Lipocalin 2 Is Required for Pulmonary Host Defense against Klebsiella Infection

Abstract

Antimicrobial proteins comprise a significant component of the acute innate immune response to infection. They are induced by pattern recognition receptors as well as by cytokines of the innate and adaptive immune pathways and play important roles in infection control and immunomodulatory homeostasis. Lipocalin 2 (siderocalin, NGAL, 24p3), a siderophore-binding antimicrobial protein, is critical for control of systemic infection with Escherichia coli; however, its role in mucosal immunity in the respiratory tract is unknown. In this study, we found that lipocalin 2 is rapidly and robustly induced by Klebsiella pneumoniae infection and is TLR4 dependent. IL-1β and IL-17 also individually induce lipocalin 2. Mucosal administration of IL-1β alone could reconstitute the lipocalin 2 deficiency in TLR4 knockout animals and rescue them from infection. Lipocalin 2-deficient animals have impaired lung bacterial clearance in this model and mucosal reconstitution of lipocalin 2 protein in these animals resulted in rescue of this phenotype. We conclude that lipocalin 2 is a crucial component of mucosal immune defense against pulmonary infection with K. pneumoniae.

Interleukin-1 Receptor-Associated Kinase M-Deficient Mice Demonstrate an Improved Host Defense during Gram-negative Pneumonia

“…This may, also, at least in part, explain the fact that IRAK-M deficiency was associated with enhanced neutrophil recruitment to the lungs during secondary pneumonia following peritonitis (9), whereas it did not influence neutrophil influx during primary airway infection (this study). In the current investigation, IRAK-M deficiency did not enhance the production of either lipocalin 2 or CCL20, both antimicrobial proteins produced by the respiratory epithelium implicated in host defense against respiratory tract infection (24,25 (38).…”

Lipocalin-2 Induces Cardiomyocyte Apoptosis by Increasing Intracellular Iron Accumulation

“…Work to date has focused principally on the proinflammatory and metabolic effects of Lcn2 (11,13,(51)(52)(53)), yet less is known regarding cardiovascular effects. Several studies have now shown that Lcn2 was elevated during ischemia-reperfusion processes and in coronary heart disease and myocardial infarction (12,20,21,23).…”

Characterization of IL-22 and antimicrobial peptide production in mice protected against pulmonary Cryptococcus neoformans infection

“…Secretion of lipocalin-2 involves signalling via Toll-like receptor 4 (TLR4) and subsequent NF-kB binding to consensus sequences upstream of the lipocalin-2 promoter (Flo et al, 2004;Li & Chan, 2011), and its production is regulated via IL-1b, IL-17A and other cytokines (Chan et al, 2009;Kolls et al, 2008;Li & Chan, 2011). Although lipocalin-2 is increased in the lungs of mice during infection with Aspergillus fumigatus, lipocalin-2-deficient mice do not demonstrate impaired fungal clearance (Gessner et al, 2012), and lipocalin-2 does not bind to fungal siderophores (Flo et al, 2004).…”