title: Immunological priming requires regulatory T cells and IL-10-producing macrophages to accelerate resolution from severe lung inflammation.
abstract: Overwhelming lung inflammation frequently occurs following exposure to both direct infectious and noninfectious agents and is a leading cause of mortality worldwide. In that context, immunomodulatory strategies may be used to limit severity of impending organ damage. We sought to determine whether priming the lung by activating the immune system, or immunological priming, could accelerate resolution of severe lung inflammation. We assessed the importance of alveolar macrophages, regulatory T cells, and their potential interaction during immunological priming. We demonstrate that oropharyngeal delivery of low-dose LPS can immunologically prime the lung to augment alveolar macrophage production of IL-10 and enhance resolution of lung inflammation induced by a lethal dose of LPS or by Pseudomonas bacterial pneumonia. IL-10-deficient mice did not achieve priming and were unable to accelerate lung injury resolution. Depletion of lung macrophages or regulatory T cells during the priming response completely abrogated the positive effect of immunological priming on resolution of lung inflammation and significantly reduced alveolar macrophage IL-10 production. Finally, we demonstrated that oropharyngeal delivery of synthetic CpG-oligonucleotides elicited minimal lung inflammation compared with low-dose LPS but nonetheless primed the lung to accelerate resolution of lung injury following subsequent lethal LPS exposure. Immunological priming is a viable immunomodulatory strategy used to enhance resolution in an experimental acute lung injury model with the potential for therapeutic benefit against a wide array of injurious exposures.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Aggarwal
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tsushima
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Eto
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Tripathi
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224.
authors.forename: Pooja
authors.initials: P
authors.lastname: Mandke
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Mock
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Garibaldi
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Singer
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224.
authors.forename: Venkataramana K
authors.initials: VK
authors.lastname: Sidhaye
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224.
authors.forename: Maureen R
authors.initials: MR
authors.lastname: Horton
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224.
authors.forename: Landon S
authors.initials: LS
authors.lastname: King
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224.
authors.forename: Franco R
authors.initials: FR
authors.lastname: D'Alessio
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D005434:Flow Cytometry; D016753:Interleukin-10 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000276:immunology* / Q000517:prevention & control; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014611:Vaccination / Q000379:methods*
chemical_list: D016207:Cytokines; C556062:IL10 protein, mouse; D008070:Lipopolysaccharides; D016753:Interleukin-10