title: Infusion of IL-10-expressing cells protects against renal ischemia through induction of lipocalin-2.
abstract: Ischemia/reperfusion injury is a leading cause of acute renal failure triggering an inflammatory response associated with infiltrating macrophages, which determine disease outcome. To repair the inflammation we designed a procedure whereby macrophages that overexpress the anti-inflammatory agent interleukin (IL)-10 were adoptively transferred. These bone marrow-derived macrophages were able to increase their intracellular iron pool that, in turn, augmented the expression of lipocalin-2 and its receptors. Infusion of these macrophages into rats after 1 h of reperfusion resulted in localization of the cells to injured kidney tissue, caused increases in regenerative markers, and a notable reduction in both blood urea nitrogen and creatinine. Furthermore, IL-10 therapy decreased the local inflammatory profile and upregulated the expression of pro-regenerative lipocalin-2 and its receptors. IL-10-mediated protection and subsequent renal repair were dependent on the presence of iron and lipocalin-2, since the administration of a neutralizing antibody for lipocalin-2 or administration of IL-10 macrophages pretreated with the iron chelating agent deferoxamine abrogated IL-10-mediated protective effects. Thus, adoptive transfer of IL-10 macrophages to ischemic kidneys blunts acute kidney injury. These effects are mediated through the action of intracellular iron to induce lipocalin-2.
authors.affiliation: Department of Ischemia and Inflammation, IIBB-CSIC-IDIBAPS, Experimental Pathology, Barcelona, Spain; Institute of Biochemistry I/ZAFES, Goethe-University Frankfurt, Frankfurt, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Jung
authors.affiliation: Department of Ischemia and Inflammation, IIBB-CSIC-IDIBAPS, Experimental Pathology, Barcelona, Spain; CIBER-BBN, Networking Center on Bioengineering, Biomaterials and Nanomedicine, Zaragoza, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Sola
authors.affiliation: MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hughes
authors.affiliation: MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Kluth
authors.affiliation: Department of Ischemia and Inflammation, IIBB-CSIC-IDIBAPS, Experimental Pathology, Barcelona, Spain.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Vinuesa
authors.affiliation: Department of Ischemia and Inflammation, IIBB-CSIC-IDIBAPS, Experimental Pathology, Barcelona, Spain; CIBER-BBN, Networking Center on Bioengineering, Biomaterials and Nanomedicine, Zaragoza, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Viñas
authors.affiliation: Department of Ischemia and Inflammation, IIBB-CSIC-IDIBAPS, Experimental Pathology, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Pérez-Ladaga
authors.affiliation: Department of Ischemia and Inflammation, IIBB-CSIC-IDIBAPS, Experimental Pathology, Barcelona, Spain; CIBER-BBN, Networking Center on Bioengineering, Biomaterials and Nanomedicine, Zaragoza, Spain. Electronic address: ghcbam@iibb.csic.es.
authors.forename: Georgina
authors.initials: G
authors.lastname: Hotter
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019264:Adoptive Transfer; D000818:Animals; D001806:Blood Urea Nitrogen; D002470:Cell Survival; D003676:Deferoxamine / Q000494:pharmacology; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D007511:Ischemia / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D007668:Kidney / Q000098:blood supply / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D018836:Inflammation Mediators; D007502:Iron Chelating Agents; C097278:Lcn2 protein, rat; D000071068:Lipocalin-2; D054834:Lipocalins; D016753:Interleukin-10; D007501:Iron; D003676:Deferoxamine