title: The alarmin concept applied to human renal transplantation: evidence for a differential implication of HMGB1 and IL-33.
abstract: The endogenous molecules high mobility group box 1 (HMGB1) and interleukin-33 (IL-33) have been identified as alarmins, capable of mediating danger signals during tissue damage. Here, we address their possible role as innate-immune mediators in ischemia-reperfusion injury (IRI) following human kidney transplantation. We analysed serum and urinary HMGB1 and IL-33 levels, all determined by enzyme-linked immunosorbent assay, in a cohort of 26 deceased renal transplant recipients. Urinary HMGB1 and IL-33 levels were significantly increased as soon as 30 min after reperfusion, as compared to those before treatment. Moreover, both serum and urinary IL-33 (but not HMGB1) increase was positively correlated with cold ischemia time, from 30 min to 3 days post-transplantation. In vitro, human umbilical vein endothelial cells subjected to hypoxia conditions released both HMGB-1 and IL-33, while only the latter was further increased upon subsequent re-oxygenation. Finally, we postulate that leukocytes from renal recipient patients are targeted by both HMGB1 and IL-33, as suggested by increased transcription of their respective receptors (TLR2/4 and ST2L) shortly after transplantation. Consistent with this view, we found that iNKT cells, an innate-like T cell subset involved in IRI and targeted by IL-33 but not by HMGB1 was activated 1 hour post-transplantation. Altogether, these results are in keeping with a potential role of IL-33 as an innate-immune mediator during kidney IRI in humans.
authors.affiliation: Service de Néphrologie-Hémodialyse-Transplantation rénale, Centre Hospitalier Universitaire de Poitiers, Poitiers, France ; Institut national de la santé et de la recherche médicale U1082, Poitiers, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Thierry
authors.affiliation: Institut national de la santé et de la recherche médicale U1082, Poitiers, France ; Université de Poitiers, Poitiers, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Giraud
authors.affiliation: Institut national de la santé et de la recherche médicale U1082, Poitiers, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Robin
authors.affiliation: Université de Poitiers, Poitiers, France ; Institut national de la santé et de la recherche médicale U935, Poitiers, France ; Laboratoire d'Immunologie, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Barra
authors.affiliation: Service de Néphrologie-Hémodialyse-Transplantation rénale, Centre Hospitalier Universitaire de Poitiers, Poitiers, France ; Université de Poitiers, Poitiers, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Bridoux
authors.affiliation: Institut national de la santé et de la recherche médicale U1082, Poitiers, France ; Université de Poitiers, Poitiers, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Ameteau
authors.affiliation: Institut national de la santé et de la recherche médicale U1082, Poitiers, France ; Université de Poitiers, Poitiers, France ; Laboratoire de Biochimie, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Hauet
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale, Toulouse, France ; Centre national de la recherche scientifique, Unité Mixte de recherche, Toulouse, France ; Université de Toulouse, Toulouse, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Girard
authors.affiliation: Service de Néphrologie-Hémodialyse-Transplantation rénale, Centre Hospitalier Universitaire de Poitiers, Poitiers, France ; Institut national de la santé et de la recherche médicale U1082, Poitiers, France ; Université de Poitiers, Poitiers, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Touchard
authors.affiliation: Institut national de la santé et de la recherche médicale U1082, Poitiers, France ; Université de Poitiers, Poitiers, France ; Laboratoire d'Immunologie, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Gombert
authors.affiliation: Institut national de la santé et de la recherche médicale U1082, Poitiers, France ; Université de Poitiers, Poitiers, France.
authors.forename: André
authors.initials: A
authors.lastname: Herbelin
mesh_terms: D000328:Adult; D000368:Aged; D015687:Cell Hypoxia / Q000502:physiology; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D024243:HMGB1 Protein / Q000097:blood / Q000378:metabolism* / Q000652:urine; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D000067596:Interleukin-33; D007378:Interleukins / Q000097:blood / Q000378:metabolism* / Q000652:urine; D016030:Kidney Transplantation / Q000009:adverse effects*; D008875:Middle Aged; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000209:etiology / Q000276:immunology*; D018709:Statistics, Nonparametric
chemical_list: D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C506536:IL33 protein, human; D000067596:Interleukin-33; D007378:Interleukins