors were stimulated with LPS for validation.

Macrophages or primary patients samples were analyzed by high-throughput surface marker profiling, RNA sequencing, 5hmC sequencing, assays of effector function, qRT-PCR, phosphoflow, and cytokine/chemokine release by ELISA.

TET1 was the most downregulated TET enzyme in CD blood and ileal tissues, correlating with reduced TET-associated gene signatures and elevated inflammatory mediators. TET1-deficient macrophages exhibited distinct surface phenotypes, reduced PTEN expression, altered 5hmC distribution, and heightened IFN gene expression, ERK activation, and chemokine release associated with enhanced neutrophil migration. PBMCs from CD patients mirrored reduced TET1 expression and exaggerated inflammatory responses.

TET1 functions as a non-redundant regulator of inflammatory macrophages and aberrant chemokine signaling linked to immune cell recruitment in Crohn’s disease.

The online version contains supplementary material available at 10.1007/s00011-026-02228-3.