Abstract
Inflammation is essential for healing and cellular homeostasis, but lack of resolution can become chronic and pathogenic. In IBD, chronic inflammation is driven by dysbiosis, dysregulated innate and adaptive immune responses, and genetic/epigenetic factors. Myeloid cells are central regulators of inflammatory recruitment, injury control, and resolution; however, aberrant myeloid responses may contribute to disease complications and fibrosis.
Distinct patterns of DNA methylation have been reported in IBD myeloid cells, but its role in differentiated or tissue-resident macrophages remains unclear. Analysis of public transcriptomic datasets identified TET1 as the most downregulated transcript in peripheral blood IBD, correlating with reduced TET gene set enrichment and increased inflammatory mediators.
We investigated TET1 function in myeloid responses using CRISPR knockout TET1 or TET2 THP-1 macrophages under disease-associated stimulation. TET1-deficient macrophages showed increased CCL-8 production, altered immune receptor expression, elevated basal ERK1/2 phosphorylation, enhanced type I IFN signaling, altered 5hmC levels, and reduced expression of PTEN and RBM38, which negatively regulate ERK1/2 activity.
Patient mononuclear cells confirmed elevated CCL-8 and reduced TET1, PTEN, and RBM38 expression, with increased proinflammatory mediator release after LPS stimulation compared with healthy controls. Bulk and single-cell RNA-seq from IBD biopsies showed similar trends. Together, these findings indicate that TET1 regulates key inflammatory pathways in IBD and that TET1 deficiency may promote pathogenic inflammation.