Human lipocalin-2 variants : therapeutic evaluations

Abstract

Lipocalin-2 is a proinflammatory protein that undergoes post-translational modification by polyamination and has unique structure-function dynamics. The presence of different lipocalin-2 variants exhibits varied expression patterns. In the present study, the role of human lipocalin-2 variants, including polyaminated lipocalin-2 (hLcn2), non-polyaminated lipocalin-2 (C87A), and highly polyaminated lipocalin-2 (R81E) in regulating neutrophil function and the formation of neutrophil extracellular traps (NETs) was investigated. The expression of distinctive human lipocalin-2 variants was examined in mouse models with obesity and/or cardiovascular dysfunctions. The therapeutical potential of targeting the different human lipocalin-2 variants was also explored.

The results demonstrated that C87A levels were significantly elevated in cardiac and epididymal white adipose tissue following a high-fat diet. Neutralization with an anti-C87A antibody effectively reduced NETs formation and downregulated key inflammatory chemokines,

I including CXCL2, which are critical for recruiting neutrophils via the CXCR2 chemokine receptor. Enhanced signaling through CXCR2 was observed in the presence of elevated C87A, correlating with increased neutrophil infiltration and NETosis, suggesting a direct link between lipocalin-2 variants and the regulation of neutrophil activity in inflammatory conditions.

Furthermore, the pathogenic role of C87A in models of obesity-induced hypertension and heart failure with preserved ejection fraction was assessed. Our results showed that modulation of C87A not only decreased neutrophil infiltration and NETosis but also mitigated the associated cardiovascular complications. Additionally, macrophage polarization was found to be protective against C87A-induced inflammation, while astrocytes in the brain may contribute to obesityinduced hypertension through the paracrine release of inflammatory factors, including lipocalin-2.

These findings highlight the complex interplay between lipocalin-2 variants, neutrophils, and inflammation, suggesting that targeting lipocalin-2 variant C87A may represent a novel therapeutic strategy to mitigate chronic inflammatory conditions and their cardiometabolic complications. This research underscores the importance of understanding the mechanisms underlying NETs formation and the potential for lipocalin-2 variants as therapeutic targets in managing obesity-related obesity and cardiometabolic diseases.