Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing

Bleeding and altered iron distribution occur in multiple gastrointestinal diseases, but the significance or regulation of these changes remains unclear. Here we report that hepcidin, the master regulator of systemic iron homeostasis, is required for tissue repair in the intestine following experimental damage. This effect was independent of hepatocyte-derived hepcidin or systemic iron levels. Rather, we identified that conventional dendritic cells (DCs) are a source of hepcidin that is induced by microbial stimulation, prominent in the inflamed intestine of humans, and essential for tissue repair. Mechanistically, DC-derived hepcidin acted on ferroportin-expressing phagocytes to promote local iron sequestration, which regulated the microbiota and subsequently facilitated intestinal repair. Collectively, these results identify a novel pathway whereby DC-derived hepcidin promotes mucosal healing in the intestine via nutritional immunity. Overall design: Mice were treated with 3.5% DSS in drinking water for 7 days, and colon lamina propria cells were sorted as follows: cDC1 (Live, CD45+, F4/80-, CD64-, CD3-, CD19-, NK1.1-, CD138-, MHCII+, CD11c+, XCR1+, CD172a-); cDC2 (Live, CD45+, F4/80-, CD64-, CD3-, CD19-, NK1.1-, CD138-, MHCII+, CD11c+, XCR1-, CD172a+).