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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute-Phase Proteins / deficiency
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Acute-Phase Proteins / genetics*
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Acute-Phase Proteins / immunology
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Animals
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Apoptosis
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Cytokines / biosynthesis
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Cytokines / immunology
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Female
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Gene Expression Regulation
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HMGB1 Protein / genetics
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HMGB1 Protein / immunology
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Immunity, Innate
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Inflammation
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Kidney Glomerulus / immunology
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Kidney Glomerulus / metabolism*
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Kidney Glomerulus / pathology
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Lipocalin-2
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Lipocalins / genetics*
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Lipocalins / immunology
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Macrophages / immunology
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Macrophages / metabolism*
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Macrophages / pathology
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Mice
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Mice, Knockout
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Nephritis / genetics*
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Nephritis / immunology
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Nephritis / metabolism
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Nephritis / pathology
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Neutrophils / immunology
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Neutrophils / metabolism*
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Neutrophils / pathology
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Oncogene Proteins / deficiency
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Oncogene Proteins / genetics*
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Oncogene Proteins / immunology
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Proteinuria / genetics*
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Proteinuria / immunology
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Proteinuria / metabolism
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Proteinuria / pathology
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RNA, Small Interfering / genetics
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RNA, Small Interfering / immunology
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Signal Transduction
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Toll-Like Receptor 2 / antagonists & inhibitors
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / immunology
Substances
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Acute-Phase Proteins
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Cytokines
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HMGB1 Protein
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HMGB1 protein, mouse
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Lipocalin-2
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Lipocalins
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Oncogene Proteins
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RNA, Small Interfering
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Tlr2 protein, mouse
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Toll-Like Receptor 2
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Lcn2 protein, mouse
Grants and funding
The work was supported by the “Tiroler Wissenschaftsfonds” (to KE), by the Austrian Research Funds (to ARR, P-21402; to GW, P-19664), by the Austrian National Bank Funds (to IT; Project 14182) and the PhD-program of the Medical University of Graz. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.