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 importance and regulation of these changes remain unclear. We found that hepcidin, the master regulator of systemic iron homeostasis, is required for tissue repair in the mouse intestine after experimental da...

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Published inScience (American Association for the Advancement of Science) Vol. 368; no. 6487; pp. 186 - 189
Main Authors Bessman, Nicholas J, Mathieu, Jacques R R, Renassia, Cyril, Zhou, Lei, Fung, Thomas C, Fernandez, Keith C, Austin, Christine, Moeller, Jesper B, Zumerle, Sara, Louis, Sabine, Vaulont, Sophie, Ajami, Nadim J, Sokol, Harry, Putzel, Gregory G, Arvedson, Tara, Sockolow, Robbyn E, Lakhal-Littleton, Samira, Cloonan, Suzanne M, Arora, Manish, Peyssonnaux, Carole, Sonnenberg, Gregory F
Format Journal Article
LanguageEnglish
Published United States The American Association for the Advancement of Science 10.04.2020
American Association for the Advancement of Science (AAAS)
Subjects
Anemia
Animal tissues
Animals
Bleeding
Cation Transport Proteins - metabolism
Dendritic cells
Dendritic Cells - metabolism
Dendritic structure
Drawing and ironing
Fecal Microbiota Transplantation
Gastrointestinal diseases
Gastrointestinal Microbiome
Gene Deletion
Geographical distribution
Healing
Hepcidin
Hepcidins - genetics
Hepcidins - metabolism
Homeostasis
Inflammatory bowel disease
Inflammatory bowel diseases
Inflammatory diseases
Intestinal Diseases - microbiology
Intestinal microflora
Intestinal Mucosa - microbiology
Intestinal Mucosa - physiology
Intestine
Iron
Iron - metabolism
Iron and steel making
Life Sciences
Macrophages
Mice
Mice, Mutant Strains
Microbiota
Microorganisms
Mucosa
Phagocytes
Phagocytes - metabolism
Repair
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Summary:Bleeding and altered iron distribution occur in multiple gastrointestinal diseases, but the importance and regulation of these changes remain unclear. We found that hepcidin, the master regulator of systemic iron homeostasis, is required for tissue repair in the mouse intestine after experimental damage. This effect was independent of hepatocyte-derived hepcidin or systemic iron levels. Rather, we identified conventional dendritic cells (cDCs) as a source of hepcidin that is induced by microbial stimulation in mice, prominent in the inflamed intestine of humans, and essential for tissue repair. cDC-derived hepcidin acted on ferroportin-expressing phagocytes to promote local iron sequestration, which regulated the microbiota and consequently facilitated intestinal repair. Collectively, these results identify a pathway whereby cDC-derived hepcidin promotes mucosal healing in the intestine through means of nutritional immunity.
Bibliography:Author contributions: N.J.B. and G.F.S. conceived the project. N.J.B., L.Z., T.C.F., K.C.F., J.B.M, J.R.R.M., C.R., S.L. and S.Z. performed experiments and analyzed data. S.V. and S.L-L. provided mouse models and expertise. H.S. performed pathological analyses. T.A. provided tools and expertise. C.P. provided mouse models, designed and supervised experiments. N.J.A. and G.G.P. analyzed sequencing data. C.A. and M.A. performed and analyzed iron imaging. R.E.S. provided essential advice and guidance. S.M.C. provided guidance and iron measurements. N.J.B. and G.F.S. wrote the manuscript, with input from all the authors.
These authors contributed equally
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aau6481