Impaired Neutrophil Function in 24p3 Null Mice Contributes to Enhanced Susceptibility to Bacterial Infections
Open accessAbstract
Lipocalin 24p3 (24p3) is a neutrophil secondary granule protein. 24p3 is also a siderocalin, which binds several bacterial siderophores. It was therefore proposed that synthesis and secretion of 24p3 by stimulated macrophages or release of 24p3 upon neutrophil degranulation sequesters iron-laden siderophores to attenuate bacterial growth. Accordingly, 24p3-deficient mice are susceptible to bacterial pathogens for which siderophores would normally be chelated by 24p3. Specific granule deficiency (SGD) is a rare congenital disorder characterized by complete absence of proteins in secondary granules. Neutrophils from SGD patients, who are prone to bacterial infections, lack normal functions, but the potential role of 24p3 in neutrophil dysfunction in SGD is not known. In this study, we show that neutrophils from mice genetically deficient for lipocalin 24p3 (24p3−/−) are defective in many neutrophil functions. Specifically, neutrophils in 24p3−/− mice do not extravasate to sites of infection and are defective for chemotaxis. A transcriptome analysis revealed that genes that control cytoskeletal reorganization are selectively suppressed in 24p3−/− neutrophils. Additionally, small regulatory RNAs (microRNAs) that control upstream regulators of cytoskeletal proteins are also increased in 24p3−/− neutrophils. Further, 24p3−/− neutrophils failed to phagocytose bacteria, which may account for the enhanced sensitivity of 24p3−/− mice to both intracellular (Listeria monocytogenes) and extracellular (Candida albicans and Staphylococcus aureus) pathogens. Listeria does not secrete siderophores, and additionally, the siderophore secreted by Candida is not sequestered by 24p3. Therefore, the heightened sensitivity of 24p3−/− mice to these pathogens is not due to sequestration of siderophores limiting iron availability, but is a consequence of impaired neutrophil function.
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NGAL is essential for neutrophil functions because it recruits cells to sites of infection and stimulates their phagocytotic capacity.
“NGAL is essential for neutrophil functions because it recruits cells to sites of infection and stimulates their phagocytotic capacity (Liu et al., 2013;Schroll et al., 2012).”
From Iron in infection and immunity (2020) · cites this paper as Liu et al., 2013
The Discussion (page not available) says 24p3-deficient mouse neutrophils have defective chemotaxis and cannot phagocytose bacteria. The Results (page not available) report reduced migration and bacterial ingestion, supporting a role in both functions. The claim overstates these mouse findings as NGAL being essential to neutrophil function generally and directly recruiting cells to infection sites. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIncreased susceptibility of Lcn2−/− mice to mycobacterial infections might be due to Lcn2's function as a chemoattractant for neutrophils rather than iron sequestration.
“Importantly, Lcn2−/− mice are more susceptible to mycobacterial infections (214), which might be different from the iron-sequestrating role of Lcn2 (215) but rather due to its function as efficient chemoattractant for neutrophils to sites of infection (216–218).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [218]
Neutrophils from Lcn-2-/- animals do not migrate to sites of infection and do not respond to chemotactic stimuli.
“Neutrophils from Lcn-2–/– animals do not migrate to sites of infection and do no longer respond to chemotactic stimuli [124], which however can be reverted by the addition of recombinant Lcn-2 [125].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [124]
Lcn-2 controls neutrophil function.
“Another aspect of Lcn-2 during infectious diseases is its ability to control neutrophil function [124,125].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [124]
Lcn2 exerts contrasting effects depending on pathogen and tissue localization, improving or mitigating resistance; it aggravates Streptococcus pneumoniae infection through an immunomodulatory effect possibly via iron metabolism regulation.
“It should be noted, however, that Lcn2 exerts contrasting effects depending on the pathogen and tissue localization, improving or mitigating resistance to infection.For example, Lcn2 aggravates the outcome of Streptococcus pneumoniae infection [134] through a immunomodulatory effect possibly acting via regulation of Fe metabolism or another not yet fully elucidated pathway [135,136].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [136]
LCN2 guides neutrophils to the site of infection and stimulates their phagocytic capacity, showing its importance for host defense against a broad range of invading pathogens.
“An additional function of LCN2 is the guidance of neutrophils to the site of infection and the stimulation of their phagocytic capacity, thus showing its importance for the host defense against a broad range of invading pathogens”
From Iron in immune cell function and host defense (2021) · cites this paper as [49]
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- Authors
- Liu, Z., Petersen, R., & Devireddy, L.
- Affiliations
- Case Comprehensive Cancer Center (US)
- Case Western Reserve University (US)
- Corresponding author
- Devireddy, Laxminarayana
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-05-01
- Volume
- 190
- Issue
- 9
- Pages
- 4692-4706
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC3633721
- OpenAlex
- W2138998607
- Cited by
- 64
- References
- 56
- Citations by year
- 2026: 1 · 2025: 3 · 2023: 7 · 2021: 9 · 2020: 5 · 2019: 8 · 2018: 4 · 2017: 6 · 2016: 5 · 2015: 9 · 2014: 5 · 2013: 2
- FWCI
- 3.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- March of Dimes Foundation
- American Society of Hematology
- Case Western Reserve University
- National Institutes of Health
- National Cancer Institute (K01CA113838)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK081395)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
- Keywords
- siderocalin, neutrophil dysfunction, bacterial infection susceptibility, neutrophil chemotaxis, neutrophil extravasation, cytoskeletal remodeling, microRNA, phagocytosis, Listeria monocytogenes, Candida albicans, Staphylococcus aureus, iron metabolism, neutrophil granules
- MeSH terms
- Lipocalin-2, Acute-Phase Proteins, Animals, Bacterial Infections, Cell Line, Chemotaxis, Cytoskeletal Proteins, Cytoskeleton, Disease Susceptibility, Mice, Inbred C57BL, Neutrophils, Phagocytosis, Oncogene Proteins, Respiratory Burst, Siderophores, Mice, Knockout, Chemokines, rho GTP-Binding Proteins, rhoA GTP-Binding Protein, MicroRNAs, NIH 3T3 Cells, Mice, Lipocalins
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