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* Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan;
Department of Molecular Genetics and
Division of Host Defense, Research Center for Prevention of Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan;
Department of Host Defense, Research Institute for Microbial Diseases and
¶ WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan; and
|| Department of Bacteriology, Osaka City University Graduate School of Medicine, Osaka, Japan
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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1 This work was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor and Welfare, as well as the Osaka Foundation for the Promotion of Clinical Immunology.
2 Address correspondence and reprint requests to Dr. Kiyoshi Takeda, Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. E-mail address: ktakeda{at}ongene.med.osaka-u.ac.jp
3 Abbreviations used in this paper: Lcn2, lipocalin 2; BCG, Mycobacterium bovis bacillus Calmette-Guérin; BALF, bronchoalveolar lavage fluid; rLcn2, recombinant Lcn2; SP-C, pro-surfactant protein C; DFO, deferoxamine; AEC, alveolar epithelial cell; CPZ, chlorpromazine.
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