title: Activation of pulmonary invariant NKT cells leads to exacerbation of acute lung injury caused by LPS through local production of IFN-γ and TNF-α by Gr-1+ monocytes.
abstract: Invariant NK T (iNKT) cells are known to play a critical role in the regulation of inflammatory responses in various clinical settings. In the present study, we assessed the contribution of iNKT cells to the development of acute lung injury (ALI), which was caused by intra-tracheal administration of LPS. Jα18 gene-disrupted mice lacking these cells underwent neutrophilic inflammatory responses in lungs at an equivalent level as control mice. Next, mice were sensitized intra-tracheally with α-galactosylceramide, an activator of iNKT cells, followed by challenge with LPS. In this model, mice showed severe lung injury, and all mice were killed within 72 h after LPS injection. IFN-γ and tumor necrosis factor (TNF)-α were strikingly elevated in the lungs of these mice. Administration of neutralizing mAb against IFN-γ and TNF-α attenuated lung injury in a histopathological analysis and improved their survival rate. Flow cytometric analysis revealed that IFN-γ was expressed in NK cells, iNKT cells and also Gr-1(dull+)Ly-6C(+) monocytes and TNF-α was detected mainly in Gr-1(bright+)Ly-6G(+) neutrophils and Gr-1(dull+)Ly-6C(+) monocytes. Otherwise, in mice treated with LPS alone, IFN-γ was not detected in the lungs and Gr-1(bright+)Ly-6G(+) neutrophil was a main cellular source of TNF-α production. Anti-Gr-1 mAb resulted in the attenuation of ALI and decrease in the level of these cytokines. These results indicated that activation of iNKT cells led to striking exacerbation of ALI caused by LPS and that Gr-1(+) monocytes were recruited in the lungs with expressing IFN-γ and TNF-α and played an important role in the development of these responses.
authors.affiliation: Department of Infection Control and Laboratory Diagnostics, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Aoyagi
authors.forename: Natsuo
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Masumitsu
authors.initials: M
authors.lastname: Hatta
authors.forename: Daiki
authors.initials: D
authors.lastname: Tanno
authors.forename: Akiko
authors.initials: A
authors.lastname: Miyazato
authors.forename: Keiko
authors.initials: K
authors.lastname: Ishii
authors.forename: Kazuo
authors.initials: K
authors.lastname: Suzuki
authors.forename: Toshinori
authors.initials: T
authors.lastname: Nakayama
authors.forename: Masaru
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kunishima
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Hirakata
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Kaku
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kawakami
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology*; D000818:Animals; D007371:Interferon-gamma / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology*; D055611:Natural Killer T-Cells / Q000276:immunology*; D019707:Receptors, Chemokine / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: C503133:Gr-1 protein, mouse; D008070:Lipopolysaccharides; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma