title: Lipocalin 2 alleviates iron toxicity by facilitating hypoferremia of inflammation and limiting catalytic iron generation.
abstract: Iron is an essential transition metal ion for virtually all aerobic organisms, yet its dysregulation (iron overload or anemia) is a harbinger of many pathologic conditions. Hence, iron homeostasis is tightly regulated to prevent the generation of catalytic iron (CI) which can damage cellular biomolecules. In this study, we investigated the role of iron-binding/trafficking innate immune protein, lipocalin 2 (Lcn2, aka siderocalin) on iron and CI homeostasis using Lcn2 knockout (KO) mice and their WT littermates. Administration of iron either systemically or via dietary intake strikingly upregulated Lcn2 in the serum, urine, feces, and liver of WT mice. However, similarly-treated Lcn2KO mice displayed elevated CI, augmented lipid peroxidation and other indices of organ damage markers, implicating that Lcn2 responses may be protective against iron-induced toxicity. Herein, we also show a negative association between serum Lcn2 and CI in the murine model of dextran sodium sulfate (DSS)-induced colitis. The inability of DSS-treated Lcn2KO mice to elicit hypoferremic response to acute colitis, implicates the involvement of Lcn2 in iron homeostasis during inflammation. Using bone marrow chimeras, we further show that Lcn2 derived from both immune and non-immune cells participates in CI regulation. Remarkably, exogenous rec-Lcn2 supplementation suppressed CI levels in Lcn2KO serum and urine. Collectively, our results suggest that Lcn2 may facilitate hypoferremia, suppress CI generation and prevent iron-mediated adverse effects.
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, 16802, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, 16802, USA.
authors.forename: Beng San
authors.initials: BS
authors.lastname: Yeoh
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, 16802, USA.
authors.forename: Piu
authors.initials: P
authors.lastname: Saha
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, 16802, USA.
authors.forename: Rodrigo Aguilera
authors.initials: RA
authors.lastname: Olvera
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, 16802, USA.
authors.forename: Vishal
authors.initials: V
authors.lastname: Singh
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, 16802, USA. mvk13@psu.edu.|Department of Medicine, The Pennsylvania State University Medical Center, Hershey, PA, 17033, USA. mvk13@psu.edu.
authors.forename: Matam
authors.initials: M
authors.lastname: Vijay-Kumar
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000378:metabolism*; D000818:Animals; D055162:Biocatalysis / Q000187:drug effects*; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism; D016264:Dextran Sulfate; D007249:Inflammation / Q000378:metabolism*; D007501:Iron / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity*; D000071068:Lipocalin-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D000071068:Lipocalin-2; C071332:Lcn2 protein, mouse; D016264:Dextran Sulfate; D007501:Iron
keywords: Anemia of inflammation; Catalytic iron; Inflammation; Iron; Lipocalin 2; Oxidative stress