title: IL-10-producing lung interstitial macrophages prevent neutrophilic asthma.
abstract: Inflammatory responses contribute to host defense against harmful organisms and allergens, whereas a failure of immune tolerance can cause chronic inflammation including asthma. The lung has several innate myeloid cell subsets. Among these subsets, there are two types of macrophages: alveolar macrophages (AMs) and interstitial macrophages (IMs). However, compared with AMs, the role of IMs in lung homeostasis remains poorly understood. In this study, we characterized AMs and IMs in healthy and inflammatory conditions. Pulmonary IMs constitutively produce the anti-inflammatory cytokine IL-10 through activation of the TLR4/MyD88 pathway in a microbiota-independent manner. In addition to IMs, Foxp3+Tregcells show persistent IL-10 expression in the lung, with IL-10-producing IMs more prevalent than Foxp3+Tregcells. IMs, but not Foxp3+Tregcells, increased IL-10 production in house dust mite (HDM)-challenged mice, a model of human asthma. HDM-challenged Il10-/-mice exhibited severe lung pathology characterized by neutrophilia compared with that of wild-type mice. In addition, transplantation of wild-type IMs reduced neutrophilic inflammation, goblet cell mucus production and decreased expression of lung IL-13 and Th17-related neutrophil-activating cytokines such as IL-17, GM-CSF, and TNF-α. Together these results demonstrate that IL-10-producing IMs negatively regulate Th2- and Th17-mediated inflammatory responses, helping prevent neutrophilic asthma.
authors.affiliation: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine and Laboratory of Mucosal Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan Department of Dermatology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Kawano
authors.affiliation: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine and Laboratory of Mucosal Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan kayama@ongene.med.osaka-u.ac.jp.
authors.forename: Hisako
authors.initials: H
authors.lastname: Kayama
authors.affiliation: Department of Dermatology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.
authors.forename: Takekuni
authors.initials: T
authors.lastname: Nakama
authors.affiliation: Kurume University Institute of Cutaneous Cell Biology, Kurume, Fukuoka 830-0011, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine and Laboratory of Mucosal Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Umemoto
authors.affiliation: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine and Laboratory of Mucosal Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000517:prevention & control*; D007249:Inflammation / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000172:deficiency / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*
chemical_list: D016753:Interleukin-10
keywords: pulmonary inflammation; pulmonary myeloid cell subsets