title: Skin TLR7 triggering promotes accumulation of respiratory dendritic cells and natural killer cells.
abstract: The TLR7 agonist imiquimod has been used successfully as adjuvant for skin treatment of virus-associated warts and basal cell carcinoma. The effects of skin TLR7 triggering on respiratory leukocyte populations are unknown. In a placebo-controlled experimental animal study we have used multicolour flow cytometry to systematically analyze the modulation of respiratory leukocyte subsets after skin administration of imiquimod. Compared to placebo, skin administration of imiquimod significantly increased respiratory dendritic cells (DC) and natural killer cells, whereas total respiratory leukocyte, alveolar macrophages, classical CD4+ T helper and CD8+ T killer cell numbers were not or only moderately affected. DC subpopulation analyses revealed that elevation of respiratory DC was caused by an increase of respiratory monocytic DC and CD11b(hi) DC subsets. Lymphocyte subpopulation analyses indicated a marked elevation of respiratory natural killer cells and a significant reduction of B lymphocytes. Analysis of cytokine responses of respiratory leukocytes after stimulation with Klebsiella pneumonia indicated reduced IFN-γ and TNF-α expression and increased IL-10 and IL-12p70 production after 7 day low dose skin TLR7 triggering. Additionally, respiratory NK cytotoxic activity was increased after 7d skin TLR7 triggering. In contrast, lung histology and bronchoalveolar cell counts were not affected suggesting that skin TLR7 stimulation modulated respiratory leukocyte composition without inducing overt pulmonary inflammation. These data suggest the possibility to modulate respiratory leukocyte composition and respiratory cytokine responses against pathogens like Klebsiella pneumonia through skin administration of a clinically approved TLR7 ligand. Skin administration of synthetic TLR7 ligands may represent a novel, noninvasive means to modulate respiratory immunity.
authors.affiliation: Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig-University Giessen, Member of the German Center for Lung Research, Giessen, Germany. Holger.Hackstein@immunologie.med.uni-giessen.de
authors.forename: Holger
authors.initials: H
authors.lastname: Hackstein
authors.forename: Nicole
authors.initials: N
authors.lastname: Hagel
authors.forename: Angela
authors.initials: A
authors.lastname: Knoche
authors.forename: Sabine
authors.initials: S
authors.lastname: Kranz
authors.forename: Jürgen
authors.initials: J
authors.lastname: Lohmeyer
authors.forename: Werner
authors.initials: W
authors.lastname: von Wulffen
authors.forename: Olivia
authors.initials: O
authors.lastname: Kershaw
authors.forename: Achim D
authors.initials: AD
authors.lastname: Gruber
authors.forename: Gregor
authors.initials: G
authors.lastname: Bein
authors.forename: Nelli
authors.initials: N
authors.lastname: Baal
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D060890:B7-H1 Antigen / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D000077271:Imiquimod; D007694:Killer Cells, Natural / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008024:Ligands; D008168:Lung / Q000187:drug effects / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000819:agonists / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012867:Skin / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D051940:B7-2 Antigen; D060890:B7-H1 Antigen; D016207:Cytokines; D008024:Ligands; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D000077271:Imiquimod