title: Hfe deficiency impairs pulmonary neutrophil recruitment in response to inflammation.
abstract: Regulation of iron homeostasis and the inflammatory response are tightly linked to protect the host from infection. Here we investigate how imbalanced systemic iron homeostasis in a murine disease model of hereditary hemochromatosis (Hfe(-/-) mice) affects the inflammatory responses of the lung. We induced acute pulmonary inflammation in Hfe(-/-) and wild-type mice by intratracheal instillation of 20 µg of lipopolysaccharide (LPS) and analyzed local and systemic inflammatory responses and iron-related parameters. We show that in Hfe(-/-) mice neutrophil recruitment to the bronchoalveolar space is attenuated compared to wild-type mice although circulating neutrophil numbers in the bloodstream were elevated to similar levels in Hfe(-/-) and wild-type mice. The underlying molecular mechanisms are likely multifactorial and include elevated systemic iron levels, alveolar macrophage iron deficiency and/or hitherto unexplored functions of Hfe in resident pulmonary cell types. As a consequence, pulmonary cytokine expression is out of balance and neutrophils fail to be recruited efficiently to the bronchoalveolar compartment, a process required to protect the host from infections. In conclusion, our findings suggest a novel role for Hfe and/or imbalanced iron homeostasis in the regulation of the inflammatory response in the lung and hereditary hemochromatosis.
authors: Department of Pediatric Oncology, Hematology and Immunology, University Hospital of Heidelberg, Heidelberg, Germany.
authors: Karolina
authors: K
authors: Benesova
authors: Maja
authors: M
authors: Vujić Spasić
authors: Sebastian M
authors: SM
authors: Schaefer
authors: Jens
authors: J
authors: Stolte
authors: Tomi
authors: T
authors: Baehr-Ivacevic
authors: Katharina
authors: K
authors: Waldow
authors: Zhe
authors: Z
authors: Zhou
authors: Ursula
authors: U
authors: Klingmueller
authors: Vladimir
authors: V
authors: Benes
authors: Marcus A
authors: MA
authors: Mall
authors: Martina U
authors: MU
authors: Muckenthaler
mesh_terms: D000818:Animals; D006432:Hemochromatosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics / Q000502:physiology*; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008070:Lipopolysaccharides; D008565:Membrane Proteins