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. Overall design: RNA was extracted from CD11b+ MACS-enriched single cell suspension from colons of Tet2f/f and Tet2DLysM mice

炎症应答由复杂的多细胞相互作用所介导，阐明此类相互作用的本质与调控机制，是理解免疫介导性疾病病理生理学的核心要点。在人类中，作为DNA去甲基化酶的Tet甲基胞嘧啶双加氧酶2（Tet methylcytosine dioxygenase 2, TET2）的体细胞突变，常见于衰老进程中的髓系细胞[1,2]，且已被证实可调控炎症应答[3]。本研究借助髓系细胞中特异性缺失TET2的小鼠模型，证实髓系细胞与交感神经元可形成信号枢纽，在结肠炎症期间调控肠嗜铬细胞的分化与5-羟色胺的生成。具体而言，本研究发现TET2可在生理状态下抑制髓系细胞产生IL-1β，进而调控肠道交感神经的激活。实验整体设计：从Tet2f/f与Tet2DLysM小鼠结肠的CD11b阳性MACS富集单细胞悬液中提取RNA。