Exposure to cigarette smoke impacts myeloid-derived regulatory cell function and exacerbates airway hyper-responsiveness
Department of Medicine, University of Alabama at Birmingham, 1900 University Boulevard, Birmingham, AL, United States; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States; Department of Cell Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States; KwaZulu-Natal Research Institute for Tuberculosis and HIV, Durban, South Africa
Cigarette smoking enhances oxidative stress and airway inflammation in asthma, the mechanisms of which are largely unknown. Myeloid-derived regulatory cells (MDRC) are free radical producing immature myeloid cells with immunoregulatory properties that have recently been demonstrated as critical regulators of allergic airway inflammation. NO (nitric oxide)-producing immunosuppressive MDRC suppress T-cell proliferation and airway-hyper responsiveness (AHR), while the O 2 •- (superoxide)-producing MDRC are proinflammatory. We hypothesized that cigarette smoke (CS) exposure may impact MDRC function and contribute to exacerbations in asthma. Exposure of bone marrow (BM)-derived NO-producing MDRC to CS reduced the production of NO and its metabolites and inhibited their potential to suppress T-cell proliferation. Production of immunoregulatory cytokine IL-10 was significantly inhibited, while proinflammatory cytokines IL-6, IL-1β, TNF-and IL-33 were enhanced in CS-exposed BM-MDRC. Additionally, CS exposure increased NF-κB activation and induced BM-MDRC-mediated production of O 2 •-, via NF-κB-dependent pathway. Intratracheal transfer of smoke-exposed MDRC-producing proinflammatory cytokines increased NF-κB activation, reactive oxygen species and mucin production in vivo and exacerbated AHR in C57BL/6 mice, mice deficient in Type I IFNR and MyD88, both with reduced numbers of endogenous MDRC. Thus CS exposure modulates MDRC function and contributes to asthma exacerbation and identifies MDRC as potential targets for asthma therapy. © 2014 USCAP, Inc All rights reserved.
cigarette smoke; interleukin 10; interleukin 1beta; interleukin 33; interleukin 6; myeloid differentiation factor 88; reactive oxygen metabolite; tumor necrosis factor alpha; Il33 protein, mouse; immunoglobulin enhancer binding protein; interleukin 33; interleukin derivative; nitric oxide; reactive oxygen metabolite; smoke; adoptive transfer; animal cell; animal experiment; animal model; Article; bone marrow cell; cell activation; cell function; controlled study; cytokine production; disease exacerbation; lymphocyte proliferation; mouse; nonhuman; oxidative stress; priority journal; respiratory tract allergy; respiratory tract inflammation; adverse effects; animal; biosynthesis; bone marrow cell; Bronchial Hyperreactivity; C57BL mouse; cell culture; metabolism; physiology; smoke; tobacco; Adoptive Transfer; Animals; Bone Marrow Cells; Bronchial Hyperreactivity; Cells, Cultured; Interleukin-33; Interleukins; Mice; Mice, Inbred C57BL; Myeloid Cells; NF-kappa B; Nitric Oxide; Reactive Oxygen Species; Smoke; Tobacco
AI076389, NIH, National Institutes of Health