title: IL-22 Controls Iron-Dependent Nutritional Immunity Against Systemic Bacterial Infections.
abstract: Host immunity limits iron availability to pathogenic bacteria, but whether immunity limits pathogenic bacteria from accessing host heme, the major source of iron in the body, remains unclear. UsingCitrobacter rodentium, a mouse enteric pathogen andEscherichia coli, a major cause of sepsis in humans as models, we find that interleukin-22, a cytokine best known for its ability to promote epithelial barrier function, also suppresses the systemic growth of bacteria by limiting iron availability to the pathogen. Using an unbiased proteomic approach to understand the mechanistic basis of IL-22 dependent iron retention in the host, we have identified that IL-22 induces the production of the plasma hemoglobin scavenger haptoglobin and heme scavenger hemopexin. Moreover, the anti-microbial effect of IL-22 depends on the induction of hemopexin expression, while haptogloblin is dispensable. Impaired pathogen clearance in infectedIl22-/-mice was restored by hemopexin administration and hemopexin-deficient mice had increased pathogen loads after infection. These studies reveal a previously unrecognized host defense mechanism regulated by IL-22 that relies on the induction of hemopexin to limit heme availability to bacteria leading to suppression of bacterial growth during systemic infections.
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Yun-Gi
authors.initials: YG
authors.lastname: Kim
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hara
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, the University of Michigan Medical School, MI 48109, USA.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kamada
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Caballero-Flores
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, 10126 Torino, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Tolosano
authors.affiliation: Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
authors.forename: Miguel P
authors.initials: MP
authors.lastname: Soares
authors.affiliation: Departamento de Microbiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos 62210, México.
authors.forename: José L
authors.initials: JL
authors.lastname: Puente
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Inohara
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez