Lipocalin-2 expressed in innate immune cells is an endogenous inhibitor of inflammation in murine nephrotoxic serum nephritis
Open accessAbstract
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.
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NGAL's functions in infections may be most important when enterobactin-producing bacteria are involved.
“Despite its diverse immunologic functions, NGAL's functions in infections may be most important when enterobactin-producing bacteria are involved, though (Bachman et al., 2009;Eller et al., 2013;Nairz et al., 2015a,b;Singh et al., 2015;Wang et al., 2019a,b;Wieser et al., 2016).”
From Iron in infection and immunity (2020) · cites this paper as Eller et al., 2013
The Introduction (page not supplied) says NGAL/Lcn-2 binds bacterial siderophores, including enterochalin, and that knockout mice have impaired defense against Gram-negative bacteria. It does not say its functions in infection are most important with enterobactin-producing bacteria; it also names other siderophores. (LLM, conf=0.84)
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- Authors
- Eller, K., Schroll, A., Banas, M., Kirsch, A. H., Huber, J. M., Nairz, M., Skvortsov, S., Weiss, G., Rosenkranz, A. R., & Theurl, I.
- Affiliations
- Medical University of Graz (AT)
- Innsbruck Medical University (AT)
- University Hospital Regensburg (DE)
- Corresponding author
- Eller, Kathrin
- Theurl, Igor
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-07-04
- Volume
- 8
- Issue
- 7
- Pages
- e67693
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3701542
- OpenAlex
- W2050162364
- Cited by
- 46
- References
- 39
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 2 · 2021: 7 · 2020: 11 · 2019: 2 · 2018: 4 · 2017: 1 · 2016: 5 · 2015: 4 · 2014: 3 · 2013: 1
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Oesterreichische Nationalbank (14182)
- Karl-Franzens-Universität Graz
- Medizinische Universität Graz
- Landes Tirols
- Topics
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Keywords
- neutrophil gelatinase-associated lipocalin, nephrotoxic serum nephritis, innate immunity, macrophages, neutrophils, HMGB1, apoptosis, necrosis, damage-associated molecular patterns, glomerular injury, proteinuria, acute kidney injury
- MeSH terms
- Lipocalin-2, Acute-Phase Proteins, Animals, Female, Gene Expression Regulation, Immunity, Innate, Inflammation, Kidney Glomerulus, Macrophages, Nephritis, Neutrophils, Proteinuria, Signal Transduction, Oncogene Proteins, Cytokines, Apoptosis, Mice, Knockout, HMGB1 Protein, RNA, Small Interfering, Toll-Like Receptor 2, Mice, Lipocalins
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