title: Lipocalin 2-dependent inhibition of mycobacterial growth in alveolar epithelium.
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.
authors.affiliation: Department of Microbiology and Immunology, Laboratory of Immune Regulation, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Saiga
authors.forename: Junichi
authors.initials: J
authors.lastname: Nishimura
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kuwata
authors.forename: Megumi
authors.initials: M
authors.lastname: Okuyama
authors.forename: Sohkichi
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Shintaro
authors.initials: S
authors.lastname: Sato
authors.forename: Makoto
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Yoshikai
authors.forename: Kenya
authors.initials: K
authors.lastname: Honda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
mesh_terms: D000209:Acute-Phase Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000502:physiology*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009163:Mycobacterium bovis / Q000254:growth & development* / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000254:growth & development* / Q000276:immunology; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology / Q000473:pathology
chemical_list: D000209:Acute-Phase Proteins; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; C071332:Lcn2 protein, mouse