Lipocalin 2: An Emerging Player in Iron Homeostasis and Inflammation

Abstract

Lipocalin 2 (Lcn2), an innate immune protein, has emerged as a critical iron regulatory protein during physiological and inflammatory conditions. As a bacteriostatic factor, Lcn2 obstructs the siderophore iron-acquiring strategy of bacteria and thus inhibits bacterial growth. As part of host nutritional immunity, Lcn2 facilitates systemic, cellular, and mucosal hypoferremia during inflammation, in addition to stabilizing the siderophore-bound labile iron pool. In this review, we summarize recent advances in understanding the interaction between Lcn2 and iron, and its effects in various inflammatory diseases. Lcn2 exerts mostly a protective role in infectious and inflammatory bowel diseases, whereas both beneficial and detrimental functions have been documented in neurodegenerative diseases, metabolic syndrome, renal disorders, skin disorders, and cancer. Further animal and clinical studies are necessary to unveil the multifaceted roles of Lcn2 in iron dysregulation during inflammation and to explore its therapeutic potential for treating inflammatory diseases.

Plasma lipocalin‐2 levels in the preclinical stage of Alzheimer's disease

“…The higher levels of plasma lipocalin-2 seen in preclinical AD are consistent with prior studies implicating lipocalin-2 in AD pathobiology [9,23]. Lipocalin-2 has been hypothesized to be an important modulator of inflammation, neurotoxicity, and brain iron homeostasis, which may all contribute directly to AD pathogenesis [7,8]. However, whether lipocalin-2 plays a significant role in AD pathogenesis is controversial.…”

“…Although experimental models support a direct role for central lipocalin-2 in various aspects of AD pathogenesis [9,23], the contribution, if any, of peripheral lipocalin-2 to AD pathogenesis is not clear. Because peripheral lipocalin-2 has been shown to cross the blood-brain barrier to modulate central pathways such as by activating hypothalamic neurons to decrease appetite [20], it is plausible for circu-lating lipocalin-2 to act on central processes involved early in AD pathogenesis including neuroinflammation, systemic metabolism, and brain iron homeostasis [7,8]. As there was a lack of association between plasma lipocalin-2 and BMI in our cohort, the results from our study do not support peripheral lipocalin-2 contributing to the early dysregulation of body weight seen in preclinical AD [6].…”

Specific Commensal Bacterium Critically Regulates Gut Microbiota Osteoimmunomodulatory Actions During Normal Postpubertal Skeletal Growth and Maturation

“…Gut microbiota‐derived ligands/metabolites are known to directly modulate inflammatory responses in liver‐residing cells, such as the synthesis of proinflammatory cytokines and acute‐phase reactants . LCN2, an iron‐sequestering antimicrobial peptide, is synthesized by the liver as an acute‐phase reactant . Microbe ligand recognition and inflammation upregulate the synthesis of LCN2 .…”

“…(79)(80)(81)(82)(83) LCN2, an iron-sequestering antimicrobial peptide, is synthesized by the liver as an acute-phase reactant. (117)(118)(119)(120)(121) Microbe ligand recognition and inflammation upregulate the synthesis of LCN2. (118)(119)(120)122) Central to the current investigation, findings that LCN2 is upregulated in the liver and serum, but not in the gut and skeletal tissues of MPF versus EF mice, demonstrate a novel immunoregulatory mechanism driven by SFB within the commensal gut microbiota.…”

Hepatocytes and neutrophils cooperatively suppress bacterial infection by differentially regulating lipocalin‐2 and neutrophil extracellular traps

“…Lipocalin‐2 (LCN2), also known as neutrophil gelatinase‐associated lipocalin (NGAL; human ortholog of the mouse Lcn2 gene), is one of the most extensively investigated acute‐phase proteins because its levels are highly elevated (up to ∼6 μg/mL in the serum) under all inflammatory conditions including in liver disease . It is well documented that LCN2 plays a critical role in host defense against bacterial infection by sequestering iron‐containing siderophores .…”