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.

Neutrophil gelatinase‐associated lipocalin regulates gut microbiota of mice

“…The TLRs pathway has been shown to play a pivotal role not only in the induction of the inflammatory status but also in the regulation and maintenance of the homeostatic condition in the gut under inflammatory conditions. Regarding the regulation of NGAL expression, peptidoglycans, such as the TLR2‐ligand, strongly modulated the up‐regulation of NGAL mRNA in an in vitro study using cultured distal convoluted tubular cells . Furthermore, TLR4−/− mice did not express NGAL mRNA in either blood cells or peritoneal cells, even in the presence of endotoxemia .…”

Fn14 deficiency protects lupus‐prone mice from histological lupus erythematosus‐like skin inflammation induced by ultraviolet light

“…The pathophysiological role of NGAL is not completely understood, however, showing both model‐dependent protective or pathogenic effects. NGAL has an anti‐inflammatory role and can “deactivate” macrophages, suppressing immune responses . Models of E. coli and Mycobacteria infection result in high levels of NGAL, which can limit bacterial growth .…”

The role of lipocalin-2 in age-related macular degeneration (AMD)

“…Two different cell-surface receptors for LCN-2 have been described: solute carrier family 22 member 17 (SLC22A17, 24p3R or NGALR2) and lowdensity lipoprotein-related protein 2 (LPRP2 or megalin) [27][28][29]. High levels of 24p3R are regularly present in specific cells, including macrophages, neutrophils [30,31], epithelia of respiratory and alimentary tracts [32], kidney epithelial cells [27], astrocytes [33], microglia [34], and neurons [35]. Megalin, a multi-ligand endocytic receptor, is highly expressed in some types of absorptive epithelial cells such as thyroid cells, epididymal, renal proximal tubule [36][37][38][39][40][41][42], and neuro-epithelium [43].…”

“…▸ LCN-2 also plays an important role in immune activation during acute infection [53]. It is known to be expressed in macrophages and polymorphonuclear cells (PMNs) and to confer protection in an animal model of nephrotoxic serum nephritis induced by either acute kidney injury or bacterial infection by triggering apoptosis in the renal epithelial cells and limiting cytokine production by the TLR2 pathway [30]. In animal models of Salmonella typhimurium infection, LCN-2 confers host defense by regulating iron homeostasis and the inflammatory pathway in macrophages [63,64].…”