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Myeloid TET2-IL-1 axis controls sympathetic-epithelial interaction to modulate intestinal inflammation

ABSTRACT: Inflammatory responses are mediated by complex multi-cellular interactions and understanding the identity and mechanism of these interactions is central to understanding the pathophysiology of immune-mediated diseases. In humans, somatic mutations in Tet methylcytosine dioxygenase 2 (TET2), a DNA demethylase, are commonly observed during ageing in myeloid cells1,2 and known to modulate inflammatory responses3. Using a mouse model that selectively lacks TET2 in myeloid cells, we show that myeloid cells and sympathetic neurons form a signaling nexus that controls the differentiation of enterochromaffin cells and serotonin production during colonic inflammation. Specifically, we demonstrate that TET2 restricts IL-1 production by myeloid cells under physiological conditions that in turn controls the intestinal sympathetic activation.

ORGANISM(S): Mus musculus

PROVIDER: GSE267700 | GEO | 2025/07/08

REPOSITORIES: GEO

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Project description:TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. The gene encoding TET2 resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML). We show here that TET2 mutations associated with myeloid malignancies compromise catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5hmC in genomic DNA compared to bone marrow samples from healthy controls. Moreover, small hairpin RNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples from patients with high 5hmC versus healthy controls, but samples from patients with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites. Our results demonstrate that Tet2 is important for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anticancer drugs. Genome wide DNA methylation profiling of patients samples with various myeloid malignancies and diffrential levels of 5hmC.The Illumina Infinium 27k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs in bone marrow samples and occasionally peripheral blood samples. Samples included 28 control healthy bone marrows, 29 patients samples with low 5hmC levels (7 patients with wild-type TET2 and 22 mutant TET2) and 24 with high levels of 5hmC (22 with wild-type TET2 and 2 mutant TET2). Bisulphite converted DNA from 81 samples was hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2

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Myeloid TET2-IL-1 axis controls sympathetic-epithelial interaction to modulate intestinal inflammation

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