A myeloid Tet2-IL-1β axis modulates intestinal inflammation by restricting catecholaminergic stimulation of...

Deciphering multicellular interactions is essential to understanding immune-mediated diseases. Myeloid cells can coordinate inflammatory responses and are central to immune crosstalk with neuronal, epithelial, and stromal cells. Here, we show that myeloid-specific loss of ten-eleven-translocation methylcytosine dioxygenase 2 (TET2) protected against colitis by limiting enterochromaffin (EC) cell differentiation and subsequent serotonin release. This protective effect was mediated by elevated interleukin (IL)-1β production by myeloid cells, which signals to tyrosine hydroxylase (TH)-positive neurons under inflammatory conditions. Neuronal IL-1R signaling dampened neuronal-epithelial interactions and consequent α₁-adrenergic signaling, thereby reducing EC differentiation. Conversely, physiological stress exacerbated colitis by enhancing catecholaminergic signals, which increased EC differentiation and serotonin production following mucosal injury. Thus, myeloid-derived IL-1β and stress exert opposing control over colitis severity through the α₁-adrenergic-EC axis, uncovering a neuro-immune-epithelial circuit that shapes intestinal inflammation.