title: Free radical-producing myeloid-derived regulatory cells: potent activators and suppressors of lung inflammation and airway hyperresponsiveness.
abstract: Levels of reactive free radicals are elevated in the airway during asthmatic exacerbations, but their roles in the pathophysiology of asthma remain unclear. We have identified subsets of myeloid-derived suppressor-like cells as key sources of nitric oxide and superoxide in the lungs of mice with evolving experimental allergic airway inflammation and established these cells as master regulators of the airway inflammatory response. The profiles of free radicals they produced depended on expression of inducible nitric oxide synthase (iNOS), arginase, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. These radicals controlled the pro- and anti-inflammatory potential of these cells, and also regulated the reciprocal pattern of their infiltration into the lung. The nitric oxide-producing cells were Ly-6C(+)Ly-6G(-) and they downmodulated T-cell activation, recruited T(reg) cells, and dramatically downregulated antigen-induced airway hyperresponsiveness. The superoxide-producing cells were Ly-6C(-)Ly-6G(+) and they expressed proinflammatory activities, exacerbating airway hyperresponsiveness in a superoxide-dependent fashion. A smaller population of Ly-6C(+)Ly-6G(+) cells also suppressed T-cell responses, but in an iNOS- and arginase-independent fashion. These regulatory myeloid cells represent important targets for asthma therapy.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: J
authors.initials: J
authors.lastname: Deshane
authors.forename: J W
authors.initials: JW
authors.lastname: Zmijewski
authors.forename: R
authors.initials: R
authors.lastname: Luther
authors.forename: A
authors.initials: A
authors.lastname: Gaggar
authors.forename: R
authors.initials: R
authors.lastname: Deshane
authors.forename: J-F
authors.initials: JF
authors.lastname: Lai
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.forename: M
authors.initials: M
authors.lastname: Spell
authors.forename: K
authors.initials: K
authors.lastname: Estell
authors.forename: C T
authors.initials: CT
authors.lastname: Weaver
authors.forename: E
authors.initials: E
authors.lastname: Abraham
authors.forename: L M
authors.initials: LM
authors.lastname: Schwiebert
authors.forename: D D
authors.initials: DD
authors.lastname: Chaplin
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001119:Arginase / Q000378:metabolism; D001249:Asthma / Q000276:immunology / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000378:metabolism; D054422:Chemokine CCL22 / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D054422:Chemokine CCL22; D005609:Free Radicals; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases; D001119:Arginase