Notch2 deficiency generates functionally impaired cDCs and macrophages that correlates with intestinal dysbiosis and low-grade inflammation

Newswise — Myeloid cell types including conventional dendritic cells (cDCs) and macrophages are key responders to innate stimuli at epithelial barriers. They are equipped with innate receptors to sense danger signals and pathogens, becoming the first line of immune defense and thereby maintaining homeostasis. The expression of selected transcription factors was shown to be essential for the development of these myeloid subsets including Batf3, Notch2, lrf4, and lrf8 among others. We performed single-cell RNA expression analysis across eight different conditional KO lines and identified multiple defects across each line that compromised the development of unique subsets and also altered expression profiles on the remaining subsets. Within CD11c expressing cells, Notch2 deficiency in particular, seems to impair not only type 2 dendritic cells (cDC2) but also macrophage subsets across several tissues. Mice defective for Notch2 were shown to be susceptible to C. rodentium infection. We observed that the lack of Notch2 was accompanied by intestinal dysbiosis, which produced low-grade inflammation. The altered microbiome could be transferred to WT mice by co-housing, which suggests that the lack of either subset enabled the growth of an opportunistic microorganism that could prevail in competitive settings. Among the dysregulated innate pathways, we identified one that appears to correlate with this dysbiosis, and its deletion was sufficient to reproduce the phenotype in preliminary experiments. Collectively, we hypothesize that Notch2 deficiency alters the functional properties of the cDCs and intestinal macrophages ultimately leading to intestinal  dysbiosis and a pre-pathologic inflammatory condition.