title: Lipocalin-2 expressed in innate immune cells is an endogenous inhibitor of inflammation in murine nephrotoxic serum nephritis.
abstract: Lipocalin-2 (Lcn-2) is involved in divergent processes such as acute kidney injury or bacterial host defence. Our study was designed to evaluate the functional role of Lcn-2 in nephrotoxic serum nephritis (NTS). Since Lcn-2 is expressed in tubular epithelial cells as well as in cells of innate immunity such as macrophages and polymorphonuclear neutrophils (PMN), we induced NTS in wild-type (WT), Lcn-2 knock-out (KO) mice and WT/Lcn-2 KO chimeras. Mice lacking Lcn-2 exhibited more glomerular damage with increased proteinuria and interstitial leukocyte accumulation compared to WT mice. Chimeras able to express Lcn-2 in macrophages and PMN but not in epithelial cells were found to develop NTS comparable to wild-type controls. In contrast, chimeras expressing Lcn-2 in tubular epithelial cells with no expression in innate immune cells developed increased NTS due to decreased concerted apoptosis but increased necrosis and formation of damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB-1) in the kidney. In vivo blockade of HMGB-1, a toll-like receptor (TLR)-2 agonist, significantly reduced inflammation and NTS in Lcn-2 knock-out mice. In parallel, TLR-2 signalling was found to drive Lcn-2 transcription in vitro. Taken together, Lcn-2 expressed in innate immune cells is protective in NTS by inducing concerted apoptosis and inhibiting the formation of HMGB-1 thereby limiting cytokine production via TLR-2 signalling. In parallel, TLR-2 dependent transcription of Lcn-2 is an endogenous inhibitor of inflammation in NTS.
authors.affiliation: Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria. kathrin.eller@medunigraz.at
authors.forename: Kathrin
authors.initials: K
authors.lastname: Eller
authors.forename: Andrea
authors.initials: A
authors.lastname: Schroll
authors.forename: Miriam
authors.initials: M
authors.lastname: Banas
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Kirsch
authors.forename: Julia M
authors.initials: JM
authors.lastname: Huber
authors.forename: Manfred
authors.initials: M
authors.lastname: Nairz
authors.forename: Sergej
authors.initials: S
authors.lastname: Skvortsov
authors.forename: Günter
authors.initials: G
authors.lastname: Weiss
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Rosenkranz
authors.forename: Igor
authors.initials: I
authors.lastname: Theurl
mesh_terms: D000209:Acute-Phase Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D024243:HMGB1 Protein / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate; D007249:Inflammation; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics* / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009393:Nephritis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D011507:Proteinuria / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology
chemical_list: D000209:Acute-Phase Proteins; D016207:Cytokines; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C071332:Lcn2 protein, mouse