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

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.