title: Innate cellular sources of interleukin-17A regulate macrophage accumulation in cigarette- smoke-induced lung inflammation in mice.
abstract: Cigarette smoke (CS) is the major cause of chronic obstructive pulmonary disease (COPD). Interleukin-17A (IL-17A) is a pivotal cytokine that regulates lung immunity and inflammation. The aim of the present study was to investigate how IL-17A regulates CS-induced lung inflammation in vivo. IL-17A knockout (KO) mice and neutralization of IL-17A in wild-type (WT) mice reduced macrophage and neutrophil recruitment and chemokine (C-C motif) ligand 2 (CCL2), CCL3 and matrix metalloproteinase (MMP)-12 mRNA expression in response to acute CS exposure. IL-17A expression was increased in non-obese diabetic (NOD) severe combined immunodeficiency SCID) mice with non-functional B- and T-cells over a 4-week CS exposure period, where macrophages accumulated to the same extent as in WT mice. Gene expression analysis by QPCR (quantitative real-time PCR) of isolated immune cell subsets detected increased levels of IL-17A transcript in macrophages, neutrophils and NK/NKT cells in the lungs of CS-exposed mice. In order to further explore the relative contribution of innate immune cellular sources, intracellular IL-17A staining was performed. In the present study, we demonstrate that CS exposure primes natural killer (NK), natural killer T (NKT) and γδ T-cells to produce more IL-17A protein and CS alone increased the frequency of IL17+ γδ T-cells in the lung, whereas IL-17A protein was not detected in macrophages and neutrophils. Our data suggest that activation of innate cellular sources of IL-17A is an essential mediator of macrophage accumulation in CS-exposed lungs. Targeting non-conventional T-cell sources of IL-17A may offer an alternative strategy to reduce pathogenic macrophages in COPD.
authors.affiliation: School of Health Sciences and Health Innovations Research Institute, RMIT University, Bundoora, VIC 3083, Australia Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, VIC 3010, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Bozinovski
authors.affiliation: Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, VIC 3010, Australia.
authors.forename: Huei Jiunn
authors.initials: HJ
authors.lastname: Seow
authors.affiliation: Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, VIC 3010, Australia.
authors.forename: Sheau Pyng Jamie
authors.initials: SP
authors.lastname: Chan
authors.affiliation: Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, VIC 3010, Australia.
authors.forename: Desiree
authors.initials: D
authors.lastname: Anthony
authors.affiliation: Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, VIC 3010, Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: McQualter
authors.affiliation: Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, VIC 3010, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Hansen
authors.affiliation: Hudson Institute of Medical Research, Monash University, Clayton, VIC 3168, Australia.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Jenkins
authors.affiliation: Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, VIC 3010, Australia.
authors.forename: Gary P
authors.initials: GP
authors.lastname: Anderson
authors.affiliation: School of Health Sciences and Health Innovations Research Institute, RMIT University, Bundoora, VIC 3083, Australia Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, VIC 3010, Australia ross.vlahos@rmit.edu.au.
authors.forename: Ross
authors.initials: R
authors.lastname: Vlahos
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054405:Chemokine CCL3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000276:immunology; D011014:Pneumonia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012906:Smoke; D014026:Nicotiana / Q000737:chemistry*
chemical_list: D018932:Chemokine CCL2; D054405:Chemokine CCL3; D020381:Interleukin-17; D016692:Receptors, Antigen, T-Cell, gamma-delta; D012906:Smoke; D053508:Matrix Metalloproteinase 12; C000602031:matrix metallopeptidase 12, mouse
keywords: chronic lung disease; chronic obstructive pulmonary disease (COPD); cigarette smoke; innate immunity; interleukin-17; macrophage