Cited by 133Tuberculosis Research and EpidemiologyImmune Response and InflammationMycobacterium research and diagnosis

Lipocalin 2-Dependent Inhibition of Mycobacterial Growth in Alveolar Epithelium

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Saiga, Hiroyuki, Nishimura, Junichi, Kuwata, Hirotaka, Okuyama, Megumi, Matsumoto, Sohkichi, Sato, Shintaro, Matsumoto, Makoto, Akira, Shizuo +4 more·2008·The Journal of Immunology

Abstract

Mycobacterium tuberculosis invades alveolar epithelial cells as well as macrophages. However, the role of alveolar epithelial cells in the host defense against M. tuberculosis remains unknown. In this study, we report that lipocalin 2 (Lcn2)-dependent inhibition of mycobacterial growth within epithelial cells is required for anti-mycobacterial innate immune responses. Lcn2 is secreted into the alveolar space by alveolar macrophages and epithelial cells during the early phase of respiratory mycobacterial infection. Lcn2 inhibits the in vitro growth of mycobacteria through sequestration of iron uptake. Lcn2-deficient mice are highly susceptible to intratracheal infection with M. tuberculosis. Histological analyses at the early phase of mycobacterial infection in Lcn2-deficient mice reveal increased numbers of mycobacteria in epithelial cell layers, but not in macrophages, in the lungs. Increased intracellular mycobacterial growth is observed in alveolar epithelial cells, but not in alveolar macrophages, from Lcn2-deficient mice. The inhibitory action of Lcn2 is blocked by the addition of endocytosis inhibitors, suggesting that internalization of Lcn2 into the epithelial cells is a prerequisite for the inhibition of intracellular mycobacterial growth. Taken together, these findings highlight a pivotal role for alveolar epithelial cells during mycobacterial infection, in which Lcn2 mediates anti-mycobacterial innate immune responses within the epithelial cells.

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Crossref · 10.4049/jimmunol.181.12.8521

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  • Microbes require iron for growth, and its chelation offers a route to bacteriostatic antibiotics or novel therapies.

    “microbes require iron for growth, its presence may be limiting even at the scale of global CO2 fixation [1506-1509], its excess can in some circumstances [1510] correlate with infectivity or virulence (see above and e.g. [180,193,1493,1511-1531]), and its chelation in a form not available to bacteria offers a route to at least a bacteriostatic kind of antibiotic or to novel therapies based on the”
  • Lcn2−/− mice are more susceptible to mycobacterial infections.

    “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 [214]

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Authors
Saiga, H., Nishimura, J., Kuwata, H., Okuyama, M., Matsumoto, S., Sato, S., Matsumoto, M., Akira, S., Yoshikai, Y., Honda, K., Yamamoto, M., & Takeda, K.
Affiliations
  • The University of Osaka (JP)
  • Department of Molecular Genetics
  • Osaka City University (JP)
  • Research Institute for Microbial Diseases, The University of Osaka (JP)
  • Immunology Frontier Research Center, The University of Osaka (JP)
  • Kyushu University (JP)
Venue
The Journal of Immunology
Published
2008-12
Volume
181
Issue
12
Pages
8521-8527
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
OpenAlex
W1898659608
Cited by
133
References
44
Citations by year
2026: 1 · 2025: 3 · 2024: 3 · 2023: 6 · 2022: 7 · 2021: 6 · 2020: 2 · 2019: 5 · 2018: 6 · 2017: 7 · 2016: 6 · 2015: 10 · 2014: 11 · 2013: 13 · 2012: 19
FWCI
6.01
Type
journal article
Language
en
Open access
Locations
  • The Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Ministry of Education, Culture, Sports, Science and Technology
Topics
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
Keywords
neutrophil gelatinase-associated lipocalin, Mycobacterium tuberculosis, alveolar epithelial cells, innate immunity, iron sequestration, endocytosis, pulmonary tuberculosis, alveolar macrophages
MeSH terms
Lipocalin-2, Acute-Phase Proteins, Animals, Cell Line, Mice, Inbred C57BL, Mice, Transgenic, Mycobacterium bovis, Mycobacterium tuberculosis, Pulmonary Alveoli, Tuberculosis, Oncogene Proteins, Macrophages, Alveolar, Mice, Knockout, Respiratory Mucosa, Mice, Lipocalins

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