Tet2 restrains inflammatory gene expression in macrophages.

Tet methylcytosine dioxygenase 2 (TET2) is one of the earliest and most frequently mutated genes in clonal hematopoiesis of indeterminate potential (CHIP) and myeloid cancers, including myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). TET2 catalyzes the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, leading to DNA demethylation, and also affects transcription by recruiting histone modifiers. Inactivating TET2 mutations cause epigenetic dysregulation, clonal hematopoietic stem cell (HSC) dominance, and monocytic lineage skewing. Here, we found that Tet2 was the most highly expressed Tet enzyme in murine macrophage (MΦ) differentiation. Tet2 transcription was further induced by lipopolysaccharide (LPS), but not interleukin (IL)-4, stimulation, potentially in a nuclear factor κβ-dependent manner. Tet2 loss did not affect early LPS gene responses in vitro, but increased Il-1b, Il-6, and Arginase 1 (Arg1) mRNA expression at later stages of stimulation in bone-marrow-derived MΦs (BMMΦs). Tet2-deficient peritoneal MΦs, however, demonstrated profound, constitutive expression of LPS-induced genes associated with an inflammatory state in vivo. In contrast, Tet2 deficiency did not affect alternative MΦ gene expression significantly in response to IL-4. These results suggested impaired resolution of inflammation in the absence of Tet2 both in vitro and in vivo. For the first time, we also detected TET2 mutations in BMMΦs from MDS and CMML patients and assayed their effects on LPS responses, including their potential influence on human IL-6 expression. Our results show that Tet2 restrains inflammation in murine MΦs and mice, raising the possibility that loss of TET2 function in MΦs may alter the immune environment in the large elderly population with TET2-mutant CHIP and in TET2-mutant myeloid cancer patients.